@article {pmid42814997,
year = {2026},
author = {Frisch, D and Fronstin, M and Zema, C},
title = {Agentic AI for Clinical Outcomes Research, Population Health Management Analyses With Large Administrative Databases, and Generating Epidemiological Estimates of Diseases: Feasibility and Validation Study.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e100284},
doi = {10.2196/100284},
pmid = {42814997},
issn = {1438-8871},
mesh = {Humans ; Female ; Male ; *Artificial Intelligence ; Feasibility Studies ; Aged ; Middle Aged ; Adult ; *Databases, Factual ; Adolescent ; *Population Health Management ; Child ; Urinary Bladder Neoplasms/epidemiology ; Infant ; *Outcome Assessment, Health Care ; Young Adult ; Child, Preschool ; Huntington Disease/epidemiology ; Leukemia, Myeloid, Acute/epidemiology ; Prevalence ; Parkinson Disease/epidemiology ; Infant, Newborn ; United States/epidemiology ; },
abstract = {BACKGROUND: There is tremendous enthusiasm for the use of AI in health care because of the ability to analyze existing data for preventative, diagnostic, and treatment support. Agentic AI can feasibly provide access to large real-world datasets for the generation of real-world evidence for health care and clinical applications to health care providers, researchers, and administrators without access to large analytic programming resources.

OBJECTIVE: The objective of this study was to understand the feasibility of using agentic AI for clinical outcome research and population health management. Specifically, this study used an agentic AI evidence-generation platform to obtain epidemiological estimates of diverse medical conditions, with the results evaluated against existing AI frameworks.

METHODS: Prevalence estimates of 6 conditions (amyotrophic lateral sclerosis, acute myeloid leukemia, bladder cancer, Huntington disease, elevated lipoprotein (a), and Parkinson disease) were estimated using an agentic AI evidence-generation platform applied to an administrative claims database with representation from every US state. Gender-specific rates were calculated within the following age categories: 0 to 17, 18 to 24, 25 to 34, 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years and 75 years and older. Period prevalence was estimated from January 1, 2020, to June 30, 2025, and annual prevalence rates for each year were estimated from 2020 to 2024. Continuous enrollment for 12 months was required during the study period for inclusion. Source code generated by the platform as part of the analysis was reviewed by an independent programmer for validation of methods and programming, and analyses were replicated using traditional programming methods. Results obtained throughout the process were evaluated against several existing AI application frameworks.

RESULTS: Regarding accuracy, epidemiological estimates obtained using the agentic AI platform were consistent with published estimates for all 6 conditions, as well as with estimates obtained from traditional programming methods. Regarding rigor, the agentic AI platform conducted the analysis with rigor by confirming acceptable methods in published literature for the type of data source used. Code lists used for the analysis were confirmed against existing algorithms when available. Appropriate statistical methods were used to compare differences in prevalence rates by age and gender. Regarding trust (explainability, transparency, replicability, traceability, and validation), the agentic AI platform generated all source code used for the analyses, which was reviewed and validated for accuracy and appropriateness. The analysis included a "human in the loop" to validate the research question, data extraction method, statistical analysis plan, and output plan prior to proceeding with each step.

CONCLUSIONS: With specific design considerations to ensure responsible use, agentic AI can be invaluable to increasing the accessibility of large datasets for applied clinical outcome research and population health management analyses.},
}

Humans
Female
Male
*Artificial Intelligence
Feasibility Studies
Aged
Middle Aged
Adult
*Databases, Factual
Adolescent
*Population Health Management
Child
Urinary Bladder Neoplasms/epidemiology
Infant
*Outcome Assessment, Health Care
Young Adult
Child, Preschool
Huntington Disease/epidemiology
Leukemia, Myeloid, Acute/epidemiology
Prevalence
Parkinson Disease/epidemiology
Infant, Newborn
United States/epidemiology

@article {pmid42825562,
year = {2026},
author = {Bromberg, MB},
title = {Amyotrophic Lateral Sclerosis.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {32},
number = {5},
pages = {1529-1544},
doi = {10.1212/cont.0000000000001753},
pmid = {42825562},
issn = {1538-6899},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology ; Female ; Male ; Middle Aged ; },
abstract = {OBJECTIVE: This article describes the nerve loss underlying amyotrophic lateral sclerosis, its clinical manifestations, examination findings leading to the diagnosis, the expanding role of genetics, and available treatment and patient management.

LATEST DEVELOPMENTS: The cause of neuron death in patients with amyotrophic lateral sclerosis is not known, but many genes are strongly linked to the disease, in both patients with a family history and those with no history. A multistep pathologic process helps to explain the onset of symptoms later in life, even in patients with associated genes. Posttranslational and epigenetic changes are also important factors. Current clinical trials are based on putative pathologic mechanisms, and some newer therapies are gene-based.

ESSENTIAL POINTS: Amyotrophic lateral sclerosis has distinctive features and can be diagnosed largely from the history and examination, and true mimics are rare. While the cause of neuronal death is not known, pathogenic and risk factor gene variations are present in a number of patients, and posttranscriptional and epigenetic changes are likely major causative factors. Environmental factors likely contribute, but specific avoidable factors have not been identified. Drugs to slow the progress of the disease are currently limited, but trials for all patients with amyotrophic lateral sclerosis continue, including a focus on genetic factors. Patient management is optimized in multidisciplinary amyotrophic lateral sclerosis clinics, and interventions for nutrition with gastric feeding tubes and respiratory insufficiency by noninvasive ventilation enhance patient comfort.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology
Female
Male
Middle Aged

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

@article {pmid42826720,
year = {2026},
author = {Li, X and Cao, Z and Jiang, O and Wu, S and Zhou, B and Feng, Y and Chen, X and Wang, J and Zhou, J and Yan, R and Chen, M and Wang, S},
title = {Nitrate-responsive Sialin2 couples stress granule assembly and clearance to maintain neuronal homeostasis.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2026.09.001},
pmid = {42826720},
issn = {1878-1551},
abstract = {Stress granules (SGs) are phase-separated ribonucleoprotein condensates that support cellular adaptation to acute stress, but how extracellular signals coordinate their assembly and recovery-phase clearance remains unclear. Here, we show that nitrate-responsive Sialin2 coordinates SG homeostasis across the stress cycle. During acute stress, Sialin2 undergoes liquid-liquid phase separation and co-assembles with Ras GTPase-activating protein SH3-domain-binding protein (G3BP)-centered scaffolds to promote SG formation. During recovery, Sialin2 preserves liquid-like SG dynamics and promotes autophagy-linked clearance. Sialin2 loss delays SG resolution, promotes retention of amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) variants, and enhances amyloid precursor protein (APP)-related amyloidogenic output. In an ALS mouse model, nitrate treatment reduces SG-like pathology and neuroinflammation, preserves neuronal integrity, and delays functional decline. Together, these findings define a nitrate-Sialin2 signaling module that couples SG assembly to recovery-phase clearance and links inorganic anion sensing to protection against neurodegeneration.},
}

@article {pmid42809516,
year = {2026},
author = {Jang, K and Morton, RL and Dennis, M and Nikolovski, J and Zhan, X and Ke, Y and Burns, B and Tran, AD},
title = {The cost-effectiveness and health equity of prehospital treatment strategies for out-of-hospital cardiac arrest patients: a systematic review.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-66},
doi = {10.1080/10903127.2026.2741269},
pmid = {42809516},
issn = {1545-0066},
abstract = {OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) remains a major public health challenge, associated with substantial mortality and significant costs for health care system. This systematic review aimed to (i) synthesise economic evaluations of prehospital treatment strategies for OHCA from ambulance attendance through to hospital discharge; (ii) assess the methodological quality and reporting of the included studies; and (iii) evaluate the reporting of health equity-relevant data.

METHODS: We searched Medline, Embase, Scopus, EconLit, and CINAHL databases for records from database inception to 12 June 2026. The QHES and CHEERS checklists were used to assess the quality and reporting standards of included studies, and the review was reported according to the PRISMA checklist. The completeness of reporting health equity outcomes was reviewed using the PROGRESS (Place of residence, Race, Occupation, Gender, Religion, Education, Socioeconomic status and Social capital) - Plus framework.

RESULTS: Ten economic evaluations met eligibility criteria. Most studies were cost-utility analyses (n = 8, 80%) and used Markov models (n = 6, 60%). Most evaluations were 'very good quality' (≥80%) (n = 6, 60%). Early defibrillation and advanced life support (ALS) delivered by trained emergency medical technicians were cost-effective compared with no intervention, emergency physician-led ALS, standard emergency medical services or paramedic care (ICER range from £11,407 to USD $56,700 per QALY gained). Prehospital extracorporeal cardiopulmonary resuscitation (ECPR) was more cost-effective than in-hospital ECPR strategies (ICER range from AUD $27,323 to $44,000 per QALY gained). Termination-of-resuscitation (TOR) strategies were cost-effective compared with no TOR or other TOR strategies, including basic life support and ALS TOR, with estimates of $110,554 saved per QALY lost and USD $23,851 per QALY gained.Survival rate and neurological outcomes influenced cost-effectiveness results. Equity reporting was limited: almost all included studies addressed less than 40% of the PROGRESS-Plus equity criteria.

CONCLUSIONS: Most strategies that increased prehospital treatment intensity, avoided futile transport, or enabled earlier advanced care were cost-effective; however, the certainty of evidence, particularly for sub-groups, was limited by heterogeneous comparators and sparse equity reporting.},
}

@article {pmid42811584,
year = {2026},
author = {Singh, R and Kumam, Y and Mahey, M and Patterson, E and Liu, S and Lancaster, S and Jugulam, M},
title = {Deciphering metabolic resistance to multiple herbicides in Amaranthus palmeri via transcriptome analysis.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71345},
pmid = {42811584},
issn = {1526-4998},
support = {//Kansas Soybean Commission/ ; },
abstract = {BACKGROUND: Multiple herbicide resistance in Palmer amaranth (Amaranthus palmeri S. Watson) poses a serious threat to US crop production. A Palmer amaranth population (KCTR) from Kansas was found resistant to herbicides across six sites-of-action, including ALS-, PS II-, EPSPS-, PPO-, HPPD-inhibitors and synthetic auxins. Previous physiological and metabolic studies suggested that resistance in this population is predominantly associated with enhanced herbicide metabolism, possibly mediated by cytochrome P450 (P450) and/or glutathione S-transferase (GST) enzyme activity. The aim of this study was to identify candidate genes potentially associated with multiple herbicide resistance in KCTR Palmer amaranth population.

RESULTS: Differential gene expression analysis revealed 414, 129, 529, 152 and 688 genes differentially expressed in resistant plants as compared to susceptible, following chlorsulfuron, 2,4-D, atrazine, mesotrione and lactofen treatments, respectively. CYP72A219 paralogs, CYP704B1-like and GST-ct genes were constitutively up-regulated in resistant plants as compared to susceptible. Validated by qRT-PCR, CYP72A219 and CYP704B1-like were 3.4- to 6.6-fold and 5.9- to 12.4-fold up-regulated in resistant plants as compared to susceptible without any treatment.

CONCLUSIONS: Identifying genes associated with multiple herbicide metabolism is critical for understanding cross-resistance and evaluating new herbicides for resistance risk. These candidate resistance-associated genes serve as targets for functional validation studies in future to help develop molecular markers for screening broad-spectrum herbicide resistance. © 2026 Society of Chemical Industry.},
}

@article {pmid42814295,
year = {2026},
author = {Chan, L and Shaikh, FA and Shah, P and Moriyama, H and Yokota, T},
title = {Development and Clinical Applications of Antisense Oligonucleotide Gapmers.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3065},
number = {},
pages = {19-51},
pmid = {42814295},
issn = {1940-6029},
mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics/chemistry ; Animals ; *Genetic Diseases, Inborn/genetics/therapy ; *Genetic Therapy/methods ; },
abstract = {Antisense oligonucleotides (AONs) are synthetic oligonucleotides designed to bind target RNA and have opened new treatment possibilities for genetic diseases by regulating gene expression. AONs are often used to suppress the expression of mutated genes, which may interfere with essential downstream pathways. Since AONs have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Tofersen is an example of a recently FDA-approved antisense oligonucleotide gapmer used for the treatment of amyotrophic lateral sclerosis. Many others are being tested in clinical trials or under preclinical development. This chapter will cover advancements in gapmer treatments for various diseases, including familial hypercholesterolemia, hereditary transthyretin amyloidosis, cancer, familial chylomicronemia syndrome, familial partial lipodystrophy, familial hypertriglyceridemia, Huntington's disease, myotonic dystrophy, prion diseases, and amyotrophic lateral sclerosis.},
}

Humans
*Oligonucleotides, Antisense/therapeutic use/genetics/chemistry
Animals
*Genetic Diseases, Inborn/genetics/therapy
*Genetic Therapy/methods

@article {pmid39947279,
year = {2025},
author = {Gelbenegger, G and Cheskes, S and Jilma, B and Zeitlinger, M and Lin, S and Drennan, IR and Jorda, A},
title = {Amiodarone dose in patients with shockable out-of-hospital cardiac arrest.},
journal = {Resuscitation},
volume = {209},
number = {},
pages = {110534},
doi = {10.1016/j.resuscitation.2025.110534},
pmid = {39947279},
issn = {1873-1570},
mesh = {Humans ; *Amiodarone/administration & dosage ; *Out-of-Hospital Cardiac Arrest/therapy/mortality/drug therapy ; Male ; Female ; *Anti-Arrhythmia Agents/administration & dosage ; Aged ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; Registries ; *Electric Countershock/methods ; Dose-Response Relationship, Drug ; Treatment Outcome ; },
abstract = {BACKGROUND: Amiodarone is used in shockable out-of-hospital cardiac arrest (OHCA), but the ideal dose is unknown.

METHODS: This was an analysis from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (2011-2015). Patients with shockable OHCA who received 5 or more defibrillation attempts and treatment with 300 or 450 mg of amiodarone were included. Outcomes were ROSC at ED arrival, survival at hospital discharge, and favorable neurologic function at discharge. Group-differences were adjusted for using inverse probability weighting and a multiple logistic regression model.

RESULTS: The present study included 910 patients; 426 received amiodarone 300 mg and 484 received amiodarone 450 mg. The amiodarone 300 mg group had a higher estimated probability of ROSC at ED arrival as compared with the amiodarone 450 mg group (30.8% [95% CI, 26.6-35.1] vs 24.2% [95% CI, 20.5-27.9], respectively; adjusted probability difference, 6.6% (0.9-12.3), p = 0.0234). The group differences in survival at hospital discharge (21.3% [95% CI, 17.2-25.4] vs 18.0% [95% CI, 14.6-21.5]; adjusted probability difference, 3.3% [-2.3-8.8]) and favorable neurologic outcome at discharge (16.5% [95% CI, 12.9-20.2] vs 12.7% [95% CI, 9.5-16.0]; adjusted probability difference, 3.8% [95% CI, -1.2-8.7]) did not reach statistical significance.

