@article {pmid42842169, year = {2026}, author = {Singh, RK and Banerjee, C and Mehan, S}, title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {}, pmid = {42842169}, issn = {1557-1904}, mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; }, abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.}, } @article {pmid42844308, year = {2026}, author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU}, title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {42844308}, issn = {1432-1912}, abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.}, } @article {pmid42833279, year = {2026}, author = {Szeligowski, T and Ie, A and Kiraly, P and Hu, M and Ivanova, T and Jalil, A and Sergouniotis, P and Black, G and Wong, SC and Patel, CK and Henderson, R and Xue, K}, title = {Genetics, management and clinical outcomes in familial exudative vitreoretinopathy (FEVR): a multicentre retrospective cohort.}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2962-8394}, pmid = {42833279}, issn = {1439-3999}, abstract = {in English Background Familial exudative vitreoretinopathy (FEVR) is a group of inherited retinal diseases characterised by abnormal retinal angiogenesis and peripheral non-perfusion. While over 10 genes have been implicated in FEVR, genotype-phenotype correlations and their clinical significance are incompletely understood. Here we describe a retrospective cohort of FEVR patients and assess the impact of defined genetic variants on protein structure, disease severity, inter-ocular variability, as well as treatment choices and visual outcomes. Methods Retrospective cohort of 51 patients with FEVR across three UK paediatric retina centres. All data was obtained from routine clinical records. Standard FEVR staging system was used throughout. Identified genetic variants were checked against genomic databases (ClinVar, GnomAD, UniProt), and their structural impact was examined using in silico algorithms (MutationTaster and PolyPhen2) to determine the likelihood of pathogenicity. Results 51 patients were included, with variants identified in FZD4 (n=16), LRP5 (n=13), TSPAN12 (n=11), KIF11 (n=6), NDP (n=4), and CTNNB1 (n=1). In silico analysis identified 11 variants not previously reported in FEVR, seven of which were classified as likely pathogenic. NDP variants were associated with the most severe and asymmetrical disease. Management included conservative monitoring (45 eyes), retinal laser photocoagulation (39 eyes), and surgical interventions (12 eyes), with the majority of patients achieving stable or improved visual acuity in all treatment groups. Conclusion This study demonstrates significant diversity among FEVR patients with regards to genetic variants, clinical presentation, and visual outcomes. Understanding genotype-phenotype correlations in FEVR may be crucial for developing novel treatment strategies. ABSTRACT in German Hintergrund Die familiäre exsudative Vitreoretinopathie (FEVR) ist eine Gruppe erblicher Netzhauterkrankungen, die durch eine abnorme retinale Angiogenese und eine periphere Minderperfusion gekennzeichnet ist. Obwohl mehr als 10 Gene mit FEVR in Verbindung gebracht wurden, sind Genotyp-Phänotyp-Korrelationen und deren klinische Bedeutung nur unvollständig verstanden. In dieser Arbeit beschreiben wir eine retrospektive Kohorte von FEVR-Patienten und untersuchen den Einfluss definierter genetischer Varianten auf die Proteinstruktur, den Krankheitsschweregrad, die interokuläre Variabilität sowie auf Behandlungsentscheidungen und visuelle Ergebnisse. Methoden Retrospektive Kohorte von 51 Patienten mit FEVR aus drei pädiatrischen Netzhautzentren im Vereinigten Königreich. Alle Daten wurden aus routinemäßigen klinischen Aufzeichnungen gewonnen. Durchgehend wurde das Standard-FEVR-Staging-System verwendet. Die identifizierten genetischen Varianten wurden mit genomischen Datenbanken (ClinVar, GnomAD, UniProt) abgeglichen, und ihre strukturelle Auswirkung wurde mittels In-silico-Algorithmen (MutationTaster und PolyPhen2) untersucht, um die Wahrscheinlichkeit einer Pathogenität zu bestimmen. Ergebnisse Es wurden 51 Patienten eingeschlossen, wobei Varianten in FZD4 (n=16), LRP5 (n=13), TSPAN12 (n=11), KIF11 (n=6), NDP (n=4) und CTNNB1 (n=1) identifiziert wurden. Die In-silico-Analyse identifizierte 11 zuvor nicht im Zusammenhang mit FEVR beschriebene Varianten, von denen sieben als wahrscheinlich pathogen eingestuft wurden. NDP-Varianten waren mit der schwersten und asymmetrischsten Erkrankung assoziiert. Das Management umfasste konservative Überwachung (45 Augen), retinale Laserphotokoagulation (39 Augen) und chirurgische Eingriffe (12 Augen), wobei die Mehrheit der Patienten in allen Behandlungsgruppen eine stabile oder verbesserte Sehschärfe erreichte. Schlussfolgerung Diese Studie zeigt eine erhebliche Vielfalt unter FEVR-Patienten hinsichtlich genetischer Varianten, klinischer Präsentation und visueller Ergebnisse. Das Verständnis der Genotyp-Phänotyp-Korrelationen bei FEVR könnte entscheidend für die Entwicklung neuartiger Behandlungsstrategien sein.}, } @article {pmid42836993, year = {2026}, author = {Al Khleifat, A and Malaspina, A and Kirby, J and Tree, T and Shaw, PJ and Leigh, PN and Al-Chalabi, A}, title = {TRICALS risk score augments but cannot replace neurofilament as a prognostic biomarker in ALS.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42836993}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Neurofilament Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Prognosis ; Female ; Male ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with substantial clinical heterogeneity, complicating the design and interpretation of clinical trials. Two strategies have been proposed to address this variability: phenotype-based prognostic modelling and biomarker-based stratification using neurofilaments. We aimed to determine whether a widely used phenotype-based method, the TRICALS risk score, could substitute for neurofilament biomarkers in a clinical trial.

METHODS: We used data from the MIROCALS phase 2b randomised controlled trial of low-dose interleukin-2 in ALS (n = 220). The TRICALS risk score was calculated for each participant. The published biomarker model includes CSF phosphorylated neurofilament heavy chain (pNFH) and a pNFH × treatment interaction. We analysed the effects of replacing CSF pNFH with the TRICALS risk score and of adding TRICALS score as an additional covariate to the original model. Model performance was assessed using likelihood ratio χ[2] statistics and - 2 log likelihood (- 2LL). The primary outcome was survival.

RESULTS: TRICALS risk score was moderately correlated with CSF pNFH (r = 0.357), explaining 12.7% of shared variance. Substituting CSF pNFH with TRICALS score reduced model performance (- 2LL 928.25 vs 793.36). The TRICALS × treatment interaction was statistically significant (hazard ratio [HR] 0.72, 95% CI 0.54-0.96 p = 0.025), but contributed modestly to model fit (Δχ[2] = 4.76), compared with the pNFH × treatment interaction (Δχ[2] = 14.24). Incorporating the pNFH × treatment interaction significantly improved model fit and identified a treatment effect (HR 0.28, 95% CI 0.12-0.63; p = 0.002).

CONCLUSIONS: The TRICALS risk score does not substitute for CSF neurofilament biomarkers as a prognostic or stratification variable but provides complementary information.}, } @article {pmid42840744, year = {2026}, author = {Mouraux, C and Santana, MM and Rosenthal, LS and Cortese, A and Santorelli, FM and Opal, P and Coarelli, G}, title = {The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag313}, pmid = {42840744}, issn = {2632-1297}, abstract = {The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich's ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich's ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.}, } @article {pmid42826761, year = {2026}, author = {Shai, Y and Alam, M and Dong, X and Zhang, Y and Hu, Y and He, Z and Feng, J and Chen, Y and Zhou, Z and Jiang, H}, title = {Mdivi-1 regulates mitochondrial fission and function via the CaMK2/Drp1 pathway in amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {617}, number = {}, pages = {107-117}, doi = {10.1016/j.neuroscience.2026.10.002}, pmid = {42826761}, issn = {1873-7544}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive motor neuron loss. Given the high energy reliance of motor neurons, mitochondrial dysfunction especially excessive fission critically contributes to disease pathogenesis. Mitochondrial division inhibitor-1 (Mdivi-1), an inhibitor of the fission protein Drp1, has shown neuroprotective potential, but its mechanism of action on mitochondrial quality control in ALS remains unclear. Here, we examined the effects of Mdivi-1 on mitochondrial dysfunction and cell injury in NSC34 cells expressing mutant SOD1^G93A and in SOD1^G93A transgenic mice. ALS models exhibited increased reactive oxygen species accumulation, reduced mitochondrial content, loss of mitochondrial membrane potential, enhanced apoptotic signaling, and increased phosphorylation of CaMK2 and Drp1. Mdivi-1 treatment improved cell viability, reduced oxidative stress, restored mitochondrial integrity and membrane potential, and suppressed apoptosis. In addition, Mdivi-1 decreased Drp1 phosphorylation, whereas co-treatment with the CaMK2 activator DCP-LA partially reversed these effects. Furthermore, direct inhibition of CaMK2 with KN93 reduced CaMK2 and Drp1 phosphorylation, providing additional evidence that CaMK2 regulates Drp1 activation in SOD1^G93A cells. These findings indicate that pharmacological modulation of the CaMK2/Drp1 pathway can attenuate aberrant mitochondrial fission and associated cellular dysfunction in ALS models.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @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.}, } @article {pmid40153582, year = {2024}, author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F}, title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.}, journal = {Aging and disease}, volume = {16}, number = {4}, pages = {2293-2314}, pmid = {40153582}, issn = {2152-5250}, mesh = {Humans ; *Nerve Growth Factor/therapeutic use ; Animals ; *Nervous System Diseases/therapy/drug therapy ; History, 20th Century ; History, 21st Century ; }, abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.}, } @article {pmid40157434, year = {2025}, author = {Pu, L and Steele, JR and Phillips, CR and Violi, JP and Rodgers, KJ}, title = {The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {106}, number = {}, pages = {106058}, doi = {10.1016/j.tiv.2025.106058}, pmid = {40157434}, issn = {1879-3177}, mesh = {*Amino Acids, Diamino/toxicity ; Humans ; Cyanobacteria Toxins ; *Serine/biosynthesis ; Energy Metabolism/drug effects ; Cell Line, Tumor ; Proteomics ; Neuroblastoma/metabolism ; *Aminobutyrates/toxicity ; *Bacterial Toxins/toxicity ; }, abstract = {Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.}, } @article {pmid40161216, year = {2025}, author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D}, title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf114}, pmid = {40161216}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.}, } @article {pmid40162390, year = {2025}, author = {Xie, Y and Xie, H and Wang, RL}, title = {Enhancing palliative care in malignant obstructive jaundice: A critical care perspective on endoscopic biliary stenting.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {3}, pages = {103431}, pmid = {40162390}, issn = {1948-9366}, abstract = {This letter responds to Wang et al's recent publication on endoscopic biliary stenting for malignant obstructive jaundice (MOJ) by offering constructive feedback and suggestions for future research. We commend the authors for their comprehensive study design and execution, which included a clear delineation of study groups and a robust set of outcome measures. We suggest that future studies incorporate additional biomarkers, such as serum levels of liver enzymes and bilirubin, to provide a more nuanced understanding of liver function changes post-intervention. The study's focus on short-term survival rates is appreciated, but we recommend exploring longer-term follow-up periods to capture the full spectrum of survival outcomes. Additionally, the inclusion of quality of life assessments using validated instruments could offer a more holistic view of patient outcomes. From a critical care perspective, we advocate for the integration of advanced imaging techniques to better characterize biliary anatomy and potentially predict treatment response or complications. We believe that incorporating these suggestions could enhance the understanding of endoscopic biliary stenting's role in MOJ management and its impact on patient outcomes, influencing future clinical guidelines and practice.}, } @article {pmid40163151, year = {2025}, author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS}, title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {398}, number = {9}, pages = {11357-11386}, pmid = {40163151}, issn = {1432-1912}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/physiopathology/therapy ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; Oxidative Stress ; }, abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.}, } @article {pmid40166719, year = {2025}, author = {Xiong, J and Chen, X and Huang, K and Pan, Y}, title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.}, journal = {Clinical, cosmetic and investigational dermatology}, volume = {18}, number = {}, pages = {735-741}, pmid = {40166719}, issn = {1178-7015}, abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.}, } @article {pmid40169452, year = {2025}, author = {Hou, X and Jiang, J and Deng, M}, title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {304}, pmid = {40169452}, issn = {1432-1459}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/diagnosis ; *Epigenesis, Genetic ; Biomarkers/metabolism ; DNA Methylation ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.}, } @article {pmid40169538, year = {2025}, author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA}, title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.}, journal = {Biochemistry}, volume = {64}, number = {8}, pages = {1698-1719}, pmid = {40169538}, issn = {1520-4995}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *Myasthenia Gravis/genetics/therapy/pathology/metabolism ; *Rare Diseases/genetics/therapy ; *Huntington Disease/genetics/therapy/pathology/metabolism ; Animals ; }, abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.}, } @article {pmid40169784, year = {2025}, author = {Simonini, C and Zucchi, E and Martinelli, I and Gianferrari, G and Lunetta, C and Sorarù, G and Trojsi, F and Pepe, R and Piras, R and Giacchino, M and Banchelli, F and Mandrioli, J}, title = {Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11034}, pmid = {40169784}, issn = {2045-2322}, support = {Ricerca Corrente funding scheme of the Italian Ministry of Health//Ministero della Salute/ ; Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project)//Università Degli Studi di Modena e Reggio Emila/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; alpha 1-Antitrypsin/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Biomarkers/cerebrospinal fluid/blood ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Disease Progression ; Neurofilament Proteins/cerebrospinal fluid/blood ; *Neuroinflammatory Diseases ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/genetics ; }, abstract = {The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.}, } @article {pmid40170672, year = {2025}, author = {Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Fiecas, M and Walk, D}, title = {Time-to-event prediction in ALS using a landmark modeling approach, using the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {417-425}, doi = {10.1080/21678421.2025.2482943}, pmid = {40170672}, issn = {2167-9223}, support = {R01 FD007630/FD/FDA HHS/United States ; R01-0007630/FD/FDA HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/physiopathology/epidemiology ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Longitudinal Studies ; Time Factors ; Noninvasive Ventilation ; }, abstract = {BACKGROUND AND OBJECTIVES: Times to clinically relevant events are a valuable outcome in observational and interventional studies, complementing linear outcomes such as functional rating scales and biomarkers. In ALS, there are several clinically relevant events. We developed dynamic prediction models for several of these times to events that can be used for clinical trial modeling and personal planning.