CONCLUSION: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300 mg was associated with a similar survival compared with a total dose of amiodarone 450 mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA.},
}

Humans
*Amiodarone/administration & dosage
*Out-of-Hospital Cardiac Arrest/therapy/mortality/drug therapy
Male
Female
*Anti-Arrhythmia Agents/administration & dosage
Aged
Middle Aged
*Cardiopulmonary Resuscitation/methods
Registries
*Electric Countershock/methods
Dose-Response Relationship, Drug
Treatment Outcome

@article {pmid39947630,
year = {2025},
author = {Moreno-Martinez, L and Gaja-Capdevila, N and Mosqueira-Martín, L and Herrando-Grabulosa, M and Rodriguez-Gomez, L and Gonzalez-Imaz, K and Calvo, AC and Sagartzazu-Aizpurua, M and Moreno-García, L and Fuentes, JM and Acevedo-Arozena, A and Aizpurua, JM and Miranda, JI and López de Munain, A and Vallejo-Illarramendi, A and Navarro, X and Osta, R and Gil-Bea, FJ},
title = {Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1[G93A] amyotrophic lateral sclerosis (ALS) mice.},
journal = {British journal of pharmacology},
volume = {182},
number = {11},
pages = {2466-2486},
doi = {10.1111/bph.17448},
pmid = {39947630},
issn = {1476-5381},
support = {PID2022-140354OB-I00//Agencia Estatal de Investigación/ ; PID2020-119780RB-100//Agencia Estatal de Investigación/ ; IKERBASQUE/PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; PIF19/184//Euskal Herriko Unibertsitatea/ ; PI2020/08-1//CIBER-CALS/ ; CB06/05/1105//Instituto de Salud Carlos III of Spain/ ; CB06/05/0041//Instituto de Salud Carlos III of Spain/ ; BIO19/ROCHE/017/BD//Roche Stop Fuga de Cerebros/ ; IT1732-22//Basque Government/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology/genetics ; Ligands ; Mice ; *Superoxide Dismutase-1/genetics ; Mice, Transgenic ; *Tacrolimus Binding Protein 1A/metabolism ; Disease Models, Animal ; Humans ; Male ; Motor Neurons/drug effects ; Ryanodine Receptor Calcium Release Channel/metabolism ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca[2+] influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca[2+], as a therapeutic target.

EXPERIMENTAL APPROACH: A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)[G93A] mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.

KEY RESULTS: Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1[G93A] mice produced preservation of motor nerve conduction, with the 61-mg·kg[-1] dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.

CONCLUSIONS AND IMPLICATIONS: FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology/genetics
Ligands
Mice
*Superoxide Dismutase-1/genetics
Mice, Transgenic
*Tacrolimus Binding Protein 1A/metabolism
Disease Models, Animal
Humans
Male
Motor Neurons/drug effects
Ryanodine Receptor Calcium Release Channel/metabolism
Mice, Inbred C57BL

@article {pmid39953725,
year = {2025},
author = {Nishida, K and Sakashita, K and Futamura, N},
title = {Decision-making trends in therapeutic interventions for multiple system atrophy: a 24-year retrospective study.},
journal = {Movement disorders clinical practice},
volume = {12},
number = {6},
pages = {823-827},
pmid = {39953725},
issn = {2330-1619},
support = {JPMH23FC1010//the Ministry of Health, Labour and Welfare, Japan/ ; },
mesh = {Humans ; *Multiple System Atrophy/therapy ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Tracheostomy/trends ; Aged ; Enteral Nutrition/trends ; Japan ; Adult ; *Respiration, Artificial/trends ; *Clinical Decision-Making ; Age Factors ; },
abstract = {BACKGROUND: Managing multiple system atrophy (MSA) is challenging. While invasive interventions for amyotrophic lateral sclerosis are well-studied, those for MSA remain less explored.

OBJECTIVES: To explore factors influencing treatment choices and trends in advanced-stage MSA.

METHODS: A retrospective cohort study analyzed 128 MSA patients at Hyogo Chuo National Hospital, Japan, from 2000 to 2024, focusing on treatment period and age at onset.

RESULTS: Tracheostomy invasive ventilation (TIV) decreased after 2014 (26.9% vs. 9.2%; P = 0.023). TIV-treated patients remained similarly young before and after 2014 (age at onset 52.7 vs. 54.5 years; P = 0.659) and tracheostomy was chosen by younger patients after 2014 (58.3 vs. 51.5 years; P < 0.001). Conversely, enteral nutrition increased in older patients (57.4 vs. 62.9 years; P = 0.011).

CONCLUSIONS: In Japanese MSA, preferences for invasive treatments shifted, with younger patients favoring TIV and tracheostomy, while older patients preferred less invasive options, emphasizing personalized care.},
}

Humans
*Multiple System Atrophy/therapy
Retrospective Studies
Male
Female
Middle Aged
*Tracheostomy/trends
Aged
Enteral Nutrition/trends
Japan
Adult
*Respiration, Artificial/trends
*Clinical Decision-Making
Age Factors

@article {pmid39954710,
year = {2025},
author = {Nadeem, ZA and Ahmed, S},
title = {Amyotrophic lateral sclerosis and lovastatin: a promising treatment perspective.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {5-6},
pages = {595-596},
doi = {10.1080/21678421.2025.2463943},
pmid = {39954710},
issn = {2167-9223},
}

@article {pmid39954940,
year = {2025},
author = {Satao, KS and Doshi, GM},
title = {Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.},
journal = {Life sciences},
volume = {365},
number = {},
pages = {123468},
doi = {10.1016/j.lfs.2025.123468},
pmid = {39954940},
issn = {1879-0631},
mesh = {Humans ; *Exosomes/metabolism/physiology ; *Neurodegenerative Diseases/physiopathology/metabolism/pathology ; *Cell Communication/physiology ; Animals ; },
abstract = {Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.},
}

Humans
*Exosomes/metabolism/physiology
*Neurodegenerative Diseases/physiopathology/metabolism/pathology
*Cell Communication/physiology
Animals

@article {pmid39958442,
year = {2025},
author = {Ozbey, D and Saribas, S and Kocazeybek, B},
title = {Gut microbiota in Crohn's disease pathogenesis.},
journal = {World journal of gastroenterology},
volume = {31},
number = {6},
pages = {101266},
pmid = {39958442},
issn = {2219-2840},
mesh = {Humans ; Colon/microbiology/pathology/immunology ; *Crohn Disease/therapy/microbiology/immunology/pathology ; Dysbiosis/therapy ; *Fecal Microbiota Transplantation/methods ; *Gastrointestinal Microbiome/immunology ; Ileum/microbiology/pathology/immunology ; Intestinal Mucosa/microbiology/pathology/immunology ; Treatment Outcome ; },
abstract = {Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.},
}

Humans
Colon/microbiology/pathology/immunology
*Crohn Disease/therapy/microbiology/immunology/pathology
Dysbiosis/therapy
*Fecal Microbiota Transplantation/methods
*Gastrointestinal Microbiome/immunology
Ileum/microbiology/pathology/immunology
Intestinal Mucosa/microbiology/pathology/immunology
Treatment Outcome

@article {pmid39958549,
year = {2025},
author = {Zhang, Y},
title = {Enhancing rectal cancer liver metastasis prediction: Magnetic resonance imaging-based radiomics, bias mitigation, and regulatory considerations.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {2},
pages = {102151},
pmid = {39958549},
issn = {1948-5204},
abstract = {In this article, we comment on the article by Long et al published in the recent issue of the World Journal of Gastrointestinal Oncology. Rectal cancer patients are at risk for developing metachronous liver metastasis (MLM), yet early prediction remains challenging due to variations in tumor heterogeneity and the limitations of traditional diagnostic methods. Therefore, there is an urgent need for non-invasive techniques to improve patient outcomes. Long et al's study introduces an innovative magnetic resonance imaging (MRI)-based radiomics model that integrates high-throughput imaging data with clinical variables to predict MLM. The study employed a 7:3 split to generate training and validation datasets. The MLM prediction model was constructed using the training set and subsequently validated on the validation set using area under the curve (AUC) and dollar-cost averaging metrics to assess performance, robustness, and generalizability. By employing advanced algorithms, the model provides a non-invasive solution to assess tumor heterogeneity for better metastasis prediction, enabling early intervention and personalized treatment planning. However, variations in MRI parameters, such as differences in scanning resolutions and protocols across facilities, patient heterogeneity (e.g., age, comorbidities), and external factors like carcinoembryonic antigen levels introduce biases. Additionally, confounding factors such as diagnostic staging methods and patient comorbidities require further validation and adjustment to ensure accuracy and generalizability. With evolving Food and Drug Administration regulations on machine learning models in healthcare, compliance and careful consideration of these regulatory requirements are essential to ensuring safe and effective implementation of this approach in clinical practice. In the future, clinicians may be able to utilize data-driven, patient-centric artificial intelligence (AI)-enhanced imaging tools integrated with clinical data, which would help improve early detection of MLM and optimize personalized treatment strategies. Combining radiomics, genomics, histological data, and demographic information can significantly enhance the accuracy and precision of predictive models.},
}

@article {pmid39960672,
year = {2025},
author = {Paganoni, S and Fournier, CN and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Ajroud-Driss, S and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Shefner, JM and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and Dagostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Heiman-Patterson, T and Caress, JB and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Harvey, B and Patel, S and Mahoney, P and Duda, PW and Cudkowicz, ME and , },
title = {Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {8},
number = {2},
pages = {e2459058},
pmid = {39960672},
issn = {2574-3805},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; },
abstract = {IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.

OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.

Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.

MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).

RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Male
Female
Middle Aged
Double-Blind Method
Aged
Treatment Outcome

@article {pmid39961673,
year = {2025},
author = {Aryapadi, V and Trivedi, J},
title = {Atypical presentation of amyotrophic lateral sclerosis with SOD1-H47R mutation.},
journal = {BMJ case reports},
volume = {18},
number = {2},
pages = {},
doi = {10.1136/bcr-2024-263293},
pmid = {39961673},
issn = {1757-790X},
mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology ; Mutation ; *Superoxide Dismutase/genetics ; *Superoxide Dismutase-1/genetics ; },
abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) is recognised as a fatal neurodegenerative disease that typically emerges in the later decades of life, with a life expectancy of 2-5 years after symptom onset. We now understand that ALS exhibits a wide phenotypic clinical spectrum, significantly influenced by genetic factors. Here, we describe a patient with familial ALS carrying a heterozygous pathogenic H47R mutation of the superoxide dismutase 1 (SOD1) gene. His clinical presentation is atypical, with a slow progressive course, lower extremity weakness, and sparing of bulbar and respiratory function, consistent with the flail leg variant of ALS. The objective of this report is to increase awareness of atypical presentations of ALS and the diagnostic challenges they pose to clinicians. In addition to a description of the clinical case, we briefly discuss the new role of gene therapy in the treatment of familial ALS with SOD1 mutations.},
}

Humans
Male
*Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology
Mutation
*Superoxide Dismutase/genetics
*Superoxide Dismutase-1/genetics

@article {pmid39963928,
year = {2025},
author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A},
title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.},
journal = {Nanomedicine (London, England)},
volume = {20},
number = {6},
pages = {603-619},
pmid = {39963928},
issn = {1748-6963},
support = {R01 DA049657/DA/NIDA NIH HHS/United States ; R01 DA052271/DA/NIDA NIH HHS/United States ; R03 AG087475/AG/NIA NIH HHS/United States ; U01 ES033265/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; *Substance-Related Disorders/drug therapy/therapy ; Blood-Brain Barrier/metabolism ; *Nanomedicine/methods ; *HIV Infections/complications/drug therapy ; *Nanoparticles/chemistry/therapeutic use ; Animals ; *Neurocognitive Disorders/drug therapy ; *AIDS Dementia Complex/drug therapy ; },
abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.},
}

Humans
*Substance-Related Disorders/drug therapy/therapy
Blood-Brain Barrier/metabolism
*Nanomedicine/methods
*HIV Infections/complications/drug therapy
*Nanoparticles/chemistry/therapeutic use
Animals
*Neurocognitive Disorders/drug therapy
*AIDS Dementia Complex/drug therapy

@article {pmid39967643,
year = {2025},
author = {Abdel-Magid, AF},
title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {2},
pages = {204-206},
pmid = {39967643},
issn = {1948-5875},
abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.},
}

@article {pmid39968231,
year = {2025},
author = {Nagadi, E and Muryani, A and Adang, RAF},
title = {Integrated Endodontic and Restorative Management of C-Shaped Canals with Severe Coronal Loss in Mandibular Second Molar: A Case Report.},
journal = {Clinical, cosmetic and investigational dentistry},
volume = {17},
number = {},
pages = {121-134},
pmid = {39968231},
issn = {1179-1357},
abstract = {This case report describes the endodontic treatment of a lower right second molar with a C-shaped root canal in a 49-year-old woman exhibiting severe loss of coronal structure. Clinical examination revealed a cavity with temporary filling on tooth 47, which tested negative to cold stimuli but was positive to percussion and bite tests. Cone beam computed tomography (CBCT) scan revealed a C-shaped canal morphology with associated periapical radiolucency, graded as CBCT-PAI score 4. The canal was classified as C3 subdivision III (Melton et al), C3 type II (Fan et al), and [2]47 M[2-2]D[2-1] (Ahmed et al's). A non-surgical endodontic procedure was performed using metallurgically gold heat-treated files, passive ultrasonic irrigation, and warm hydraulic condensation obturation. Post-endodontic restoration included a post and core build-up with the wallpapering technique and a zirconia overlay. This case highlights the importance of CBCT imaging for diagnosis and treatment planning, careful selection of endodontic instruments and technique, and the use of advanced restoration methods to improve the outcome of challenging C-shaped canal treatments with extensive cavity involvement.},
}

@article {pmid39976261,
year = {2025},
author = {Menendez-Gonzalez, M},
title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {2},
pages = {e14591},
pmid = {39976261},
issn = {1552-5279},
support = {PI21/00467//Instituto de Salud Carlos III/ ; },
mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; Biomarkers ; Neuroimaging ; },
abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.},
}

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

@article {pmid39981400,
year = {2025},
author = {Yang, EJ and Lee, SH},
title = {Herbal Medicine Extracts Improve Motor Function by Anti-Inflammatory Activity in hSOD1[G93A] Animal Model.},
journal = {Mediators of inflammation},
volume = {2025},
number = {},
pages = {1999953},
pmid = {39981400},
issn = {1466-1861},
mesh = {Animals ; Mice ; Mice, Transgenic ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Plant Extracts/therapeutic use/pharmacology ; Muscle, Skeletal/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; *Herbal Medicine ; Male ; Superoxide Dismutase-1/metabolism/genetics ; Spinal Cord/drug effects/metabolism ; Inflammation/drug therapy ; Paeonia/chemistry ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a multicomplex neurodegenerative disorder characterized by motor neuron death, muscle atrophy, and respiratory failure. Owing to its multicomplex mechanisms and multifactorial nature in the skeletal muscle and spinal cord (SC), no effective therapy has been developed. However, herbal medicines, known for their multitarget properties, have demonstrated promising efficacy with limited side effects in treating various diseases. Specifically, Paeonia lactiflora Pallas has been demonstrated to exhibit analgesic, antidepressant, anti-inflammatory, and neuroprotective effects. However, the pharmacological mechanisms underlying the beneficial effects of P. lactiflora in hSOD1[G93A] animal models remain unexplored. Therefore, this study was conducted to investigate the multitarget effects of P. lactiflora in hSOD1[G93A] transgenic mice, an ALS model. Footprint tests, western blot assays, and immunohistochemical analysis were used to assess the effect of P. lactiflora on the tibia anterior (TA), gastrocnemius (GC), and SC. The results revealed that P. lactiflora augmented motor function and decreased motor neuron loss in hSOD1[G93A] mice. Furthermore, P. lactiflora significantly lowered the expression of proteins associated with inflammation and oxidative stress in the skeletal muscle (TA and GC) and SC. P. lactiflora also regulated autophagy function by reducing the levels of key markers, such as P62/sequestosome 1 (SQSTM1), microtubule-associated proteins 1A/1B light chain 3B, and SMAD family member 2, in the muscle and SC. Overall, P. lactiflora treatment improved motor function, prevented motor neuron death, and exhibited anti-inflammatory and antioxidative effects in the skeletal muscle and SC of ALS mouse models. These results suggest that P. lactiflora could serve as a promising multitarget therapeutic agent for systemic and multipathological diseases.},
}

Animals
Mice
Mice, Transgenic
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Disease Models, Animal
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism
*Plant Extracts/therapeutic use/pharmacology
Muscle, Skeletal/drug effects/metabolism
Motor Neurons/drug effects/metabolism
Oxidative Stress/drug effects
*Herbal Medicine
Male
Superoxide Dismutase-1/metabolism/genetics
Spinal Cord/drug effects/metabolism
Inflammation/drug therapy
Paeonia/chemistry

@article {pmid39982687,
year = {2025},
author = {Loher, P and Londin, E and Ilieva, H and Pasinelli, P and Rigoutsos, I},
title = {Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.},
journal = {Molecular neurobiology},
volume = {62},
number = {7},
pages = {8135-8149},
pmid = {39982687},
issn = {1559-1182},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; Prognosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; *MicroRNAs/genetics/blood ; Biomarkers/blood ; RNA, Ribosomal/genetics/blood ; Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease for which accurate diagnostic and prognostic biomarkers are needed. Toward this goal, we reanalyzed two published collections of datasets generated from the plasma and serum of ALS patients and controls. We profiled these datasets for isoforms of microRNAs (miRNAs) known as isomiRs, transfer RNA-derived fragments (tRFs), and ribosomal RNA-derived fragments (rRFs), placing all remaining reads into a group labeled "not-itrs." We found that plasma and serum are rich in isomiRs (canonical, non-canonical, and non-templated), tRFs, rRFs, and members of an emerging class of small RNAs known as Y RNA-derived fragments (yRFs). In both analyzed collections, we found many isomiRs, tRFs, rRFs, and yRFs that are differentially abundant between patients and controls. We also performed a survival analysis that considered Riluzole treatment status, demographics (age at onset, age at enrollment, sex), and disease characteristics (ALSFRS, rD50, onset type) and found many of the differentially abundant small RNAs to be associated with survival time, with some of these associations being independent of Riluzole treatment. Unexpectedly, many not-itrs that did not map to the human genome mapped exactly to sequences from the SILVA database of ribosomal DNAs (rDNAs). Not-itrs from the plasma datasets mapped primarily to rDNAs from the order of Burkholderiales, and several of them were associated with patient survival. Not-itrs from the serum datasets also showed support for rDNA from Burkholderiales but a stronger support for rDNAs from the fungi group of the Nucletmycea taxon. The findings suggest that many previously unexplored small non-coding RNAs, including human isomiRs, tRFs, rRFs, and yRFs, could potentially serve as novel diagnostic and prognostic biomarkers for ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood
Prognosis
Male
Female
Case-Control Studies
Middle Aged
*MicroRNAs/genetics/blood
Biomarkers/blood
RNA, Ribosomal/genetics/blood
Aged

@article {pmid39985812,
year = {2025},
author = {Filippi, M and Ghirelli, A and Spinelli, EG and Agosta, F},
title = {A comprehensive update on neuroimaging endpoints in amyotrophic lateral sclerosis.},
journal = {Expert review of neurotherapeutics},
volume = {25},
number = {4},
pages = {397-413},
doi = {10.1080/14737175.2025.2470324},
pmid = {39985812},
issn = {1744-8360},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/therapy ; *Neuroimaging/methods ; Magnetic Resonance Imaging/methods ; Positron-Emission Tomography/methods ; Disease Progression ; Biomarkers ; },
abstract = {INTRODUCTION: There are currently few treatments approved for amyotrophic lateral sclerosis (ALS). Additionally, there remains a significant unmet need for reliable, standardized biomarkers to assess endpoints in clinical trials. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-derived metrics could help in patient selection and stratification, shortening trial duration and reducing costs.

AREAS COVERED: This review focuses on the potential use of neuroimaging endpoints in the context of ALS therapeutic trials, providing insights on structural and functional neuroimaging, plexus and muscle alterations, glial involvement and neuroinflammation, envisioning how these surrogates of disease progression could be implemented in clinical trials. A PubMed search covering the past 15 years was performed.

EXPERT OPINION: Neuroimaging is essential in understanding ALS pathophysiology, aiding in disease progression tracking and evaluating therapeutic interventions. High costs, limited accessibility, lack of standardization, and patient tolerability limit their use in routine ALS care. Addressing these obstacles is essential for fully harnessing neuroimaging potential in improving diagnostics and treatment in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/therapy
*Neuroimaging/methods
Magnetic Resonance Imaging/methods
Positron-Emission Tomography/methods
Disease Progression
Biomarkers

@article {pmid39987111,
year = {2025},
author = {Zeng, L and Yang, F and Xu, D and Zhou, J and Qiao, G and Wu, M and Li, C and Yu, Y and Qiu, Y and Liu, J},
title = {Actual needs of patients with amyotrophic lateral sclerosis: a qualitative study from Wuhan, China.},
journal = {BMC palliative care},
volume = {24},
number = {1},
pages = {50},
pmid = {39987111},
issn = {1472-684X},
support = {2023AFD160//Hubei Provincial Natural Science Foundation and Traditional Chinese Medicine Innovation and Development Joint/ ; 2024AFD279//Department of Science and Technology, Hubei Province, China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; China ; Qualitative Research ; Male ; Female ; Middle Aged ; Aged ; Adult ; Quality of Life/psychology ; *Health Services Needs and Demand ; *Needs Assessment ; Medicine, Chinese Traditional/methods ; Interviews as Topic/methods ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that significantly impacts individuals and families. Previous research on ALS has predominantly focused on its pathophysiology, genetic factors, and potential therapeutic interventions. While these aspects are essential for understanding and treating the disease, there has been a growing recognition of the importance of studying patients' actual needs. Understanding these needs is vital for developing patient-centered care models that can enhance the well-being of ALS patients. However, existing studies on patients' needs are often limited in scope. Many are conducted in Western countries, and the results may not be directly applicable to patients in other cultural and socioeconomic contexts. China, with its large population and diverse cultural, economic, and healthcare landscapes, presents a unique setting for studying ALS patients' needs. At the same time, traditional Chinese medicine (TCM) practices are deeply ingrained in their healthcare system and may affect the way people with ALS seek treatment and manage their condition. Therefore, these differences may lead to differences in the actual needs of ALS patients in China. In conclusion, this qualitative study on the actual needs of ALS patients in China aims to bridge the gap in the existing research. By exploring these needs, it can provide valuable insights for healthcare providers, policymakers, and researchers, ultimately contributing to the improvement of care and quality of life for ALS patients in China.

METHOD: We carried out a qualitative study using an empirical phenomenological approach. Individual in-depth interviews were performed among 22 people with ALS from the motor neuron disease rehabilitation center of a tertiary Chinese medicine hospital in China, and the interview content was analyzed qualitatively. Interview recordings were converted to text content by NVivo 11.0 software and analyzed using Colaizzi's phenomenological method.

RESULT: Three main themes were identified in this study: (1) Demand for healthcare services, (2) Emotional requirements, (3) Functional requirements. In addition, 8 sub-themes were extracted as the actual needs of ALS patients.

CONCLUSION: This study is based on the real experience of ALS patients after diagnosis, and a deep understanding of these experiences can explore the actual needs of patients from many aspects and give reasonable advice and help. Given the particularity of the disease and the uncertainty of treatment, patients will have practical needs for relevant medical support, emotional requirements, physical functions, and other aspects during the period of illness, and the corresponding support is an effective measure to reduce the burden on patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/therapy/complications
China
Qualitative Research
Male
Female
Middle Aged
Aged
Adult
Quality of Life/psychology
*Health Services Needs and Demand
*Needs Assessment
Medicine, Chinese Traditional/methods
Interviews as Topic/methods

@article {pmid39987285,
year = {2025},
author = {Fang, M and Zhou, Y and He, K and Lu, Y and Tao, F and Huang, H},
title = {Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.},
journal = {Molecular neurobiology},
volume = {62},
number = {7},
pages = {8204-8221},
pmid = {39987285},
issn = {1559-1182},
support = {82204651//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Microglia/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology/therapy ; *Glucose/metabolism ; Animals ; *Molecular Targeted Therapy ; Glycolysis ; Metabolic Reprogramming ; },
abstract = {As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.},
}

Humans
*Microglia/metabolism/drug effects
*Neurodegenerative Diseases/metabolism/drug therapy/pathology/therapy
*Glucose/metabolism
Animals
*Molecular Targeted Therapy
Glycolysis
Metabolic Reprogramming

@article {pmid39992655,
year = {2025},
author = {Liu, X and Shang, H and Wei, Q and Yao, X and Lian, L and Dang, J and Jia, R and Wu, Z and Li, H and Niu, Q and Cheng, X and Zou, Z and Chen, S and Zhang, M and Liu, Y and Liu, Y and Liu, Q and Huang, X and Wang, H and Feng, H and Wang, S and Fan, D and , },
title = {Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {8},
number = {2},
pages = {e2461055},
pmid = {39992655},
issn = {2574-3805},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Pyrazines/therapeutic use/administration & dosage ; Male ; Female ; Middle Aged ; Aged ; Double-Blind Method ; China ; Treatment Outcome ; },
abstract = {IMPORTANCE: Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

OBJECTIVE: To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS.

This phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial was conducted from December 24, 2020, through July 14, 2023, in 11 centers in China, with a 180-day follow-up. Patients aged 45 to 70 years, with ALS onset within 2 years, ALS Functional Rating Scale-Revised (ALSFRS-R) scores of at least 2 points on each item, and forced vital capacity (FVC) of at least 80% were included. Patients experienced a 1- to 4-point decrease in ALSFRS-R score during a 3-month screening period.

INTERVENTIONS: Patients were randomly assigned 1:1:1 to receive low-dose tetramethylpyrazine nitrone (600 mg twice daily), high-dose tetramethylpyrazine nitrone (1200 mg twice daily), or placebo (twice daily) for 180 days.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in ALSFRS-R score (range of 0-48, with lower scores indicating worse function) from baseline to 180 days. The secondary outcomes were changes in FVC, grip strength, ALS Assessment Questionnaire-40 (ALSAQ-40) score, and end point events. Safety outcomes included adverse events.

RESULTS: A total of 155 patients (mean [SD] age, 55.0 [6.5] years; 115 men [74.2%]) were randomized (51 [32.9%] to the low-dose tetramethylpyrazine nitrone group, 52 [33.6%] to the high-dose tetramethylpyrazine nitrone group, and 52 [33.6%] to the placebo group). No significant differences were observed in ALSFRS-R score changes between low-dose tetramethylpyrazine nitrone (least squares [LS] mean difference, -0.89 points; 95% CI -3.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, -0.20 points; 95% CI -2.48 to 2.07 points) compared with placebo. High-dose tetramethylpyrazine nitrone showed a significantly slower decline in grip strength at day 180 (LS mean difference, 2.46 kg; 95% CI, 0.15-4.76 kg). In a subgroup of patients younger than 65 years with slower disease progression, tetramethylpyrazine nitrone significantly attenuated the decline in grip strength (LS mean difference, 3.63 kg; 95% CI, 0.84-6.41 kg), bulbar scores (LS mean difference, 0.66 points; 95% CI, 0.03-1.29 points), and respiratory scores (LS mean difference, 0.54 points; 95% CI, 0.03-1.06 points). Adverse events were mostly mild or moderate, with no severe treatment-related adverse events or deaths.

CONCLUSIONS AND RELEVANCE: This randomized clinical trial demonstrates that tetramethylpyrazine nitrone is safe and well-tolerated in patients with ALS. There was no difference in the primary end point across the low-dose, high-dose, and placebo groups, with significant benefits in a subgroup of younger patients with slower disease progression.

TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2000039689.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Pyrazines/therapeutic use/administration & dosage
Male
Female
Middle Aged
Aged
Double-Blind Method
China
Treatment Outcome

@article {pmid39995125,
year = {2025},
author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV},
title = {ISR Modulators in Neurological Diseases.},
journal = {Current neuropharmacology},
volume = {23},
number = {10},
pages = {1184-1214},
pmid = {39995125},
issn = {1875-6190},
support = {23-15-00539//Russian Science Foundation, RSF/ ; },
mesh = {Humans ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; *Signal Transduction/drug effects/physiology ; *Stress, Physiological/physiology/drug effects ; },
abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.},
}

Humans
*Nervous System Diseases/metabolism/drug therapy
Animals
*Signal Transduction/drug effects/physiology
*Stress, Physiological/physiology/drug effects

@article {pmid39996130,
year = {2025},
author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK},
title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.},
journal = {Neurology. Genetics},
volume = {11},
number = {2},
pages = {e200246},
pmid = {39996130},
issn = {2376-7839},
support = {U24 HG011453/HG/NHGRI NIH HHS/United States ; },
abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.},
}

@article {pmid39998031,
year = {2025},
author = {Burke, KM and Shea, C and Arulanandam, V and Sullivan, S and Ellrodt, AS and MacAdam, C and Carney, K and Casagrande, G and Christiansen, E and Paganoni, S},
title = {Cervical Collar Satisfaction and Functional Impact in Amyotrophic Lateral Sclerosis: A Survey Study.},
journal = {American journal of physical medicine & rehabilitation},
volume = {104},
number = {9},
pages = {809-813},
doi = {10.1097/PHM.0000000000002716},
pmid = {39998031},
issn = {1537-7385},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/complications/physiopathology ; Female ; Male ; Middle Aged ; *Patient Satisfaction ; Aged ; Activities of Daily Living ; *Neck Pain/etiology/rehabilitation ; Cervical Vertebrae ; Quality of Life ; Adult ; Surveys and Questionnaires ; *Muscle Weakness/etiology/rehabilitation ; *Braces ; },
abstract = {OBJECTIVES: Many people with amyotrophic lateral sclerosis develop cervical muscle weakness, often managed with cervical collars. Finding supportive and comfortable collars can be challenging. This study aimed to evaluate satisfaction with various collars and their impact on activities of daily living.