METHODS: Landmark time-to-event analysis was implemented to determine the effect of patient characteristics on disease progression. Longitudinal data from 1557 participants in the ALS Natural History Consortium dataset were used. Five outcomes in the ALS disease progression were considered: loss of ambulation, loss of speech, gastrostomy, noninvasive ventilation (NIV) use, and continuous NIV use. Covariates in our models include age at diagnosis, sex, onset location, riluzole use, diagnostic delay, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Internal and external validation techniques were used.

RESULTS: For each of our models and landmark times, we present risk prediction intervals for random sets of patient characteristics. We demonstrate our models' application for an individual's personal predicted time-to-event. Our internal and external validation metrics indicate good concordance and overall performance. The time to loss of speech models perform the best for each metric in terms of both internal and external validation.

DISCUSSION: Landmarking is an efficient, individualized risk prediction model that is intuitive for both clinicians and patients. Importantly, landmarking can be used for clinical trial modeling, personal planning, and development of real-world evidence of the impacts of treatment interventions.}, } @article {pmid40176466, year = {2025}, author = {Zhang, Y and Robinson, K and Xia, Y and Sun, J}, title = {Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut-Neuron Axis.}, journal = {Comprehensive physiology}, volume = {15}, number = {2}, pages = {e70009}, pmid = {40176466}, issn = {2040-4603}, support = {I01BX004824-06//U.S. Department of Veterans Affairs/ ; R01DK134343/NH/NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; I01 BX004824/BX/BLRD VA/United States ; R01DK105118/NH/NIH HHS/United States ; R01DK114126/NH/NIH HHS/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Mice ; *Butyric Acid/pharmacology/therapeutic use ; Disease Progression ; *Neuroprotective Agents/pharmacology ; Male ; Mice, Transgenic ; Drug Synergism ; Disease Models, Animal ; *Neurons/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1[G93A], restores the gut-brain barrier function, and delays ALS progression. SOD1[G93A] mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1[G93A] aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1[G93A] aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.}, } @article {pmid40180646, year = {2025}, author = {Temiz, K and Gul, A and Gov, E}, title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {24}, pmid = {40180646}, issn = {1559-1174}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.}, } @article {pmid40181198, year = {2025}, author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D}, title = {Extracellular vesicles: translational research and applications in neurology.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {5}, pages = {265-282}, pmid = {40181198}, issn = {1759-4766}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Translational Research, Biomedical/methods ; Biomarkers/metabolism ; *Nervous System Diseases/therapy/diagnosis/metabolism ; Animals ; *Neurology/methods/trends ; }, abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.}, } @article {pmid40185536, year = {2025}, author = {Uzgiris, AJ and Ladic, LA and Pfister, SX}, title = {Advances in neurofilament light chain analysis.}, journal = {Advances in clinical chemistry}, volume = {126}, number = {}, pages = {31-71}, doi = {10.1016/bs.acc.2025.01.006}, pmid = {40185536}, issn = {2162-9471}, mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; }, abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.}, } @article {pmid40187044, year = {2025}, author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B}, title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100053}, doi = {10.1016/j.pharmr.2025.100053}, pmid = {40187044}, issn = {1521-0081}, mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Animals ; *Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.}, } @article {pmid40188375, year = {2025}, author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP}, title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.}, journal = {Expert opinion on drug delivery}, volume = {22}, number = {6}, pages = {805-822}, doi = {10.1080/17425247.2025.2489558}, pmid = {40188375}, issn = {1744-7593}, mesh = {Humans ; *Drug Delivery Systems ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Oxidation-Reduction ; Blood-Brain Barrier/metabolism ; Animals ; *Central Nervous System Agents/administration & dosage/pharmacokinetics ; Brain/metabolism ; }, abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.

AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.

EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.}, } @article {pmid40196013, year = {2025}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HK and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Arnold, WD}, title = {Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43[Q331K] mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40196013}, issn = {2693-5015}, support = {R01 AG078129/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging in ALS. This promotes senescent cell accumulation-marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation-disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&Q) in TDP-43[Q331K] ALS mice. D&Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy.}, } @article {pmid40196899, year = {2025}, author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M}, title = {Management Approaches to Spastic Gait Disorders.}, journal = {Muscle & nerve}, volume = {72}, number = {2}, pages = {179-200}, doi = {10.1002/mus.28402}, pmid = {40196899}, issn = {1097-4598}, mesh = {Humans ; *Gait Disorders, Neurologic/therapy/etiology/diagnosis/physiopathology ; *Muscle Spasticity/therapy/complications/physiopathology/diagnosis ; *Disease Management ; }, abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.}, } @article {pmid40198473, year = {2025}, author = {Seok, HY}, title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {8}, pages = {3427-3430}, pmid = {40198473}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; *Free Radical Scavengers/therapeutic use ; Disease Progression ; Riluzole/therapeutic use ; }, abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.}, } @article {pmid40200577, year = {2025}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Perez, KD and Li, D and Cheung, VG and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {HGG advances}, volume = {6}, number = {3}, pages = {100435}, pmid = {40200577}, issn = {2666-2477}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Alleles ; HEK293 Cells ; *Mutation ; *RNA Helicases/genetics ; *Multifunctional Enzymes/genetics ; RNA, Small Interfering/genetics ; *Gene Silencing ; DNA Helicases/genetics ; RNA Interference ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele while sparing the wild-type allele and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.}, } @article {pmid40205152, year = {2025}, author = {Mohan, M and Mannan, A and Singh, TG}, title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {377}, pmid = {40205152}, issn = {1573-4978}, mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; }, abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.}, } @article {pmid40209306, year = {2025}, author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A}, title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {118044}, doi = {10.1016/j.biopha.2025.118044}, pmid = {40209306}, issn = {1950-6007}, mesh = {Humans ; *Receptor, Cannabinoid, CB2/metabolism/agonists ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Endocannabinoids/metabolism ; Molecular Targeted Therapy ; Cannabinoid Receptor Agonists/therapeutic use ; }, abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.}, } @article {pmid40209696, year = {2025}, author = {Nashwan, AJ and Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH}, title = {Clinical Features, Diagnostic Implications, and Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.}, journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre}, volume = {34}, number = {5}, pages = {432-442}, pmid = {40209696}, issn = {1423-0151}, mesh = {Humans ; *Myasthenia Gravis/diagnosis/complications/physiopathology/epidemiology/therapy ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/physiopathology/therapy/epidemiology ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; Male ; }, abstract = {UNLABELLED:

Objective: This review aimed to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.

RESULTS: Forty-two cases were categorized into four groups as follows: the first group had 26 cases with MG onset (age range 26-82 years) preceding ALS (age range 46-83 years). The second group had 9 cases with ALS onset (age range 34-89 years) preceding MG (age range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.

CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.

.}, } @article {pmid40213632, year = {2025}, author = {Dezawa, M}, title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1553382}, pmid = {40213632}, issn = {2296-4185}, abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.}, } @article {pmid40216746, year = {2025}, author = {Rezaei, A and Kocsis-Jutka, V and Gunes, ZI and Zeng, Q and Kislinger, G and Bauernschmitt, F and Isilgan, HB and Parisi, LR and Kaya, T and Franzenburg, S and Koppenbrink, J and Knogler, J and Arzberger, T and Farny, D and Nuscher, B and Katona, E and Dhingra, A and Yang, C and Gouna, G and LaClair, KD and Janjic, A and Enard, W and Zhou, Q and Hagan, N and Ofengeim, D and Beltrán, E and Gokce, O and Simons, M and Liebscher, S and Edbauer, D}, title = {Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3442}, pmid = {40216746}, issn = {2041-1723}, support = {390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 407495230//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 423957469//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 101057649//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 101117710//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {Animals ; Female ; Mice ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Male ; Cholesterol/metabolism ; Humans ; *2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Mice, Transgenic ; Myelin Sheath/metabolism ; Spinal Cord/metabolism/pathology ; Longevity/drug effects/genetics ; }, abstract = {Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.}, } @article {pmid40222103, year = {2025}, author = {Lum, JS and Brown, ML and Farrawell, NE and Bartlett, R and Chisholm, CG and Gorman, J and Dosseto, A and Dux, F and McInnes, LE and Ecroyd, H and McAlary, L and Crouch, PJ and Donnelly, PS and Yerbury, JJ}, title = {A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {115}, number = {}, pages = {105692}, pmid = {40222103}, issn = {2352-3964}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; Organoselenium Compounds/pharmacology/administration & dosage/therapeutic use ; Isoindoles ; Animals ; Mice ; Azoles/pharmacology/administration & dosage ; Cell Line ; Drug Therapy, Combination ; Mutation ; Disease Models, Animal ; Cell Survival/drug effects ; Protein Folding ; Motor Neurons/metabolism/drug effects ; }, abstract = {BACKGROUND: SOD1 mutations are a significant contributor of familial amyotrophic lateral sclerosis (ALS) cases. SOD1 mutations increase the propensity for the protein to misfold and aggregate into insoluble proteinaceous deposits within motor neurons and neighbouring cells. The small molecule, CuATSM, has repeatedly shown in mouse models to be a promising therapeutic treatment for SOD1-associated ALS and is currently in Phase II/III clinical trials for the treatment of ALS. We have previously shown CuATSM stabilises various ALS-associated variants of the SOD1 protein, reducing misfolding and toxicity. Two additional FDA-approved small molecules, ebselen and telbivudine, have also been identified to reduce mutant SOD1 toxicity, providing additional potential therapeutic candidates that could be used in combination with CuATSM. Here, we aimed to investigate if CuATSM, ebselen and telbivudine (CET) polytherapy could improve on the therapeutic efficacy of CuATSM monotherapy for the treatment of SOD1-associated ALS.

METHODS: We utilised a 3D checkerboard approach to investigate whether a matrix of different concentrations CuATSM, ebselen and telbivudine could provide therapeutic improvements on cell survival, SOD1 folding and aggregation in SOD1[G93A]-transfected NSC-34 cells, compared to CuATSM alone. To progress the preclinical development of CET polytherapy, we evaluated the bioavailability and safety of in vivo polytherapy administration. Furthermore, we assessed and compared the effects of CET- and CuATSM-treatment on disease onset, motor function, survival and neuropathological features in SOD1[G93A] mice.

FINDINGS: CET polytherapy reduced inclusion formation and increased cell survival of NSC-34 cells overexpressing SOD1[G93A] compared to higher concentrations of CuATSM monotherapy. In addition, CET administration was bioavailable and tolerable in mice. CET treatment in SOD1[G93A] mice delayed disease onset, reduced motor impairments, and increased survival compared to vehicle- and CuATSM-treated mice. In line with these findings, biochemical analysis of lumbar spinal cords showed CET administration improved SOD1 folding, decreased misfolded SOD1 accumulation, and reduced motor neuron loss.

INTERPRETATION: These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.