DESIGN: This electronic survey study collected demographic information, clinical status, and participant experiences with commonly used cervical collars.

RESULTS: Thirty-four participants (33 with amyotrophic lateral sclerosis, 1 with primary lateral sclerosis) completed the survey, with 79% reporting neck weakness and 38% experiencing neck pain. Among those who tried cervical collars (65%), many had tried multiple options. The mean satisfaction across all collar types was 5.03 (SD = 2.92) out of 10.

CONCLUSIONS: These findings suggest current collars do not fully meet the needs of people living with amyotrophic lateral sclerosis, emphasizing the importance of improved treatment options. Future research should explore innovative technologies to improve cervical support, function, and quality of life.},
}

Humans
*Amyotrophic Lateral Sclerosis/rehabilitation/complications/physiopathology
Female
Male
Middle Aged
*Patient Satisfaction
Aged
Activities of Daily Living
*Neck Pain/etiology/rehabilitation
Cervical Vertebrae
Quality of Life
Adult
Surveys and Questionnaires
*Muscle Weakness/etiology/rehabilitation
*Braces

@article {pmid40000618,
year = {2025},
author = {Ru, Q and Li, Y and Zhang, X and Chen, L and Wu, Y and Min, J and Wang, F},
title = {Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.},
journal = {Bone research},
volume = {13},
number = {1},
pages = {27},
pmid = {40000618},
issn = {2095-4700},
support = {82071970//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072506//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970689//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32330047//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024AFB971//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; },
mesh = {Humans ; *Ferroptosis/physiology ; *Iron/metabolism ; *Homeostasis ; *Muscular Diseases/metabolism/pathology/therapy ; Animals ; Muscle, Skeletal/metabolism ; },
abstract = {The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.},
}

Humans
*Ferroptosis/physiology
*Iron/metabolism
*Homeostasis
*Muscular Diseases/metabolism/pathology/therapy
Animals
Muscle, Skeletal/metabolism

@article {pmid40001529,
year = {2025},
author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML},
title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.},
journal = {Biomolecules},
volume = {15},
number = {2},
pages = {},
pmid = {40001529},
issn = {2218-273X},
support = {R01 GM125082/GM/NIGMS NIH HHS/United States ; R35 GM149271/GM/NIGMS NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; GM125082/GF/NIH HHS/United States ; },
mesh = {Humans ; *Inositol Phosphates/metabolism ; *Neurodegenerative Diseases/metabolism/enzymology ; Animals ; Inositol/metabolism ; Signal Transduction ; },
abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.},
}

Humans
*Inositol Phosphates/metabolism
*Neurodegenerative Diseases/metabolism/enzymology
Animals
Inositol/metabolism
Signal Transduction

@article {pmid40001624,
year = {2025},
author = {Ma, B and Ren, J and Qian, X},
title = {Study on the Polarization of Astrocytes in the Optic Nerve Head of Rats Under High Intraocular Pressure: In Vitro.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {2},
pages = {},
pmid = {40001624},
issn = {2306-5354},
support = {12472309 12072210//National Natural Science Foundation of China/ ; },
abstract = {Astrocytes, the most common glial cells in the optic nerve head (ONH), provide support and nutrition to retinal ganglion cells. This study aims to investigate the polarization types of astrocytes in the ONH of rats under high intraocular pressure (IOP) and explore signaling pathways potentially associated with different types of polarized astrocytes. The rat models with chronic high IOP were established. High IOP lasted for 2, 4, 6, and 8 weeks. Astrocytes were extracted from the ONH of rats using the tissue block cultivation method. Western blot was used to detect the expression of proteins associated with astrocyte polarization. Proteomics was employed to identify differential proteins associated with astrocyte polarization. Astrocytes polarized into A2 astrocytes after 2, 4, 6, and 8 weeks of high IOP, while polarization into A1 astrocytes began only after 8 weeks of high IOP. The differential proteins associated with A1 astrocyte polarization are primarily enriched in pathways of neurodegeneration with respect to multiple diseases, while the differential proteins associated with A2 astrocyte polarization are primarily enriched in pathways of spliceosome in amyotrophic lateral sclerosis. Our findings could provide a better understanding of the role of ONH astrocytes in the pathogenesis of glaucoma and offer new perspectives for glaucoma treatment.},
}

@article {pmid40002740,
year = {2025},
author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J},
title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
pmid = {40002740},
issn = {2227-9059},
support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; },
abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.},
}

@article {pmid40007904,
year = {2025},
author = {Esteruelas, G and Ettcheto, M and Haro, I and Herrando-Grabulosa, M and Gaja-Capdevila, N and Gomara, MJ and Navarro, X and Espina, M and Souto, EB and Camins, A and García, ML and Sánchez-López, E},
title = {Novel Tissue-Specific Multifunctionalized Nanotechnological Platform Encapsulating Riluzole Against Motor Neuron Diseases.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {2273-2288},
pmid = {40007904},
issn = {1178-2013},
mesh = {*Riluzole/administration & dosage/pharmacokinetics/chemistry ; Animals ; *Nanoparticles/chemistry ; *Neuroprotective Agents/administration & dosage/pharmacokinetics/chemistry ; *Motor Neuron Disease/drug therapy ; Humans ; Motor Neurons/drug effects/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy ; Drug Carriers/chemistry ; Mice ; Polyethylene Glycols/chemistry ; Drug Delivery Systems/methods ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Blood-Brain Barrier/metabolism ; },
abstract = {BACKGROUND: Motor neuron diseases are neurological disorders characterized by progressive degeneration of upper and/or lower motor neurons. Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron diseases, where patients suffer progressive paralysis, muscle atrophy and finally death. Despite ALS severity, no treatment is safe and fully effective. In this area, Riluzole was the first drug approved and it constitutes the gold-standard for this pathology. However, to obtain suitable therapeutic efficacy, Riluzole requires high doses that are associated with severe adverse effects in other tissues. To attain Riluzole therapeutic efficacy avoiding other organs side-effects, new therapeutic strategies to enhance the delivery of Riluzole specifically to motor neurons constitute an unmet medical need. In this area, we have developed a novel multifunctional nanostructurated carrier to selectively deliver Riluzole to motor neurons.

RESULTS: This work develops and characterizes at in vitro and in vivo levels a tissue-targeted formulation of peptide and PEG-labelled PLGA nanoparticles encapsulating Riluzole. For this purpose, pVEC, a cell penetrating peptide able to increase transport through the blood-brain barrier, was attached to the nanoparticles surface. The multifunctionalized nanoparticles show suitable characteristics for the release of Riluzole in the central nervous system and were detected in motor neurons within 1 h after administration while significantly reducing the concentration of Riluzole in non-therapeutic organs responsible of side effects.

CONCLUSION: A novel drug delivery system has been developed and characterized, demonstrating enhanced CNS biodistribution of riluzole, which shows promise as efficient therapeutic tool for motor neuron diseases, including amyotrophic lateral sclerosis.},
}

*Riluzole/administration & dosage/pharmacokinetics/chemistry
Animals
*Nanoparticles/chemistry
*Neuroprotective Agents/administration & dosage/pharmacokinetics/chemistry
*Motor Neuron Disease/drug therapy
Humans
Motor Neurons/drug effects/metabolism
Amyotrophic Lateral Sclerosis/drug therapy
Drug Carriers/chemistry
Mice
Polyethylene Glycols/chemistry
Drug Delivery Systems/methods
Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
Blood-Brain Barrier/metabolism

@article {pmid40008327,
year = {2025},
author = {van Eijk, RPA and Steyn, FJ and Janse van Mantgem, MR and Schmidt, A and Meyjes, M and Allen, S and Daygon, DV and Loeffler, JP and Al-Chalabi, A and van den Berg, LH and Henderson, RD and Ngo, ST},
title = {An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {1},
pages = {fcaf063},
pmid = {40008327},
issn = {2632-1297},
abstract = {Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.},
}

@article {pmid40009238,
year = {2025},
author = {Ruffo, P and Traynor, BJ and Conforti, FL},
title = {Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.},
journal = {Journal of neurology},
volume = {272},
number = {3},
pages = {233},
pmid = {40009238},
issn = {1432-1459},
support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Genetic Therapy/methods/trends ; Animals ; },
abstract = {This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/therapy
*Genetic Therapy/methods/trends
Animals

@article {pmid40009414,
year = {2025},
author = {Hamad, AA},
title = {Tofersen for Amyotrophic Lateral Sclerosis: Genetic Treatment With Precision Medicine: The Future of ALS Treatment.},
journal = {Journal of clinical neuromuscular disease},
volume = {26},
number = {3},
pages = {117-119},
doi = {10.1097/CND.0000000000000517},
pmid = {40009414},
issn = {1537-1611},
}

@article {pmid40010009,
year = {2025},
author = {Mikuriya, S and Takegawa-Araki, T and Tamura, M},
title = {Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.},
journal = {Free radical biology & medicine},
volume = {230},
number = {},
pages = {283-293},
doi = {10.1016/j.freeradbiomed.2025.01.012},
pmid = {40010009},
issn = {1873-4596},
mesh = {*Edaravone/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *X-Box Binding Protein 1/genetics/metabolism ; *Motor Neurons/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/drug effects/metabolism ; *Sirtuin 1/metabolism/genetics ; Endoplasmic Reticulum Stress/drug effects ; Signal Transduction/drug effects ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.},
}

*Edaravone/pharmacology
Humans
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism
*DNA-Binding Proteins/genetics/metabolism
*X-Box Binding Protein 1/genetics/metabolism
*Motor Neurons/drug effects/metabolism/pathology
Induced Pluripotent Stem Cells/drug effects/metabolism
*Sirtuin 1/metabolism/genetics
Endoplasmic Reticulum Stress/drug effects
Signal Transduction/drug effects

@article {pmid40011434,
year = {2025},
author = {Gao, G and Shi, Y and Deng, HX and Krainc, D},
title = {Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1982},
pmid = {40011434},
issn = {2041-1723},
support = {R21 NS114765/NS/NINDS NIH HHS/United States ; NS114765//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS099623/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; NS122257//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS099623//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Animals ; *Mitochondria/metabolism/enzymology ; *Ketoglutarate Dehydrogenase Complex/metabolism/genetics ; Humans ; *Lipid Peroxidation/drug effects ; *Parkinson Disease/metabolism/genetics/pathology ; Male ; Mice ; Disease Models, Animal ; alpha-Synuclein/metabolism ; Dopaminergic Neurons/metabolism/drug effects ; *Transcription Factors/genetics/metabolism ; Mice, Knockout ; Thioctic Acid/pharmacology ; DNA-Binding Proteins/metabolism/genetics ; Brain/metabolism ; *Mitochondrial Proteins/metabolism/genetics ; Ketoglutaric Acids/metabolism ; Mice, Inbred C57BL ; },
abstract = {Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.},
}

Animals
*Mitochondria/metabolism/enzymology
*Ketoglutarate Dehydrogenase Complex/metabolism/genetics
Humans
*Lipid Peroxidation/drug effects
*Parkinson Disease/metabolism/genetics/pathology
Male
Mice
Disease Models, Animal
alpha-Synuclein/metabolism
Dopaminergic Neurons/metabolism/drug effects
*Transcription Factors/genetics/metabolism
Mice, Knockout
Thioctic Acid/pharmacology
DNA-Binding Proteins/metabolism/genetics
Brain/metabolism
*Mitochondrial Proteins/metabolism/genetics
Ketoglutaric Acids/metabolism
Mice, Inbred C57BL

@article {pmid40011745,
year = {2025},
author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ},
title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.},
journal = {Nature structural & molecular biology},
volume = {32},
number = {7},
pages = {1167-1174},
pmid = {40011745},
issn = {1545-9985},
support = {102161/WT_/Wellcome Trust/United Kingdom ; 215519/WT_/Wellcome Trust/United Kingdom ; MR/W017741/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; Cryoelectron Microscopy ; *Potassium Channels, Tandem Pore Domain/chemistry/metabolism/ultrastructure/genetics ; Halothane/pharmacology/chemistry ; Models, Molecular ; Binding Sites ; Ion Channel Gating/drug effects ; *Anesthetics/pharmacology ; Protein Conformation ; },
abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.},
}

Humans
Cryoelectron Microscopy
*Potassium Channels, Tandem Pore Domain/chemistry/metabolism/ultrastructure/genetics
Halothane/pharmacology/chemistry
Models, Molecular
Binding Sites
Ion Channel Gating/drug effects
*Anesthetics/pharmacology
Protein Conformation

@article {pmid40012174,
year = {2025},
author = {Rajamanickam, G and Hu, Z and Liao, P},
title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.},
journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry},
volume = {31},
number = {5},
pages = {464-482},
doi = {10.1177/10738584251318979},
pmid = {40012174},
issn = {1089-4098},
mesh = {*TRPM Cation Channels/metabolism/antagonists & inhibitors ; Humans ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; },
abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.},
}

*TRPM Cation Channels/metabolism/antagonists & inhibitors
Humans
*Nervous System Diseases/metabolism/drug therapy
Animals

@article {pmid40017137,
year = {2025},
author = {Lovett, A and Chary, S and Babu, S and Bruneteau, G and Glass, JD and Karlsborg, M and Ladha, S and Mayl, K and McDermott, C and Bucelli, RC and Chiò, A and Ferguson, TA and Cochrane, T and Fradette, S and Smirnakis, K and Inra, J and Malek, S and Fanning, L},
title = {Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {71},
number = {6},
pages = {1006-1015},
pmid = {40017137},
issn = {1097-4598},
support = {//Biogen/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Middle Aged ; Male ; Female ; *Oligonucleotides/adverse effects/therapeutic use ; Adult ; Aged ; Superoxide Dismutase-1/genetics ; Myelitis/chemically induced ; Papilledema/chemically induced ; },
abstract = {INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.

METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.

RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.

DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/genetics
Middle Aged
Male
Female
*Oligonucleotides/adverse effects/therapeutic use
Adult
Aged
Superoxide Dismutase-1/genetics
Myelitis/chemically induced
Papilledema/chemically induced

@article {pmid40019593,
year = {2025},
author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C},
title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.},
journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society},
volume = {51},
number = {1},
pages = {122},
pmid = {40019593},
issn = {1863-9941},
mesh = {Humans ; *Cardiopulmonary Resuscitation/adverse effects ; Male ; *Flail Chest/surgery/etiology ; Female ; Middle Aged ; Retrospective Studies ; *Thoracic Wall/surgery ; *Rib Fractures/surgery ; Sternum/injuries/surgery ; Adult ; *Plastic Surgery Procedures/methods ; *Fracture Fixation, Internal/methods ; Aged ; Length of Stay/statistics & numerical data ; *Thoracic Injuries/surgery ; Germany ; Bone Plates ; Treatment Outcome ; },
abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.

METHOD: Data acquisition was performed using medical records of a Level I Trauma Centre in Germany and compare patients with radiologically or clinically diagnosed flail chest as a result of cardiopulmonary mechanical resuscitation (CPR). The retrospective study included patients in the period 2018-2023 after surgical CWR. The patients were either post-CPR (n = 29; CPR) or trauma patients (n = 36; trauma). The collective was described and analyzed using the digital patient file, as well as data on ICU stay and duration of ventilation or conversion to assisted ventilation modes, reason for chest wall instability, time of surgery, length of stay and mortality. As a long-term follow-up, body plethysmography was analyzed comparatively. Primary endpoints were mean length of stay in ICU, time to surgery, ventilator dependency and mortality rate. Secondary endpoints were time to transfer to rehabilitation, ventilation disorders and long term outcome.