FUNDING: This work was supported by a FightMND Drug Development Grant, an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (No. 1194872) and a Motor Neuron Disease Research Institute of Australia Bill Gole Postdoctoral Fellowship.}, } @article {pmid40226510, year = {2025}, author = {Ufarry Alvarado, AJ and Zaidi Pons, MA and Plaza Hernández, J and Torres Ortiz, C}, title = {Improvements of Paraquat Treatment in Liquid Media for Behavior and Neurodegenerative Tests.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40226510}, issn = {2578-9430}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by misfolded and aggregated proteins that have toxic effects on motor neurons. The missense mutation, G85R, of the sod-1 gene associated with ALS displays locomotor impairments in Caenorhadbitis elegans (C. elegans). We treated the sod-1 (G85R) strain with 0 and 2.5 mM Paraquat treatments in a liquid M9 buffer for 4 hours and in solid NGM media for 18 hours. In both methodologies, the locomotion defects and neurodegeneration were significantly increased with 2.5 mM Paraquat. Our work provides evidence of methodology that is more cost effective, rapid and reproducible to perform behavior and neurodegenerative assay in worms.}, } @article {pmid40228660, year = {2025}, author = {Veenstra, J and Ozog, D and Stephens, A}, title = {Response to Barbieri, "Response to Veenstra et al's 'Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {2}, pages = {e71-e72}, doi = {10.1016/j.jaad.2025.03.090}, pmid = {40228660}, issn = {1097-6787}, } @article {pmid40229540, year = {2025}, author = {Ghimire, S and Kreilaus, F and Rosa Porto, R and Anderson, LL and Yerbury, JJ and Arnold, JC and Karl, T}, title = {Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1[G93 A]) mouse model of amyotrophic lateral sclerosis.}, journal = {Psychopharmacology}, volume = {242}, number = {9}, pages = {2077-2095}, pmid = {40229540}, issn = {1432-2072}, mesh = {Animals ; *Cannabidiol/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology/psychology ; Female ; Male ; Mice ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; *Behavior, Animal/drug effects ; Social Behavior ; Administration, Oral ; Prepulse Inhibition/drug effects ; Fear/drug effects ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Superoxide Dismutase ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1[G93A]).

METHODS: Male and female SOD1[G93A] and wild type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.

RESULTS: CBD treatment ameliorated the bodyweight loss in female SOD1[G93A] mice, tended to reinstate sociability in SOD1[G93A] males, strengthened social recognition memory in SOD1[G93A] females, and improved the PPI response in younger SOD1[G93A] females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1[G93A] mice and decreased the acoustic startle response and strengthened cue freezing in male mice.

CONCLUSION: Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1[G93A] mice in a sex specific manner without altering the motor phenotype.}, } @article {pmid40235867, year = {2025}, author = {Sundararaju, U and Rajakumar, HK}, title = {Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {4}, pages = {103128}, pmid = {40235867}, issn = {1948-5204}, abstract = {Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al's systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR's clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR's reliability as a prognostic marker for GC.}, } @article {pmid40237254, year = {2025}, author = {Russek, M and Peltner, J and Haenisch, B}, title = {Supplementing Single-Arm Trials with External Control Arms-Evaluation of German Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {118}, number = {6}, pages = {1443-1450}, pmid = {40237254}, issn = {1532-6535}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Germany ; *Breast Neoplasms/drug therapy ; Female ; *Research Design ; *Clinical Trials as Topic/methods ; Registries ; }, abstract = {As single-arm trials (SATs) are increasingly used in pharmaceutical research, the validity of such study designs needs to be critically assessed. We characterize the feasibility of supplementing SATs with real-world data (RWD)-derived external control arms by determining the proportion of SATs on breast cancer and amyotrophic lateral sclerosis (ALS) for which an external control arm based on RWD can be constructed. The main outcome measure is the number and percentage of trials for which all important eligibility criteria and at least one primary endpoint could be identified in one of five German RWD sources. We surveyed all SATs concerning breast cancer or ALS treatment registered in the European Union's clinical trial registers between 2004 and 2023. Ten out of 379 breast cancer SATs and 2 of 11 ALS SATs could feasibly be supplemented with RWD-derived external control arms, if all important eligibility criteria and a primary endpoint have to be identifiable in the RWD source. Ninety-three breast cancer trials had at least one outcome ascertainable in a RWD source, and 35 trials had all important eligibility criteria recorded in a RWD source. Nine ALS trials had at least one primary endpoint ascertainable in RWD sources, and 2 had all important eligibility criteria recorded in a RWD source. Our study shows that SATs with RWD-derived external control arms will rarely be suitable to establish treatment effects of medicines in the current setting for the investigated phenotypes and that SATs should be designed with limitations of the source of external controls in mind.}, } @article {pmid40244061, year = {2025}, author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T}, title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, pmid = {40244061}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.}, } @article {pmid40250093, year = {2025}, author = {Casiraghi, V and Pellegrini, E and Brusati, A and Peverelli, S and Invernizzi, S and Santangelo, S and Colombrita, C and Verde, F and Ticozzi, N and Silani, V and Ratti, A}, title = {Characterization of human healthy i[3] lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123508}, doi = {10.1016/j.jns.2025.123508}, pmid = {40250093}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics/pathology ; *C9orf72 Protein/genetics ; *Motor Neurons/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells ; *Nerve Tissue Proteins/genetics ; Male ; Genotype ; Female ; Polymorphism, Single Nucleotide/genetics ; Middle Aged ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i[3]LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus as non-disease controls (ND). A chronic and low-dose sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i[3]LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only CSF from UNC13A CC patients induced some ALS-associated pathological features in healthy i[3]LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.}, } @article {pmid40251832, year = {2025}, author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR}, title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.}, journal = {Glia}, volume = {73}, number = {8}, pages = {1627-1641}, pmid = {40251832}, issn = {1098-1136}, support = {R01 NS122973/NS/NINDS NIH HHS/United States ; R01 NS132760/NS/NINDS NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; R01NS122973/NH/NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Fatty Acid-Binding Protein 7/metabolism/genetics ; Mice ; Humans ; *Endotoxemia/metabolism/chemically induced ; Lipopolysaccharides/toxicity ; Cells, Cultured ; Mice, Inbred C57BL ; Male ; Coculture Techniques ; Tumor Suppressor Proteins ; }, abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.}, } @article {pmid40255098, year = {2025}, author = {Regnault, R and Kouach, M and Goossens, L and Thuru, X and Bailly, C and Goossens, JF}, title = {HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {39}, number = {14}, pages = {e10050}, pmid = {40255098}, issn = {1097-0231}, support = {//Comité de l'Oise de la Ligue Contre le Cancer/ ; //French Ligue Against Cancer/ ; }, mesh = {Edaravone/chemistry ; *Mass Spectrometry/methods ; *Oligonucleotides/chemistry/metabolism ; *Pyrimidines/chemistry ; *DNA/chemistry ; *Cytidine/chemistry/analogs & derivatives ; Cytosine/analogs & derivatives ; }, abstract = {RATIONALE: Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis and used as a research tool to explore treatment of neurodegenerative diseases and cancers. It is also a reactive agent, known as PMP (1-phenyl-3-methyl-5-pyrazolone), used for the analysis of polysaccharides composition. EDA can react with sugars and aromatic aldehydes. In this context, we have investigated the reactivity of EDA toward the biologically relevant formylated nucleobases, nucleosides, and an oligonucleotide containing a formylated residue.

METHODS: The formation of both mono- and bis-adducts between EDA and the formylated nucleobases (5-formyluracil (5fU) and 5-formylcytosine (5fC)) or the corresponding nucleosides 5-fdU and 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, the covalent binding of EDA to an 8-mer palindromic oligonucleotide d (TATG[*C]ATA) containing a single 5-fdC residue [*C] under physiological conditions was investigated using mass spectrometry.

RESULTS: For the first time, EDA is shown to react with formylated pyrimidines. Covalent and stable adducts were identified. EDA was found to react efficiently with the formylated oligonucleotide to generate mono- and bis-adducts. The rate of formation of the mono-adduct was five times higher than that of the bis-adduct. The reaction of EDA with aldehydic DNA modifications such as 5fU/5fC may have important consequences in terms of gene expression.

CONCLUSIONS: These observations raise implications for an epigenetic contribution to the mechanism of action of EDA. The biological implications of our in vitro results are discussed, notably in the frame of neurodegenerative diseases and cancers.}, } @article {pmid40261116, year = {2025}, author = {Shneider, NA and Nesta, AV and Rifai, OM and Yasek, J and Elyaman, W and Aziz-Zaman, S and Lyu, MA and Levy, SHS and Hoover, BN and Vlad, G and Huang, M and Zeng, K and Sadeghi, T and Reddy, A and Flowers, CR and Parmar, S}, title = {Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDoa2400249}, doi = {10.1056/EVIDoa2400249}, pmid = {40261116}, issn = {2766-5526}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *T-Lymphocytes, Regulatory/transplantation ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; Treatment Outcome ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.

METHODS: Participants with ALS received infusions of a fixed dose (100×10[6] cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.

RESULTS: Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66±1.03 points/month before treatment, -0.41±0.45/month during treatment, and -0.60±0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1δ (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GROα (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.

CONCLUSIONS: This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.}, } @article {pmid40262277, year = {2025}, author = {Turner, N and Palmer, J and Faull, C and Davidson, S and Turner, MR and Wilson, E}, title = {Tracheostomy ventilation in ALS: healthcare practitioner perspectives on quality of life and implications for decision-making.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {5-6}, pages = {444-451}, doi = {10.1080/21678421.2025.2495014}, pmid = {40262277}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Quality of Life/psychology ; *Tracheostomy/psychology/methods ; Male ; Female ; *Decision Making ; *Health Personnel/psychology ; Qualitative Research ; Middle Aged ; *Attitude of Health Personnel ; *Respiration, Artificial/psychology/methods ; Adult ; }, abstract = {Objectives: This qualitative study aimed to increase understanding of how healthcare practitioners (HCPs) perceive quality of life for people with ALS who use tracheostomy ventilation (TV) and the extent to which such views inform discussions regarding future treatment and care. Methods: A thematic analysis was applied to data derived from online semi-structured interviews with a professionally diverse group of 24 HCPs with experience of supporting people with ALS to use TV. Results: Four main themes relating to TV use emerged: i) Positive benefits; ii) Risks and challenges; iii) Factors influencing HCP perspectives; iv) Concepts informing HCP discussions. HCPs acknowledged that TV has the potential to extend life but were concerned with prolonging a serious decline in physical and cognitive functioning. HCPs tried to identify the 'tipping point' between quantity and quality of life for the individual and their family, taking into account the likelihood of a higher burden of care. HCPs drew on prior experience to assess anticipated quality of life, yet most HCPs in the UK have limited experience of TV for this group. HCPs also drew on principles of person-centered care, patient autonomy and value for money to guide their approach to discussing TV. Conclusions: HCP experience of positive outcomes of TV can foster a more proactive approach to initiating conversations about its potential use. Sharing best practice and improving guidance for HCPs may support early and on-going future care planning and enable people with ALS to make choices which are informed and in their best interests.}, } @article {pmid40262868, year = {2025}, author = {Shi, Y and Wu, Z and Cheng, R and Zhang, L and Guo, X and Li, X and Bi, Y}, title = {The Trp-574-Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Fimbristylis littoralis.}, journal = {Pesticide biochemistry and physiology}, volume = {210}, number = {}, pages = {106385}, doi = {10.1016/j.pestbp.2025.106385}, pmid = {40262868}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Mutation ; Molecular Docking Simulation ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Sulfonylurea Compounds/pharmacology ; Piperonyl Butoxide/pharmacology ; }, abstract = {Fimbristylis littoralis Gaudich., an important weed in Chinese paddy fields, has caused significant yield losses in rice and other crops. Acetolactate synthase (ALS) inhibitors, such as halosulfuron-methyl, are widely used for weed control. This study identified a highly resistant population (R23-1) of F. littoralis to halosulfuron-methyl, with an exceptionally high resistance index (RI) of 3441.66. The resistant mechanisms of F. littoralis to ALS inhibitors have not been reported previously. We employed a comprehensive approach to address this, including whole-plant bioassay, ALS target gene sequencing, molecular docking, synergistic tests with metabolic enzyme inhibitors, glutathione S-transferases (GSTs) activity assays, and cross-resistance testing. The results revealed the first report of a Trp-574-Leu mutation in the ALS gene of the R23-1 population, which significantly increased binding energy, as shown by molecular docking analysis. Synergistic tests demonstrated that the cytochrome P450 monooxygenase (P450) inhibitor piperonyl butoxide (PBO) and the GSTs inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) markedly enhanced the sensitivity of the R23-1 population to halosulfuron-methyl, with synergistic ratios of 4.11 and 8.15, respectively, while malathion had no effect. GST activity decreased in both populations after halosulfuron-methyl treatment, with the R23-1 population consistently showing significantly higher levels, peaking on day five. Furthermore, the R23-1 population demonstrated cross-resistance to multiple ALS inhibitors. These findings provide novel insights into the resistance mechanisms of F. littoralis and lay a theoretical foundation for developing effective strategies to mitigate or delay the evolution of resistance.}, } @article {pmid40267187, year = {2025}, author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M}, title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq6077}, pmid = {40267187}, issn = {2375-2548}, mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; }, abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.}, } @article {pmid40271071, year = {2025}, author = {Luo, H and Wei, S and Fu, S and Han, L}, title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1511011}, pmid = {40271071}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.}, } @article {pmid40278411, year = {2025}, author = {Di Sarno, A and Romano, F and Arianna, R and Serpico, D and Lavorgna, M and Savastano, S and Colao, A and Di Somma, C}, title = {Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View.}, journal = {Metabolites}, volume = {15}, number = {4}, pages = {}, pmid = {40278411}, issn = {2218-1989}, abstract = {Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.}, } @article {pmid40279084, year = {2026}, author = {Singh, P and Borkar, M and Doshi, G}, title = {Network pharmacology approach to unravel the neuroprotective potential of natural products: a narrative review.}, journal = {Molecular diversity}, volume = {30}, number = {1}, pages = {59-100}, pmid = {40279084}, issn = {1573-501X}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Biological Products/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Network Pharmacology/methods ; Animals ; Aging ; }, abstract = {Aging is a slow and irreversible biological process leading to decreased cell and tissue functions with higher risks of multiple age-related diseases, including neurodegenerative diseases. It is widely accepted that aging represents the leading risk factor for neurodegeneration. The pathogenesis of these diseases involves complex interactions of genetic mutations, environmental factors, oxidative stress, neuroinflammation, and mitochondrial dysfunction, which complicate treatment with traditional mono-targeted therapies. Network pharmacology can help identify potential gene or protein targets related to neurodegenerative diseases. Integrating advanced molecular profiling technologies and computer-aided drug design further enhances the potential of network pharmacology, enabling the identification of biomarkers and therapeutic targets, thus paving the way for precision medicine in neurodegenerative diseases. This review article delves into the application of network pharmacology in understanding and treating neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinal muscular atrophy. Overall, this article emphasizes the importance of addressing aging as a central factor in developing effective disease-modifying therapies, highlighting how network pharmacology can unravel the complex biological networks associated with aging and pave the way for personalized medical strategies.}, } @article {pmid40280464, year = {2025}, author = {Gritsiuta, AI and Reep, G and Parupudi, S and Petrov, RV}, title = {Optimizing the management of anastomotic leaks after esophagectomy: a narrative review of salvage strategies and outcomes.}, journal = {Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract}, volume = {29}, number = {7}, pages = {102069}, doi = {10.1016/j.gassur.2025.102069}, pmid = {40280464}, issn = {1873-4626}, mesh = {Humans ; *Esophagectomy/adverse effects ; *Anastomotic Leak/therapy/etiology ; *Salvage Therapy/methods ; Drainage/methods ; Treatment Outcome ; Nutritional Support ; Anti-Bacterial Agents/therapeutic use ; }, abstract = {BACKGROUND: Anastomotic leaks (ALs) after esophagectomy remain a major postoperative complication, leading to increased morbidity, prolonged hospital stays, and higher mortality. Despite advancements in surgical techniques and perioperative care, AL management lacks standardized protocols. This review aimed to evaluate current salvage strategies, including conservative, endoscopic, and surgical approaches, to optimize outcomes and reduce complications.