RESULTS: In the period 65 patients (48 m, 17w) were included, 29 of whom had been mechanically resuscitated (CPR), 36 formed to post-traumatic cohort (trauma). The CPR were significantly older (69 vs. 58 years; p-value 0.003). The duration from CPR to surgery was on average significantly longer than trauma to surgery (16.76 vs. 4.11 days). The mean length of stay in ICU were 30 days (trauma) and 45 days for CPR (significantly longer, p-value 0.0008). The mean duration of ventilation was 188 h for trauma and 593 h for CPR. Extubation or conversion to assisted, relevant de-escalating ventilation modes was possible in both groups after a mean of 38 h post-OP. Among the CPR patients, 4 died in hospital (hospital mortality: CPR 20.7% vs. trauma 5.6%), 7 (30%) were transferred to an early clinical rehabilitation and 10 were discharged to home or follow-up treatment. In the case of trauma, 5 (14.7%) were transferred to an early clinical rehabilitation and 20 were discharged to home or follow-up treatment. Bodyplethysmography 6 months after CPR / trauma showed no differences in both collectives with regard to ventilation disorders. Diffusion was prolonged in both groups, presumably due to the healing process of lungs contusion. Both showed no restriction disorders.

CONCLUSION: Chest wall reconstruction, including plate osteosynthesis of the sternum in combination with transsternal fixation of the 5th rib on both sides can largely restore physiological respiratory mechanics immediately after surgery and accelerate the weaning success. In the management of patients after CPR, the initial diagnosis which had indicated resuscitation, is the main focus and can often be an obstacle to extubation. Nevertheless, independent breathing can be accelerated by restoring the biomechanics through early surgical treatment using CWR and saves long-term ICU stays with the potential for further complication and resource consumption. CWR forms the essential basis for early rehabilitation of the underlying cause of resuscitation. Ventilation disorders do not occur after surgical CWR, even during the course of the procedure.},
}

Humans
*Cardiopulmonary Resuscitation/adverse effects
Male
*Flail Chest/surgery/etiology
Female
Middle Aged
Retrospective Studies
*Thoracic Wall/surgery
*Rib Fractures/surgery
Sternum/injuries/surgery
Adult
*Plastic Surgery Procedures/methods
*Fracture Fixation, Internal/methods
Aged
Length of Stay/statistics & numerical data
*Thoracic Injuries/surgery
Germany
Bone Plates
Treatment Outcome

@article {pmid40024955,
year = {2025},
author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M},
title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {46},
number = {7},
pages = {2985-2994},
pmid = {40024955},
issn = {1590-3478},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Randomized Controlled Trials as Topic ; *Neuroprotective Agents/adverse effects/therapeutic use ; Treatment Outcome ; Hydroxylamines ; },
abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.

METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.

RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD = 0.4495; 95% CI: -0.39, 1.27; p = 0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD = 1.00; 95% CI: -2.68, 4.67; p = 0.60), increase in transaminases (RR = 1.05; 95% CI: 0.19, 5.70; p = 0.95), mortality rate (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), and adverse events (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), showed no statistically significant differences between the groups.

CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Randomized Controlled Trials as Topic
*Neuroprotective Agents/adverse effects/therapeutic use
Treatment Outcome
Hydroxylamines

@article {pmid40025240,
year = {2025},
author = {Maier, A and Kettemann, D and Weyen, U and Grehl, T and Schulte, PC and Steinbach, R and Rödiger, A and Weydt, P and Petri, S and Wolf, J and Grosskreutz, J and Koch, JC and Weishaupt, JH and Rosseau, S and Norden, J and Körtvélyessy, P and Koch, B and Holm, T and Hildebrandt, B and Schumann, P and Walter, B and Riitano, A and Münch, C and Meyer, T and Spittel, S},
title = {Provision, cough efficacy and treatment satisfaction of mechanical insufflation-exsufflation in a large multicenter cohort of patients with amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {7360},
pmid = {40025240},
issn = {2045-2322},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Cough/therapy/etiology ; Male ; Female ; Middle Aged ; *Insufflation/methods ; Aged ; *Patient Satisfaction ; Treatment Outcome ; Longitudinal Studies ; Germany ; Adult ; },
abstract = {In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights the symptomatic and palliative potential of MI-E therapy for ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology
*Cough/therapy/etiology
Male
Female
Middle Aged
*Insufflation/methods
Aged
*Patient Satisfaction
Treatment Outcome
Longitudinal Studies
Germany
Adult

@article {pmid40027570,
year = {2025},
author = {Giorgio, A and Ciracì, E and De Luca, M and Stella, G and Giorgio, V},
title = {Hepatic abscess and hydatid liver cyst: European infectious disease point of view.},
journal = {World journal of hepatology},
volume = {17},
number = {2},
pages = {103325},
pmid = {40027570},
issn = {1948-5182},
abstract = {This manuscript is based on a recent study by Pillay et al that was published in recently. Liver abscesses can be caused by rare potentially life-threatening infections of either bacterial or parasitic origin. The incidence rate in Europe is lower than in developing countries, but it is a major complication with high morbidity, particularly in immunocompromised patients. They are most frequently caused by Enterobacterales infections, but hypervirulent Klebsiella strains are an emerging problem in Western countries. Amoebiasis has been a public health problem in Europe, primarily imported from other endemic foci. At the same time, this infection is becoming an emerging disease, as the number of infected patients who have not traveled to endemic areas is rising. Treatment options for hydatid liver cyst include chemotherapy, open or laparoscopic surgery, percutaneous treatment (percutaneous aspiration, re-aspiration and injection and its modification) and ''wait and watch'' strategy. Most hydatid liver cyst patients in Pillay et al's study received surgical treatment, but several studies have confirmed the safety and efficacy of percutaneous aspiration, re-aspiration and injection.},
}

@article {pmid40029136,
year = {2025},
author = {Revi, N and Nandeshwar, M and Harijan, D and Sankaranarayanan, SA and Joshi, M and Prabusankar, G and Rengan, AK},
title = {Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.},
journal = {ACS chemical neuroscience},
volume = {16},
number = {6},
pages = {1103-1116},
doi = {10.1021/acschemneuro.4c00791},
pmid = {40029136},
issn = {1948-7193},
mesh = {*Microglia/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Animals ; *DNA-Binding Proteins/metabolism/antagonists & inhibitors ; Humans ; Mice ; *Acridines/pharmacology/chemistry ; *Benzimidazoles/pharmacology/chemistry ; Molecular Docking Simulation ; *Neuroprotective Agents/pharmacology ; Cell Polarity/drug effects ; },
abstract = {Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.},
}

*Microglia/drug effects/metabolism
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy
Animals
*DNA-Binding Proteins/metabolism/antagonists & inhibitors
Humans
Mice
*Acridines/pharmacology/chemistry
*Benzimidazoles/pharmacology/chemistry
Molecular Docking Simulation
*Neuroprotective Agents/pharmacology
Cell Polarity/drug effects

@article {pmid40030015,
year = {2025},
author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB},
title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {10},
pages = {e2402117122},
pmid = {40030015},
issn = {1091-6490},
support = {AG061708//HHS | National Institutes of Health (NIH)/ ; S10 OD032367/OD/NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; AG050492//HHS | National Institutes of Health (NIH)/ ; },
mesh = {*Amyloid beta-Peptides/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Neurons/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Mice ; Autophagy/drug effects ; Protein Aggregation, Pathological/drug therapy/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Lysosomes/metabolism ; Protein Aggregates/drug effects ; },
abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.},
}

*Amyloid beta-Peptides/metabolism
Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
Neurons/metabolism/drug effects
Hippocampus/metabolism/drug effects
Mice
Autophagy/drug effects
Protein Aggregation, Pathological/drug therapy/metabolism
Alzheimer Disease/metabolism/drug therapy
Lysosomes/metabolism
Protein Aggregates/drug effects

@article {pmid40030850,
year = {2025},
author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L},
title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.},
journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control},
volume = {72},
number = {2},
pages = {191-201},
doi = {10.1109/TUFFC.2024.3525143},
pmid = {40030850},
issn = {1525-8955},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A}}
$) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A}}
$ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A}}
$ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A}}
$ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.},
}

Animals
*Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics
Mice
Disease Models, Animal
Mice, Transgenic
*Ultrasonic Therapy/methods
Superoxide Dismutase-1/genetics
Disease Progression
Muscle, Skeletal/physiopathology
Male
Motor Cortex
Humans
Elasticity Imaging Techniques

@article {pmid40033250,
year = {2025},
author = {Lu, C and Huang, XX and Huang, M and Liu, C and Xu, J},
title = {Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {82},
pmid = {40033250},
issn = {1471-2377},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Mendelian Randomization Analysis/methods ; *Proteomics/methods ; Genome-Wide Association Study ; *Blood Proteins/genetics/metabolism ; Biomarkers/blood ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive.

OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment.

METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis.

RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.

CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.},
}

*Amyotrophic Lateral Sclerosis/genetics/blood
Humans
*Mendelian Randomization Analysis/methods
*Proteomics/methods
Genome-Wide Association Study
*Blood Proteins/genetics/metabolism
Biomarkers/blood

@article {pmid40038221,
year = {2025},
author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK},
title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.},
journal = {Journal of neurovirology},
volume = {31},
number = {1},
pages = {1-15},
pmid = {40038221},
issn = {1538-2443},
mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; },
abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.},
}

Humans
*HIV Infections/drug therapy/complications/virology
Male
Middle Aged
*Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology
Female
Adult
*Motor Neuron Disease/virology/drug therapy
Viral Load
CD4 Lymphocyte Count
Anti-HIV Agents/therapeutic use

@article {pmid40041912,
year = {2025},
author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB},
title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {1},
pages = {15-34},
pmid = {40041912},
issn = {2211-3835},
abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.},
}

@article {pmid40044193,
year = {2025},
author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA},
title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.},
journal = {BMJ open},
volume = {15},
number = {3},
pages = {e097372},
pmid = {40044193},
issn = {2044-6055},
support = {K23 HD110710/HD/NICHD NIH HHS/United States ; KL2 TR002346/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Female ; Humans ; Academic Medical Centers ; *Chronic Pain/therapy/etiology ; *Endometriosis/therapy/complications ; *Pain Management/methods ; Pain Measurement ; *Patient Care Team ; *Pelvic Pain/therapy/etiology ; Pilot Projects ; Quality of Life ; Randomized Controlled Trials as Topic ; },
abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.

METHODS AND ANALYSIS: This is a hybrid type 1 effectiveness-implementation mixed-methods RCT in which 60 participants will be randomised using computer-generated random numbers stratified by group in the ratio 1:1 to PEEPS plus usual versus educational handout plus usual care. The primary outcome is change in pain interference from baseline to intervention completion. Secondary outcomes include change in pain interference from baseline to 6 months and 12 months postintervention, as well as change in other quality-of-life measures as measured by nine validated questionnaires from baseline to completion, 6 months and 12 months. Proctor et al's Implementation Outcomes Framework will be used to evaluate acceptability, appropriateness and feasibility of PEEPS implementation, and the Consolidated Framework for Implementation Research will be used to guide the evaluation of barriers and facilitators of PEEPS at the patient and provider levels. Primary data analyses will follow the intention-to-treat principle. Descriptive statistics and two-sample t-tests for normally distributed values and Wilcoxon Rank-Sum test were performed for non-normally distributed values. Frequency analysis and Fisher's exact or χ[2] tests will be used for categoric variables as appropriate. Longitudinal analysis of the primary and secondary outcomes will be conducted with a mixed-effects model to investigate the effect of PEEPS compared with education. Least square means (LSMs) and the corresponding 95% CIs at each timepoint, as well as LSM differences and 95% CIs between any post-baseline and baseline will be provided for the outcomes. ORs and 95% CIs will be calculated for categorical outcomes. Qualitative data will be collected in the form of open-ended feedback, focus groups with programme completers and semistructured interviews with participants who complete two or fewer sessions. The analysis will use an embedded design-experimental model in which quantitative and qualitative outcomes will occur concurrently with weight priority given to quantitative data.

ETHICS AND DISSEMINATION: This trial was approved by the Washington University in St. Louis Institutional Review Board (protocol 202402082) on 27 March 2024 and has low risk of harm to participants. All deidentified data from this project will be shared via Digital Commons@Becker. The findings of this study will be disseminated via scientific meetings and peer-reviewed journals. The results and conclusions will be summarised for patients and the public in common language using infographics to make the findings accessible. This pilot RCT will yield the effect size for PEEPS and generate implementation context and outcomes data to guide PEEPS application to real-world practice. If PEEPS proves to be effective, this study will inform adaptation and scaling to improve the lives of people with endometriosis through a non-hormonal, fertility-preserving approach.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT06549985.},
}

Adult
Female
Humans
Academic Medical Centers
*Chronic Pain/therapy/etiology
*Endometriosis/therapy/complications
*Pain Management/methods
Pain Measurement
*Patient Care Team
*Pelvic Pain/therapy/etiology
Pilot Projects
Quality of Life
Randomized Controlled Trials as Topic

@article {pmid40056503,
year = {2025},
author = {Zhan, A and Zhong, K and Zhang, K},
title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.},
journal = {Biochemical and biophysical research communications},
volume = {756},
number = {},
pages = {151582},
doi = {10.1016/j.bbrc.2025.151582},
pmid = {40056503},
issn = {1090-2104},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Homeostasis ; Mitochondria/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
Humans
*Proteostasis
Animals
Homeostasis
Mitochondria/metabolism

@article {pmid40057669,
year = {2025},
author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX},
title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.},
journal = {Therapeutic innovation & regulatory science},
volume = {59},
number = {3},
pages = {519-526},
pmid = {40057669},
issn = {2168-4804},
mesh = {*Drug Development/legislation & jurisprudence ; Humans ; *Biomarkers ; United States ; United States Food and Drug Administration ; Drug Approval ; },
abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.},
}

*Drug Development/legislation & jurisprudence
Humans
*Biomarkers
United States
United States Food and Drug Administration
Drug Approval

@article {pmid40061972,
year = {2025},
author = {Yi, XM and Cai, HQ and Jiao, Y},
title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {2},
pages = {100257},
pmid = {40061972},
issn = {1948-9366},
abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.},
}

@article {pmid40064491,
year = {2025},
author = {Izumi, Y and Nakayama, Y},
title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {3},
pages = {259-263},
doi = {10.11477/mf.188160960770030259},
pmid = {40064491},
issn = {1881-6096},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Humans ; *Communication ; },
abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.},
}

*Amyotrophic Lateral Sclerosis/diagnosis/psychology
Humans
*Communication

@article {pmid40064496,
year = {2025},
author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ},
title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.},
journal = {eNeuro},
volume = {12},
number = {3},
pages = {},
pmid = {40064496},
issn = {2373-2822},
mesh = {Animals ; *Electroacupuncture/methods ; Cyclophosphamide ; *Hyperalgesia/therapy/metabolism/physiopathology/etiology ; *Brain-Derived Neurotrophic Factor/metabolism ; Signal Transduction/physiology ; *Receptor, trkB/metabolism ; Female ; *Cystitis/chemically induced/therapy/metabolism/physiopathology ; Rats, Sprague-Dawley ; Down-Regulation ; Disease Models, Animal ; Rats ; *Urinary Bladder/physiopathology/metabolism ; *Membrane Glycoproteins/metabolism ; },
abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.},
}

Animals
*Electroacupuncture/methods
Cyclophosphamide
*Hyperalgesia/therapy/metabolism/physiopathology/etiology
*Brain-Derived Neurotrophic Factor/metabolism
Signal Transduction/physiology
*Receptor, trkB/metabolism
Female
*Cystitis/chemically induced/therapy/metabolism/physiopathology
Rats, Sprague-Dawley
Down-Regulation
Disease Models, Animal
Rats
*Urinary Bladder/physiopathology/metabolism
*Membrane Glycoproteins/metabolism

@article {pmid40067754,
year = {2025},
author = {, and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S},
title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.},
journal = {JAMA neurology},
volume = {82},
number = {4},
pages = {333-343},
pmid = {40067754},
issn = {2168-6157},
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; *Enzyme Inhibitors/therapeutic use ; Treatment Outcome ; },
abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.

Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.

RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.

CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.

TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.},
}

Adult
Aged
Female
Humans
Male
Middle Aged
*Amyotrophic Lateral Sclerosis/drug therapy
Double-Blind Method
*Enzyme Inhibitors/therapeutic use
Treatment Outcome

@article {pmid40067755,
year = {2025},
author = {, and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , },
title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.},
journal = {JAMA},
volume = {333},
number = {13},
pages = {1128-1137},
pmid = {40067755},
issn = {1538-3598},
abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.

Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.

INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.

RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).

CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.},
}

@article {pmid40067821,
year = {2025},
author = {, and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , },
title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.},
journal = {JAMA},
volume = {333},
number = {13},
pages = {1138-1149},
pmid = {40067821},
issn = {1538-3598},
support = {U24 NS095871/NS/NINDS NIH HHS/United States ; },
abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.

CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.

RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).

CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.},
}

@article {pmid40069959,
year = {2025},
author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C},
title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {5-6},
pages = {389-398},
doi = {10.1080/21678421.2025.2475893},
pmid = {40069959},
issn = {2167-9223},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Humans ; *Minimal Clinically Important Difference ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Quality of Life ; },
abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/diagnosis
Humans
*Minimal Clinically Important Difference
Randomized Controlled Trials as Topic
Treatment Outcome
Quality of Life

@article {pmid40076771,
year = {2025},
author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C},
title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076771},
issn = {1422-0067},
support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; },
mesh = {*Edaravone/chemistry/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Polyethylene Glycols/chemistry ; Drug Carriers/chemistry ; Cell Line, Tumor ; },
abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.},
}

*Edaravone/chemistry/pharmacology/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy
Humans
*Nanoparticles/chemistry
*Drug Delivery Systems/methods
Polyethylene Glycols/chemistry
Drug Carriers/chemistry
Cell Line, Tumor

@article {pmid40089090,
year = {2025},
author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X},
title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.},
journal = {Cellular signalling},
volume = {131},
number = {},
pages = {111715},
doi = {10.1016/j.cellsig.2025.111715},
pmid = {40089090},
issn = {1873-3913},
mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/pathology ; DNA Methylation ; Animals ; Histones/metabolism ; RNA, Untranslated/genetics/metabolism ; Chromatin Assembly and Disassembly ; },
abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.},
}

Humans
*Epigenesis, Genetic
*Neurodegenerative Diseases/genetics/therapy/pathology
DNA Methylation
Animals
Histones/metabolism
RNA, Untranslated/genetics/metabolism
Chromatin Assembly and Disassembly

@article {pmid40090808,
year = {2025},
author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP},
title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.},
journal = {Trends in endocrinology and metabolism: TEM},
volume = {36},
number = {11},
pages = {1029-1042},
doi = {10.1016/j.tem.2025.02.004},
pmid = {40090808},
issn = {1879-3061},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Energy Metabolism/physiology ; Animals ; Mitochondria/metabolism ; Motor Neurons/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.},
}

*Amyotrophic Lateral Sclerosis/metabolism
Humans
*Energy Metabolism/physiology
Animals
Mitochondria/metabolism
Motor Neurons/metabolism

@article {pmid40091916,
year = {2025},
author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F},
title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.},
journal = {Cureus},
volume = {17},
number = {2},
pages = {e78903},
pmid = {40091916},
issn = {2168-8184},
abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.},
}

@article {pmid40092960,
year = {2025},
author = {Liu, Y and Li, XF},
title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {3},
pages = {100463},
pmid = {40092960},
issn = {1948-5204},
abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.},
}

@article {pmid40095345,
year = {2025},
author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A},
title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.},
journal = {Molecular neurobiology},
volume = {62},
number = {7},
pages = {9190-9215},
pmid = {40095345},
issn = {1559-1182},
mesh = {*Exosomes/metabolism ; Humans ; *Neurodegenerative Diseases/therapy/diagnosis/metabolism/drug therapy ; *Biomarkers/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; },
abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.},
}

*Exosomes/metabolism
Humans
*Neurodegenerative Diseases/therapy/diagnosis/metabolism/drug therapy
*Biomarkers/metabolism
Animals
Blood-Brain Barrier/metabolism
Drug Delivery Systems

@article {pmid40097075,
year = {2025},
author = {Cuevas, EP and Madruga, E and Valenzuela-Martínez, I and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A},
title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.},
journal = {Neurobiology of disease},
volume = {208},
number = {},
pages = {106871},
doi = {10.1016/j.nbd.2025.106871},
pmid = {40097075},
issn = {1095-953X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/diagnosis ; *MicroRNAs/metabolism/genetics ; Biomarkers/metabolism ; Middle Aged ; Female ; *Lymphocytes/metabolism ; Male ; Aged ; Superoxide Dismutase-1/genetics ; Adult ; High-Throughput Nucleotide Sequencing ; },
abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/metabolism/diagnosis
*MicroRNAs/metabolism/genetics
Biomarkers/metabolism
Middle Aged
Female
*Lymphocytes/metabolism
Male
Aged
Superoxide Dismutase-1/genetics
Adult
High-Throughput Nucleotide Sequencing

@article {pmid40097762,
year = {2025},
author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH},
title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.},
journal = {Molecular neurobiology},
volume = {62},
number = {7},
pages = {9216-9239},
pmid = {40097762},
issn = {1559-1182},
mesh = {*Amyotrophic Lateral Sclerosis/diet therapy/microbiology ; Humans ; *Diet, Ketogenic/methods ; *Gastrointestinal Microbiome/physiology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Brain/metabolism ; *Nutrients/therapeutic use ; *Neuroprotection ; *Brain-Gut Axis/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.},
}

*Amyotrophic Lateral Sclerosis/diet therapy/microbiology
Humans
*Diet, Ketogenic/methods
*Gastrointestinal Microbiome/physiology
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
*Brain/metabolism
*Nutrients/therapeutic use
*Neuroprotection
*Brain-Gut Axis/physiology

@article {pmid40099353,
year = {2025},
author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV},
title = {Cutting-edge insights: line-field confocal optical coherence tomography and 5% cyclosporine for early lichen sclerosus treatment.},
journal = {Dermatology reports},
volume = {17},
number = {4},
pages = {},
pmid = {40099353},
issn = {2036-7392},
abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting the genital area. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. [...].},
}

@article {pmid40099804,
year = {2025},
author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z},
title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {3},
pages = {e70316},
pmid = {40099804},
issn = {1755-5949},
support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; },
mesh = {Humans ; Double-Blind Method ; Male ; Female ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Middle Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; Aged ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Adult ; *Prefrontal Cortex ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.

METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10 Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6 months post-treatment, and 12 months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.

RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74 ± 6.39 to 81.98 ± 6.51 and 79.22 ± 6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p = 0.031, p = 0.042). The Zarit score also significantly decreased from 57.65 ± 3.42 to 52.24 ± 3.34 and 56.42 ± 3.41 at the 3-month and 6-month post-treatment time points, respectively (p = 0.003, p = 0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6 months' follow-up.

CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.},
}

Humans
Double-Blind Method
Male
Female
*Amyotrophic Lateral Sclerosis/therapy/complications/psychology
*Transcranial Magnetic Stimulation/methods
Middle Aged
*Cognitive Dysfunction/therapy/etiology/psychology
Aged
*Dorsolateral Prefrontal Cortex/physiology
Treatment Outcome
Adult
*Prefrontal Cortex

@article {pmid40100796,
year = {2025},
author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J},
title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.},
journal = {Journal of medicinal chemistry},
volume = {68},
number = {6},
pages = {6558-6575},
doi = {10.1021/acs.jmedchem.4c03127},
pmid = {40100796},
issn = {1520-4804},
mesh = {Animals ; *Armadillo Domain Proteins/antagonists & inhibitors/metabolism ; Mice ; *Cytoskeletal Proteins/antagonists & inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Drug Discovery ; Male ; },
abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.},
}

Animals
*Armadillo Domain Proteins/antagonists & inhibitors/metabolism
Mice
*Cytoskeletal Proteins/antagonists & inhibitors/metabolism
Humans
Structure-Activity Relationship
Drug Discovery
Male

@article {pmid40100917,
year = {2025},
author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S},
title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319866},
pmid = {40100917},
issn = {1932-6203},
mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; *Sesquiterpenes/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Superoxide Dismutase-1 ; Superoxide Dismutase/genetics/metabolism ; Cells, Cultured ; },
abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.},
}

Animals
*Microglia/drug effects/metabolism/pathology
*Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy
*Motor Neurons/drug effects/metabolism/pathology
*Neuroprotective Agents/pharmacology
*Sesquiterpenes/pharmacology
Mice
*Astrocytes/drug effects/metabolism
Superoxide Dismutase-1
Superoxide Dismutase/genetics/metabolism
Cells, Cultured

@article {pmid40105198,
year = {2025},
author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , },
title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.},
journal = {Muscle & nerve},
volume = {71},
number = {6},
pages = {1032-1042},
pmid = {40105198},
issn = {1097-4598},
support = {//Immunity Pharma/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; Neurofilament Proteins/blood ; *Proto-Oncogene Proteins c-akt/metabolism ; Treatment Outcome ; Disease Progression ; Adult ; },
abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.

METHODS: Nine participants with ALS and a progression rate > 0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.

RESULTS: The mean ± SD duration of IPL344 follow-up was 14.0 ± 12.5 months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean ± SE slope of decline in ALSFRS-R was -0.53 ± 0.15 (48% slower progression vs. historical controls, p = 0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p = 0.034), with increased rather than reduced body weight (p = 0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p = 0.04). Plasma NfL concentrations were lowered by 27% (n = 6). Unadjusted median survival for participants in the IPL344 group was 43.4 months [95% CI: 20.5, NA] compared with 19.1 months [17.4, 23.0] in the historical control group.

DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/blood
Male
Female
Middle Aged
Aged
Neurofilament Proteins/blood
*Proto-Oncogene Proteins c-akt/metabolism
Treatment Outcome
Disease Progression
Adult

@article {pmid40105291,
year = {2025},
author = {Ozeki-Hayashi, R and Wilkinson, DJC},
title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.},
journal = {AJOB empirical bioethics},
volume = {16},
number = {3},
pages = {172-184},
pmid = {40105291},
issn = {2329-4523},
support = {203132/WT_/Wellcome Trust/United Kingdom ; 203132/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Tracheostomy/ethics ; United Kingdom ; Qualitative Research ; Japan ; *Cross-Cultural Comparison ; United States ; *Personal Autonomy ; Female ; *Respiration, Artificial/ethics ; Male ; *Decision Making/ethics ; *Clinical Decision-Making/ethics ; Middle Aged ; *Physicians ; Adult ; Attitude of Health Personnel ; },
abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.

METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n = 7), the UK (n = 5), and the US (n = 4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.

RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.

CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
*Tracheostomy/ethics
United Kingdom
Qualitative Research
Japan
*Cross-Cultural Comparison
United States
*Personal Autonomy
Female
*Respiration, Artificial/ethics
Male
*Decision Making/ethics
*Clinical Decision-Making/ethics
Middle Aged
*Physicians
Adult
Attitude of Health Personnel

@article {pmid40116017,
year = {2025},
author = {Addy, G and Scirocco, E and Gelevski, D and Rohrer, M and Roderick, A and McCormack, M and Weiss Sadan, A and Scalia, J and Parikh, N and Giacomelli, E and Locatelli, M and Neel, DV and D'Agostino, D and Leite, A and Yu, H and Sherman, AV and Mock, J and Kalmes, A and Luppino, S and Babu, S and Berry, J and Cudkowicz, M and Paganoni, S},
title = {An Expanded Access Protocol of RNS60 in Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {72},
number = {1},
pages = {124-129},
pmid = {40116017},
issn = {1097-4598},
support = {T32 GM144273/GM/NIGMS NIH HHS/United States ; //The study drug was provided at no cost by Revalesio, and program costs were covered by philanthropic donations to the Sean M. Healey & AMG Center for ALS/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Middle Aged ; Male ; Female ; Aged ; Adult ; Pilot Projects ; Nebulizers and Vaporizers ; Treatment Outcome ; },
abstract = {AIMS: RNS60 is an investigational product in clinical development for amyotrophic lateral sclerosis (ALS). RNS60 slowed disease progression in the ALS SOD1[G93A] mouse model and was safe and well tolerated both in an open-label pilot study and a randomized, placebo-controlled, multicenter phase 2 trial in people living with ALS. The objective of this ongoing expanded access protocol (EAP) was to provide RNS60 to people living with ALS who are ineligible for controlled clinical trials and to collect data on the safety and tolerability of dosing RNS60 via twice-daily nebulization rather than the previously studied daily nebulization with weekly intravenous administration.

METHODS: Eligible participants (≥ 18 years old, diagnosed with ALS per investigator assessment, and ineligible for an ALS clinical trial testing RNS60) were treated with twice-daily nebulization of RNS60 at home. Safety was evaluated by the assessment of adverse events and routine safety labs.

RESULTS: A total of 84 participants have been treated with RNS60 via nebulization twice daily for up to 48 months so far. The most common treatment-related adverse event was increased secretions [N = 27 (32%)]. Serious adverse events (SAEs) [69 occurrences; N = 38 (45%) with at least one SAE] and deaths [N = 24 (28%)] were deemed not related to RNS60.

DISCUSSION: This EAP supports the benign side effect profile of RNS60 when administered via twice-daily nebulization and demonstrates the feasibility of long-term EAPs as a complementary approach to controlled trials in people with advanced ALS.},
}

*Amyotrophic Lateral Sclerosis/drug therapy
Humans
Middle Aged
Male
Female
Aged
Adult
Pilot Projects
Nebulizers and Vaporizers
Treatment Outcome

@article {pmid40116361,
year = {2025},
author = {Li, C and Noonan, AM and Hays, J and Roychowdhury, S and Malalur, P and Elkhatib, R and Manne, A and Mittra, A and Rahman, S and Yan, L and Hill, K and Abbott, N and Phelps, M and Na, JY and Liang, B and Storts, H and Khan, M and Zhang, EH and Miles, W and Yildiz, V and Wei, L and Wang, JJ and Jin, N},
title = {Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase I Clinical Trial.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {31},
number = {11},
pages = {2115-2123},
pmid = {40116361},
issn = {1557-3265},
support = {K12 CA133250/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA273924/CA/NCI NIH HHS/United States ; K12CA133250//Paul Calabresi Career Development Award for Clinical Oncology/ ; },
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Bevacizumab/administration & dosage ; *Colorectal Neoplasms/drug therapy/pathology/mortality ; Fluorouracil/administration & dosage ; Leucovorin/administration & dosage ; Neoplasm Metastasis ; Organoplatinum Compounds/administration & dosage ; Riluzole/administration & dosage ; Treatment Outcome ; },
abstract = {PURPOSE: Colorectal cancer is the second leading cause of cancer-related mortality in the United States. Chemotherapies based on 5-fluorouracil (5-FU), when combined with targeted agents, remain the standard of care for patients with metastatic or locally advanced disease. New treatment strategies are needed for patients with metastatic colorectal cancer with microsatellite stable disease. Preclinical studies have shown that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-fluorouracil to reduce cell viability in colorectal cancer cell lines.

PATIENTS AND METHODS: In this single-arm, phase I trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic colorectal cancer, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLFOX6/bevacizumab for eight cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapies.

RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients had previously received FOLFOX, and five patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, nine had stable disease, and one had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% confidence interval, 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively.

CONCLUSIONS: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic colorectal cancer and may have clinical activity in patients whose disease is resistant to FOLFOX.},
}

Adult
Aged
Female
Humans
Male
Middle Aged
*Antineoplastic Combined Chemotherapy Protocols/administration & dosage
Bevacizumab/administration & dosage
*Colorectal Neoplasms/drug therapy/pathology/mortality
Fluorouracil/administration & dosage
Leucovorin/administration & dosage
Neoplasm Metastasis
Organoplatinum Compounds/administration & dosage
Riluzole/administration & dosage
Treatment Outcome

@article {pmid40124885,
year = {2025},
author = {Dethier, C and Azirar, S and Verluyten, L and Boonen, H and Grosber, M and Gutermuth, J},
title = {Response to Fässler et al's "Successful treatment of refractory folliculitis decalvans with apremilast".},
journal = {JAAD case reports},
volume = {57},
number = {},
pages = {122-123},
pmid = {40124885},
issn = {2352-5126},
}

@article {pmid40125702,
year = {2025},
author = {Madhavan, S and Deshmukh, S and Cummings, M and Doshi, A and Rezania, K and Freels, S and Sawa, G},
title = {Home-Based Tele-tDCS in Amyotrophic Lateral Sclerosis: Feasibility, Safety, and Preliminary Efficacy.},
journal = {Annals of clinical and translational neurology},
volume = {12},
number = {5},
pages = {1022-1033},
pmid = {40125702},
issn = {2328-9503},
support = {R21 HD102722/HD/NICHD NIH HHS/United States ; R21HD102722//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; Middle Aged ; Pilot Projects ; Double-Blind Method ; Feasibility Studies ; Aged ; *Transcranial Direct Current Stimulation/methods/adverse effects ; Telemedicine ; Adult ; Disease Progression ; Treatment Outcome ; },
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Transcranial direct current stimulation (tDCS) shows promise as a neuromodulatory intervention in various neurological disorders, but its application in ALS, particularly in a remote, home-based format, remains underexplored. This study investigates the feasibility, safety, and preliminary efficacy of remotely supervised tele-tDCS in ALS patients.

METHODS: This double-blinded pilot study included 14 spinal-onset ALS participants randomized into two groups: the intervention group received 72 tele-tDCS sessions over 24 weeks, and the delayed-start group received 36 sham sessions followed by 36 tele-tDCS sessions. Stimulation was delivered at 2 mA for 20 min 3 times a week. Primary outcomes included feasibility, safety, and disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Adherence and adverse effects were monitored throughout.

RESULTS: Ten participants completed the study, with an overall compliance rate of 98.3%. No serious adverse events were reported, and mild side effects, like itching and tingling, were consistent with tDCS literature. The intervention group demonstrated a significantly slower decline in ALSFRS-R scores than the delayed-start group. At 24 weeks, the intervention group had a mean ALSFRS-R change of -1.7, compared to -13.6 in the delayed-start group (p = 0.0018). Additionally, the change in ALSFRS-R between pre- and mid-intervention significantly differed between groups (p = 0.0071).

INTERPRETATION: Tele-tDCS was feasible, safe, and well-tolerated in individuals with ALS. Preliminary efficacy results suggest that tele-tDCS may slow disease progression, underscoring the potential of tele-tDCS as a promising home-based neuromodulatory intervention in ALS management.

TRIAL REGISTRATION: Clinical trial registration: NCT04866771.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
Female
Male
Middle Aged
Pilot Projects
Double-Blind Method
Feasibility Studies
Aged
*Transcranial Direct Current Stimulation/methods/adverse effects
Telemedicine
Adult
Disease Progression
Treatment Outcome

@article {pmid40125959,
year = {2025},
author = {Gupta, U and Kumar, A and Alam, MI and Balaji, PG and Sharma, A and Yadav, AK},
title = {Synthesis and characterization of protein nanohybrid systems for the brain delivery of Riluzole.},
journal = {Therapeutic delivery},
volume = {16},
number = {6},
pages = {569-579},
pmid = {40125959},
issn = {2041-6008},
mesh = {Humans ; *Riluzole/administration & dosage/chemistry ; Cell Survival/drug effects ; Particle Size ; *Brain/metabolism/drug effects ; Animals ; *Serum Albumin, Bovine/chemistry ; *Fullerenes/chemistry ; *Nanoparticles/chemistry ; Cell Line, Tumor ; *Neuroprotective Agents/administration & dosage/chemistry ; Drug Delivery Systems ; Drug Carriers/chemistry ; },
abstract = {AIMS: Synthesis and Characterization of Protein NanoHybrid Systems for the Brain Delivery of Riluzole.

METHODS/MATERIALS: Fullerene is converted into carboxylated fullerene (CF) and then, prepared RZU-loaded BSA nanoparticles conjugated with CF.

RESULTS: The particle size and zeta potential of RZU-PNH were found to be 210 ± 1.15 nm and -18.5 ± 0.615 mV respectively, and entrapment efficiency and loading efficiency of RZU-PNH were found to be 98.8 ± 0.53% and 11.6 ± 0.43%, respectively. The XRD of the RZU-PNH shows the amorphism behavior and CD revealed that secondary structure of the protein mainly consists of α-helix andβ-sheet. The MTT assay showed 88.60% and 90.84% cell viability in both SH-SY5Yand N2a cell lines at a concentration of 20 μg/ml and also, no significant nasal ciliotoxicity was observed after incubation with RZU-PNH.

CONCLUSIONS: Obtained results indicated RZU-PNH formulation to treat amyotrophic lateral sclerosis.},
}

Humans
*Riluzole/administration & dosage/chemistry
Cell Survival/drug effects
Particle Size
*Brain/metabolism/drug effects
Animals
*Serum Albumin, Bovine/chemistry
*Fullerenes/chemistry
*Nanoparticles/chemistry
Cell Line, Tumor
*Neuroprotective Agents/administration & dosage/chemistry
Drug Delivery Systems
Drug Carriers/chemistry

@article {pmid40126464,
year = {2025},
author = {Shefner, JM and Cudkowicz, ME and Genge, A and Hardiman, O and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and de Carvalho, M and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and van den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA and , },
title = {Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {82},
number = {5},
pages = {477-485},
pmid = {40126464},
issn = {2168-6157},
support = {UL1 TR002369/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; *Oxadiazoles/therapeutic use ; Disease Progression ; Pyrazines ; Pyrimidines ; Imidazoles ; Pyrroles ; Pyridines ; },
abstract = {IMPORTANCE: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.

OBJECTIVE: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.

A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.

INTERVENTIONS: Oral reldesemtiv, 300 mg, or placebo twice daily.

MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 24.

RESULTS: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).

CONCLUSIONS AND RELEVANCE: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04944784.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Male
Female
Middle Aged
Double-Blind Method
Aged
Treatment Outcome
*Oxadiazoles/therapeutic use
Disease Progression
Pyrazines
Pyrimidines
Imidazoles
Pyrroles
Pyridines

@article {pmid40128246,
year = {2025},
author = {Hu, X and Wei, M and Zhang, H and Yu, M and Wang, M and Zhou, B and Luo, Y and Li, B},
title = {The experience of pain symptoms in patients with amyotrophic lateral sclerosis: a qualitative study.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {10183},
pmid = {40128246},
issn = {2045-2322},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Pain/psychology/etiology/physiopathology ; Qualitative Research ; Pain Management ; Adaptation, Psychological ; Adult ; Pain Measurement ; },
abstract = {ALS is a progressive neurodegenerative disease that has a serious impact on patients and their caregivers. For a long time in the past, ALS was considered a painless disease that was largely ignored by clinicians. Describing the complexity and needs of pain symptoms from the perspective of patients can provide the most intuitive direction for future research. The purpose of our research is to explore the experience of pain symptoms in patients with amyotrophic lateral sclerosis (ALS), provide reference for better understanding of pain symptoms in ALS patients. From April 2023 to May 2023, 27 patients experiencing pain symptoms in Peking University Third Hospital who met the diagnostic criteria of "Chinese Guidelines for the Diagnosis and Treatment of amyotrophic lateral sclerosis" were interviewed by means of objective sampling. The content analysis method was used to describe the pain changes since the disease (amyotrophic lateral sclerosis), the factors that aggravate the pain, the measures to cope with the pain and the needs. The interview results included 3 themes and 11 subthemes. (1) Pain is diverse: the type of pain, the time when pain occurs, the change in pain intensity, and the factors that aggravate pain; (2) Individualized pain coping measures: posture adjustment, medication, physical therapy, warmth, emotional regulation; (3) Patients lack of understanding of pain: insufficient source of knowledge, the single orientation of the solution. The nature, location and aggravating factors of pain in amyotrophic lateral sclerosis patients in China are complicated, which should be paid attention to by clinical staff and scientific researchers. The situation of pain management is not optimistic, and the pain of the vast majority of patients has not been effectively alleviated. It is necessary to realize the importance of self-management and care of others in coping with pain, and conduct further research in the future to find a breakthrough in pain relief, so as to strengthen pain intervention in clinical practice.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/psychology/physiopathology
Male
Female
Middle Aged
Aged
*Pain/psychology/etiology/physiopathology
Qualitative Research
Pain Management
Adaptation, Psychological
Adult
Pain Measurement

@article {pmid40128823,
year = {2025},
author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X},
title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {14},
pmid = {40128823},
issn = {2047-9158},
support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; },
mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; },
abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.},
}

Humans
*Retroelements/genetics
*Aging/genetics
*Nervous System Diseases/genetics
Animals

@article {pmid40129929,
year = {2025},
author = {Liang, F and Sun, Y and Yang, J and Shen, Z and Wang, G and Zhu, J and Zhou, C and Xia, Y},
title = {Gut microbiome is associated with radiotherapy response in lung cancer patients with brain metastases.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1562831},
pmid = {40129929},
issn = {2235-2988},
mesh = {Humans ; *Gastrointestinal Microbiome/radiation effects ; Male ; Female ; *Lung Neoplasms/radiotherapy/pathology ; Middle Aged ; *Brain Neoplasms/radiotherapy/secondary ; Aged ; Feces/microbiology ; RNA, Ribosomal, 16S/genetics ; *Bacteria/classification/genetics/isolation & purification ; Treatment Outcome ; DNA, Bacterial/genetics/chemistry ; },
abstract = {PURPOSE: To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.

METHODS AND MATERIALS: This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and α-diversity, β-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.

RESULTS: No significant difference in α-diversity was observed between the groups (P > 0.05), but β-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.

CONCLUSIONS: The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.},
}

Humans
*Gastrointestinal Microbiome/radiation effects
Male
Female
*Lung Neoplasms/radiotherapy/pathology
Middle Aged
*Brain Neoplasms/radiotherapy/secondary
Aged
Feces/microbiology
RNA, Ribosomal, 16S/genetics
*Bacteria/classification/genetics/isolation & purification
Treatment Outcome
DNA, Bacterial/genetics/chemistry

@article {pmid40134643,
year = {2025},
author = {Guo, YX and Yan, X and Liu, XC and Liu, YX and Liu, C},
title = {Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease.},
journal = {World journal of nephrology},
volume = {14},
number = {1},
pages = {100825},
pmid = {40134643},
issn = {2220-6124},
abstract = {In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.},
}

@article {pmid40135522,
year = {2025},
author = {Bai, D and Fang, Y and Tian, J and Liao, Y and Liu, M and Pan, L},
title = {Tribenuron-methyl resistance in Capsella bursa-pastoris: the co-existence of ALS target enzyme mutation (Pro-197-Ser) and overexpression of GSTF12 and ADP/ATP carrier protein.},
journal = {Pest management science},
volume = {81},
number = {8},
pages = {4365-4372},
doi = {10.1002/ps.8794},
pmid = {40135522},
issn = {1526-4998},
support = {//Scientific Research Fund of Hunan Provincial Education Department/ ; //National Natural Science Foundation of China/ ; //National Key Research and Development Program of China/ ; //China Agriculture Research System/ ; //Modern Agricultural Industrial Technology System of Hunan Province/ ; },
mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; *Arylsulfonates/pharmacology ; Mutation ; *Capsella/genetics/drug effects/enzymology ; *Plant Proteins/genetics/metabolism ; },
abstract = {BACKGROUND: Capsella bursa-pastoris, a prevalent wheat-field weed in China, demonstrates substantial resistance to tribenuron-methyl, a herbicide-targeting acetolactate synthase (ALS). Understanding weed herbicide-resistance mechanisms is crucial for managing resistant weed populations. However, the genes potentially involved in nontarget-site resistance (NTSR) in herbicide-resistant C. bursa-pastoris remain poorly understood and require further investigation. This research aimed to elucidate the resistance level and underlying mechanisms of a field population (R) from Shandong Province, China, to tribenuron-methyl.

RESULTS: Whole-plant bioassays revealed that the relative resistance index (RI) of the R population was 54-fold greater than that of the tribenuron-methyl-sensitive population (S). Additionally, treatment with the cytochrome P450 (CYP450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially mitigated the resistance of the R population to tribenuron-methyl. Sequencing of the ALS target enzyme identified a substitution of proline (CCT) at position 197 with serine (TCT). RNA sequencing combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) verification identified upregulation of a candidate GST gene (GSTF12) and an ADP/ATP carrier protein in the R population. Heterologous expression of the two candidate genes in yeast cells demonstrated enhanced growth in the presence of tribenuron-methyl.