METHODS: A comprehensive literature search was conducted using PubMed, Scopus, Cochrane Library, and Google Scholar databases to identify studies published between 2000 and 2025 on AL management after esophagectomy. Peer-reviewed clinical trials, guidelines, and expert consensus reports were reviewed, focusing on minimally invasive and surgical interventions, patient outcomes, and emerging treatment strategies.

RESULTS: AL management strategies were classified into 3 primary approaches. Conservative management includes nutritional support, antibiotic therapy, and percutaneous drainage, particularly for contained leaks. Endoscopic interventions, such as self-expanding metal stents and endoscopic vacuum-assisted closure, have shown high success rates, with vacuum-assisted closure achieving superior closure outcomes. Hybrid techniques, including stent-over-sponge and vacuum-assisted closure-stent, are emerging as promising alternatives. Surgical interventions remain the gold standard for severe or refractory leaks with options, including primary repair, esophageal diversion, and delayed conduit reconstruction.

CONCLUSION: A multidisciplinary approach is crucial for optimizing AL management, incorporating enhanced recovery protocols, early risk assessment, and individualized treatment plans. Endoscopic techniques have reduced the need for surgical revisions, but surgical intervention remains necessary for severe cases. Future research should focus on refining treatment algorithms, integrating novel technologies, and establishing standardized guidelines to improve patient survival and quality of life.}, } @article {pmid40281300, year = {2025}, author = {Upadhayay, S and Soni, D and Dhureja, M and Temgire, P and Kumar, V and Arthur, R and Kumar, P}, title = {Role of Fibroblast Growth Factors in Neurological Disorders: Insight into Therapeutic Approaches and Molecular Mechanisms.}, journal = {Molecular neurobiology}, volume = {62}, number = {11}, pages = {14367-14386}, pmid = {40281300}, issn = {1559-1182}, mesh = {Humans ; *Nervous System Diseases/metabolism/therapy/drug therapy ; Animals ; *Fibroblast Growth Factors/metabolism ; Signal Transduction/physiology ; }, abstract = {In the last few decades, the incidence and progression of neurological disorders have consistently increased, which mainly occur due to environmental pollution, genetic abnormalities, and modern lifestyles. Several case reports suggested that these factors enhanced oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, leading to neurological disease. The pathophysiology of neurological disorders is still not understood, mainly due to the diversity within affected populations. Existing treatment options primarily provide symptomatic relief but frequently come with considerable side effects, including depression, anxiety, and restlessness. Fibroblast growth factors (FGFs) are key signalling molecules regulating various cellular functions, including cell proliferation, differentiation, electrical excitability, and injury responses. Hence, several investigations claimed a relationship between FGFs and neurological disorders, and their findings indicated that they could be used as therapeutic targets for neurological disorders. The FGFs are reported to activate various signalling pathways, including Ras/MAPK/PI3k/Akt, and downregulate the GSK-3β/NF-κB pathways responsible for anti-oxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, researchers are interested in developing novel treatment options for neurological disorders. The emergence of unreported FGFs contributes to our understanding of their involvement in these conditions and encourages further exploration of innovative therapeutic approaches. All the data were obtained from published articles using PubMed, Web of Science, and Scopus databases using the search terms Fibroblast Growth Factor, PD, HD, AD, ALS, signalling pathways, and neurological disorders.}, } @article {pmid40283201, year = {2025}, author = {González-Sánchez, M and Ramírez-Expósito, MJ and Martínez-Martos, JM}, title = {Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {40283201}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2-4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care-integrating physical therapy, respiratory support, nutritional management, and cognitive assessments-is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.}, } @article {pmid40283933, year = {2025}, author = {Martín-Ruiz, J and Maset-Roig, R and Caplliure-Llopis, J and Villarón-Casales, C and Alarcón-Jiménez, J and de Bernardo, N and Proaño, B and Menargues-Ramírez, R and Selvi-Sabater, P and de la Rubia-Ortí, JE}, title = {Enhanced Acute Muscle Activation in ALS Patients Following Liposomal Curcumin, Resveratrol, and Dutasteride Administration.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {4}, pages = {}, pmid = {40283933}, issn = {1424-8247}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of electrical activity and motor control at the muscular level. Therapeutic alternatives, such as the polyphenolic antioxidants curcumin and resveratrol in liposome form, or the drug dutasteride, could be effective for muscular activity. Objective: To measure the acute change in electrical muscle activation after administration of a combination of curcumin in liposomal form, resveratrol, and dutasteride in patients with ALS. Materials and methods: Patients with bulbar and spinal ALS were selected and randomly distributed into an intervention group (IG), which received an oral combination of curcumin in liposomal form/resveratrol[®] and dutasteride for 2 months, and a control group (CG), which received a placebo. Electrical activity to determine basal muscle activation and fasciculations was measured before and after the intervention using surface electromyography of the biceps brachii (BB), triceps brachii (TB), rectus femoris (RF), and tibialis anterior (TA). Within comparisons of pre and post-muscular variations in each group were conducted. Results: Electrical basal activity increased only for the IG in the right (p = 0.05; g = -0.45) and left (p = 0.004; g = -0.74) hemibody muscles and also presented less variation among them after treatment in the IG. For fasciculations, there was an increase in the total activation of the upper muscles in the IG (p = 0.017; g = -0.86) and for the lower muscles in the CG (p = 0.037; g = -0.68). The pattern of muscle activation remained constant in the IG but experienced variations in the CG.