CONCLUSION: We first identified that, in tribenuron-methyl-resistant C. bursa-pastoris, the Pro-197-Ser mutation in the ALS gene, along with GSTF12 and ADP/ATP carrier protein overexpression, jointly mediate its resistance. This enhances our understanding of herbicide-resistance mechanisms and offers a novel perspective for managing tribenuron-methyl-resistant weeds in agricultural practices. © 2025 Society of Chemical Industry.},
}

*Herbicide Resistance/genetics
*Herbicides/pharmacology
*Acetolactate Synthase/genetics/metabolism
*Arylsulfonates/pharmacology
Mutation
*Capsella/genetics/drug effects/enzymology
*Plant Proteins/genetics/metabolism

@article {pmid40135631,
year = {2025},
author = {Novy, C and Tysnes, OB and Busk, ØL and Jaioun, K and Holmøy, T and Holla, ØL and Høyer, H},
title = {Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {5-6},
pages = {566-572},
doi = {10.1080/21678421.2024.2447922},
pmid = {40135631},
issn = {2167-9223},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Norway/epidemiology ; Female ; Middle Aged ; Aged ; *Genetic Predisposition to Disease/genetics ; Cohort Studies ; *Motor Neurons/pathology ; *Nerve Tissue Proteins/genetics ; *Polymorphism, Single Nucleotide/genetics ; Genotype ; Gene Frequency ; Adult ; },
abstract = {Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
Male
Norway/epidemiology
Female
Middle Aged
Aged
*Genetic Predisposition to Disease/genetics
Cohort Studies
*Motor Neurons/pathology
*Nerve Tissue Proteins/genetics
*Polymorphism, Single Nucleotide/genetics
Genotype
Gene Frequency
Adult

@article {pmid40135721,
year = {2025},
author = {Fayaz, MU and Wang, Q and Xu, M and Chen, D and Pan, F and Song, C},
title = {Compressive Strain-Induced Uphill Hydrogen Distribution in Strontium Ferrite Films.},
journal = {ACS applied materials & interfaces},
volume = {17},
number = {14},
pages = {21371-21379},
doi = {10.1021/acsami.4c21825},
pmid = {40135721},
issn = {1944-8252},
abstract = {Hydrogen incorporation into metal oxides enhances their electrochemical properties, making them highly suitable for various energy conversion applications. The controlled distribution of hydrogen ions in material systems and their conduction at elevated temperatures have garnered significant attention for various energy storage and environmental monitoring applications, including fuel cells, smart windows, and sensor technologies. In this work, cost-effective, high-concentration hydrogen-doped SrFeO3-δ (HSrFeO3-δ) films were prepared under ambient conditions by treating Al(s)|SrFeO3-δ(s) films with KOH(aq), utilizing electron-proton codoping to investigate hydrogen distribution. The uphill hydrogen distributions in SrFeO3-δ films with compressive strain, in contrast to the density gradient behavior under tensile strain, suggest the fundamental role of the strain states in the hydrogen accommodation. Compressively strained films with a rich Al source follow an anomalous uphill feature of hydrogen distribution, highlighting their potential use as electrolyte for fuel cells. The strain significantly influences the structure, chemical lattice coupling, and consequently the ionic transport in SrFeO3-δ. Ionic conductivity measurements reveal that compressively strained HSrFeO3-δ films with uphill hydrogen distributions exhibit a significant ionic conductivity of 0.189 S/cm at 413 K, with an activation energy of approximately 0.29 eV, making them suitable for low-temperature electrochemical applications. These findings provide a promising approach for tuning material properties and valuable insights for building iontronic devices.},
}

@article {pmid40137226,
year = {2025},
author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C},
title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {11},
number = {3},
pages = {},
pmid = {40137226},
issn = {2309-608X},
abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.},
}

@article {pmid40138872,
year = {2025},
author = {Liang, T and Jiang, T and Liang, Z and Li, L and Chen, Y and Chen, T and Yang, L and Zhang, N and Dong, B and Xie, X and Gu, B and Wu, Q},
title = {Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China.},
journal = {Microbiological research},
volume = {296},
number = {},
pages = {128145},
doi = {10.1016/j.micres.2025.128145},
pmid = {40138872},
issn = {1618-0623},
mesh = {*Diabetes Mellitus, Type 2/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Staphylococcus aureus/enzymology/genetics/metabolism ; *Amino Acids, Branched-Chain/biosynthesis ; *Acetolactate Synthase/metabolism/genetics ; Humans ; Animals ; Mice ; China ; Male ; Insulin Resistance ; Female ; Middle Aged ; *Glycemic Control ; Blood Glucose ; Feces/microbiology ; Staphylococcal Infections/microbiology ; Metagenomics ; Prediabetic State/microbiology ; Metabolomics ; Insulin ; },
abstract = {An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.},
}

*Diabetes Mellitus, Type 2/microbiology/metabolism
*Gastrointestinal Microbiome/physiology
*Staphylococcus aureus/enzymology/genetics/metabolism
*Amino Acids, Branched-Chain/biosynthesis
*Acetolactate Synthase/metabolism/genetics
Humans
Animals
Mice
China
Male
Insulin Resistance
Female
Middle Aged
*Glycemic Control
Blood Glucose
Feces/microbiology
Staphylococcal Infections/microbiology
Metagenomics
Prediabetic State/microbiology
Metabolomics
Insulin

@article {pmid40140966,
year = {2025},
author = {Balaban, E and Köse, TE and Günaçar, DN and Naralan, ME and Gonca, M},
title = {Comparison of methods for detecting mandibular lingula and can antilingula be used in lingula mandibula detection?.},
journal = {BMC oral health},
volume = {25},
number = {1},
pages = {430},
pmid = {40140966},
issn = {1472-6831},
support = {02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; },
mesh = {Humans ; Female ; Male ; Retrospective Studies ; Adult ; *Cone-Beam Computed Tomography/methods ; Middle Aged ; *Mandible/diagnostic imaging/anatomy & histology/surgery ; Aged ; Adolescent ; Young Adult ; Aged, 80 and over ; *Orthognathic Surgical Procedures/methods ; Anatomic Landmarks ; Mandibular Nerve ; },
abstract = {OBJECTIVE: The aim of this study is to evaluate the relationship between anatomical reference points used during orthognathic surgery and to minimize the risks of iatrogenic neurovascular damage.

MATERIALS AND METHODS: This retrospective study included cone-beam computed tomography (CBCT) images involving the mandible from patients who visited Recep Tayyip Erdoğan University Faculty of Dentistry between January 2018 and September 2023. The age range of the included individuals was set between 18 and 80 years. Horizontal and vertical distances between mandibular anatomical structures, such as the lingula mandibula (LM), mandibular foramen (MF), antilingula (AL), and surrounding structures were measured using CBCT software. Individuals with intraosseous pathology, insufficient image quality, or a history of surgical/orthodontic treatment were excluded from the study.

RESULTS: A total of 240 hemimandibles from 120 patients were analyzed (55.83% female, 44.17% male; mean age: 46.78 ± 15.30 years). Significant differences were identified in LM positions according to different AL types. The LM was found to be more inferior and posterior relative to hill and ridge type ALs, while it was more anterior relative to plateau type ALs. In 26.25% of mandibular rami, AL was not detected.

CONCLUSION: The position of the AL can serve as a guide in determining the osteotomy line during inferior vertical ramus osteotomy (IVRO). However, relying solely on AL as a reference point may increase the risk of inferior alveolar nerve (IAN) injury. Preoperative tomographic evaluations to determine the relationships among LM, MF, and AL can provide a safer approach in surgical planning, reduce complications, and help protect neurovascular structures.},
}

Humans
Female
Male
Retrospective Studies
Adult
*Cone-Beam Computed Tomography/methods
Middle Aged
*Mandible/diagnostic imaging/anatomy & histology/surgery
Aged
Adolescent
Young Adult
Aged, 80 and over
*Orthognathic Surgical Procedures/methods
Anatomic Landmarks
Mandibular Nerve

@article {pmid40141987,
year = {2025},
author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT},
title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {6},
pages = {},
pmid = {40141987},
issn = {1420-3049},
mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/etiology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Polyphenols/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; Iron/metabolism ; },
abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.},
}

*Ferroptosis/drug effects
Humans
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/etiology
*Neuroprotective Agents/pharmacology/therapeutic use
*Polyphenols/pharmacology/therapeutic use
Animals
Reactive Oxygen Species/metabolism
Lipid Peroxidation/drug effects
Mitochondria/metabolism/drug effects
Oxidative Stress/drug effects
Iron/metabolism

@article {pmid40143051,
year = {2025},
author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H},
title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.},
journal = {Pharmaceutics},
volume = {17},
number = {3},
pages = {},
pmid = {40143051},
issn = {1999-4923},
support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; },
abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.},
}

@article {pmid40145977,
year = {2026},
author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J},
title = {Potential targets of microglia in the treatment of neurodegenerative diseases: Mechanism and therapeutic implications.},
journal = {Neural regeneration research},
volume = {21},
number = {4},
pages = {1497-1511},
pmid = {40145977},
issn = {1673-5374},
abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial over-activation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.},
}

@article {pmid40148057,
year = {2025},
author = {De Marchi, F and Spinelli, EG and Bendotti, C},
title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Handbook of clinical neurology},
volume = {210},
number = {},
pages = {45-67},
doi = {10.1016/B978-0-443-19102-2.00004-1},
pmid = {40148057},
issn = {0072-9752},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology/metabolism ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology
*Frontotemporal Dementia/pathology
*Neuroglia/pathology/metabolism
Animals

@article {pmid40149599,
year = {2025},
author = {Yang, W and Xiao, W and Liu, X and Li, H and Huang, T and Fan, D},
title = {Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.},
journal = {Biomedicines},
volume = {13},
number = {3},
pages = {},
pmid = {40149599},
issn = {2227-9059},
support = {82071426//National Natural Science Foundation of China/ ; },
abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.},
}

@article {pmid40150989,
year = {2025},
author = {Matsumoto, S and Tateishi-Karimata, H and Ohyama, T and Sugimoto, N},
title = {Controlling the Local Conformation of RNA G-Quadruplex Results in Reduced RNA/Peptide Cytotoxic Accumulation Associated with C9orf72 ALS/FTD.},
journal = {Small methods},
volume = {9},
number = {6},
pages = {e2401630},
doi = {10.1002/smtd.202401630},
pmid = {40150989},
issn = {2366-9608},
mesh = {*G-Quadruplexes/drug effects ; Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA/chemistry/metabolism/genetics ; *Peptides/metabolism/chemistry ; *Frontotemporal Dementia/genetics/metabolism ; Cell Line, Tumor ; DNA Repeat Expansion ; Nucleic Acid Conformation ; },
abstract = {Repeat expansion of d(G4C2) in the noncoding region of the C9orf72 gene contributes to neurodegenerative diseases. The repeat expansion transcript r(G4C2) induces RNA/peptide accumulation, which, in turn, induces cytotoxicity and accelerates the development of neurodegenerative diseases. Such cytotoxic accumulation is triggered by peptide aggregation. Here, a technique is developed to prevent accumulation by regulating RNA interactions, assuming that RNA structure is important for peptide interactions. A screening method is used to identify compounds that suppress RNA accumulation of r(G4C2) repeats. The four compounds are identified with wide π-planes containing hydroxyl, methoxy, and cyclic ether groups that suppressed RNA accumulation. Interestingly, these compounds also suppressed RNA/peptide accumulation in neuroblastoma cells, indicating that RNA accumulation is a key regulator of RNA/peptide cytotoxic aggregate formation. In vitro and in silico physicochemical analyses reveal that these compounds bind to the loop region of the G-quadruplex via hydrogen bonds or CH-π interactions, resulting in an altered loop conformation. Importantly, these conformational changes inhibited RNA G-quadruplex associations. These results show that conformational changes are promising for controlling the interactions between G-quadruplexes and further RNA accumulation. These findings may be useful in the development of therapeutic strategies for the treatment of neurodegenerative diseases.},
}

*G-Quadruplexes/drug effects
Humans
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/metabolism
*RNA/chemistry/metabolism/genetics
*Peptides/metabolism/chemistry
*Frontotemporal Dementia/genetics/metabolism
Cell Line, Tumor
DNA Repeat Expansion
Nucleic Acid Conformation

@article {pmid40151398,
year = {2025},
author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM},
title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {1},
pages = {e70073},
pmid = {40151398},
issn = {2352-8737},
support = {R01 AG031311/AG/NIA NIH HHS/United States ; U01 AG066722/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.

RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.

DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.},
}

@article {pmid40151753,
year = {2025},
author = {Carqueja, I and Montenegro Sá, F and Monteiro, S},
title = {Ventricular Arrhythmias Caused by Left Main Coronary Artery Vasospasm: A Diagnostic Challenge in a Cardiac Arrest Victim.},
journal = {Cureus},
volume = {17},
number = {2},
pages = {e79554},
pmid = {40151753},
issn = {2168-8184},
abstract = {Sudden cardiac death (SCD) is a common cause of cardiovascular deaths. It may be caused by primary electrical diseases, cardiomyopathies, myocarditis, valvular heart diseases, or coronary artery disease (including acute coronary syndrome). Coronary artery vasospasm is defined as a transient total or subtotal coronary artery obstruction, associated with angina symptoms and ischemic findings on electrocardiogram (ECG). It is a cause of myocardial infarction, life-threatening arrhythmias, atrioventricular block, and SCD. A 55-year-old man presented to the hospital after an out-of-hospital cardiac arrest (OHCA). He had a previous history of cardiovascular risk factors, excessive alcohol intake, non-obstructive coronary artery disease, and paroxysmic atrial fibrillation. On the day of the OHCA, he had a sudden collapse while exercising, with ventricular fibrillation and return of spontaneous circulation (ROSC) after advanced life support (ALS). No ECG or echocardiographic anomalies were identified on hospital admission. The patient suffered three more episodes of cardiac arrest during the hospital stay, with atypical arrhythmic presentations. No ECG or echocardiographic abnormalities were observed after ROSC. The fourth cardiac arrest had concomitant segmental ST changes and de novoechocardiographic segmental motility abnormalities suggestive of left main coronary artery occlusion. These findings were transient, with a normal ECG and echocardiogram obtained one hour after ROSC. No electrolyte abnormalities or other causes of cardiac arrest were identified. The hypothesis of left main coronary vasospasm was raised as the likely diagnosis. Coronary artery vasospasm is a possible cause of major cardiac events. Diagnosis can be challenging due to the transient findings and varied manifestations, often in patients with normal coronary arteries. The correct diagnosis and treatment of coronary artery vasospasm can have a determinant effect on prognosis and mortality, as appropriate treatment can lead to prolonged event-free survival. Provocative coronary vasospasm tests performed in patients with atypical cardiovascular manifestations can allow for the timely diagnosis of vasospasm and avoid critical events. The authors aim to raise awareness of the different clinical presentations of coronary artery vasospasm and its consequences. The performance of provocative tests in selected patients should be considered to promote early diagnosis and potentially avoid major events.},
}