}, } @article {pmid40283960, year = {2025}, author = {Salomon-Zimri, S and Kerem, N and Linares, GR and Russek-Blum, N and Ichida, JK and Tracik, F}, title = {Elucidating the Synergistic Effect of the PrimeC Combination for Amyotrophic Lateral Sclerosis in Human Induced Pluripotent Stem Cell-Derived Motor Neurons and Mouse Models.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {4}, pages = {}, pmid = {40283960}, issn = {1424-8247}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the involvement of multiple pathways and mechanisms. The complexity of its pathophysiology is reflected in the diverse hypotheses relating to its underlying causes. Given this intricate interplay of processes, a combination therapy approach offers a promising strategy. Combination therapies have demonstrated significant success in treating complex diseases, where they aim to achieve synergistic therapeutic effects and reduce drug dosage. PrimeC is an oral combination treatment composed of a patented novel formulation consisting of specific and unique doses of two well-characterized drugs (ciprofloxacin and celecoxib). It aims to synergistically inhibit the progression of ALS by addressing key elements of its pathophysiology. Objectives: Demonstrating the synergistic effect of the PrimeC combination compared to each of its individual components, celecoxib and ciprofloxacin, and assessing its ability to improve the drug concentration profile and efficacy. Methods: The efficacy of the PrimeC combination was assessed in a survival assay using human induced pluripotent stem cell (iPSC)-derived motor neurons. Additionally, a drug profiling study was conducted, measuring drug levels in the brain and serum of C57BL mice treated with a single compound versus the combination. Results: Motor neurons modeling ALS treated with the PrimeC combination exhibited better survival rates compared to treatment with either individual compound alone. The enhanced efficacy of the combination was further supported by a drug concentration profiling study in rodents, demonstrating that the PrimeC combination resulted in increased ciprofloxacin concentrations in both brain tissue and serum-highlighting the optimized interaction and synergistic potential of its two comprising agents. Conclusions: Our findings support the potential of combination therapy as an effective strategy for ALS treatment. Specifically, the PrimeC combination demonstrated promising therapeutic effects, providing a strong rationale for its ongoing development as a targeted treatment for ALS.}, } @article {pmid40284157, year = {2025}, author = {Sousa-Catita, D and Mascarenhas, P and Oliveira, C and Grunho, M and Santos, CA and Cabrita, J and Correia, P and Fonseca, J}, title = {Nutrition and Survival of 150 Endoscopic Gastrostomy-Fed Patients with Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {17}, number = {8}, pages = {}, pmid = {40284157}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/complications ; *Gastrostomy/methods/mortality ; Male ; Female ; Aged ; *Enteral Nutrition/methods/mortality ; *Nutritional Status ; Middle Aged ; Kaplan-Meier Estimate ; Aged, 80 and over ; }, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and paralysis. Treatment focuses on symptom management, using medication, physiotherapy, and nutritional support. In this context, endoscopic gastrostomy (PEG) can provide adequate feeding, hopefully improving nutrition and preventing complications. Methods: We studied ALS patients undergoing PEG over three months post-procedure, using anthropometry ((BMI)-body mass index; (MUAC)-mid-upper arm circumference; (TSF)-tricipital skinfold; (MAMC)-mid-arm muscle circumference) and laboratory data (Albumin; Transferrin; total cholesterol and hemoglobin), evaluating survival, complications, and nutritional/clinical status. Statistical analysis included Kaplan-Meier survival estimation and Cox regression to assess nutritional markers associated with survival. Results: 150 ALS patients underwent gastrostomy, mostly older adults (mean age: 66.1 years; median: 67). Mean survival was 527 [95% CI: 432-622] days, median 318 [95% CI: 236-400]. ALS bulbar subtype, MUAC and MAMC positively impacted PEG-feeding survival time (p < 0.05, Wald test). During the first three months of PEG feeding, each unit increase (cm) in MUAC and MAMC lowered death risk by 10% and 11%, respectively, highlighting the importance of nutrition care for survival. The bulbar subtype showed higher PEG feeding survival, with a 55.3% lower death hazard than the spinal subtype. There were no major PEG complications. Conclusions: ALS patients present a high risk of malnutrition. Patients that improved MAMC and MUAC in the first three PEG-fed months presented longer survival. Early PEG nutrition, even when some oral feeding is still possible, may reinforce the preventative role of enteral feeding in maintaining nutrition and potentially improving survival.}, } @article {pmid40286795, year = {2025}, author = {Murdock, BJ and Zhao, B and Webber-Davis, IF and Teener, SJ and Pawlowski, KD and Famie, JP and Piecuch, CE and Jang, DG and Feldman, EL and Zhao, L and Goutman, SA}, title = {Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression.}, journal = {Med (New York, N.Y.)}, volume = {6}, number = {8}, pages = {100673}, pmid = {40286795}, issn = {2666-6340}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; R01 TS000339/TS/ATSDR CDC HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R21 NS102960/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/immunology ; Disease Progression ; Case-Control Studies ; Biomarkers/blood ; Flow Cytometry ; Longitudinal Studies ; *Immunity, Cellular ; Humans ; Male ; Female ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure and limited treatment options. The immune system is implicated in disease pathology, unlocking a potential therapeutic avenue. However, it is unclear whether immune changes are a cause or consequence of disease progression.

METHODS: Peripheral immune cells were longitudinally measured at monthly intervals in 55 ALS and 50 control participants. 22 peripheral immune markers in the blood were assessed using flow cytometry, and clinical progression was assessed using the revised ALS functional rating scale (ALSFRS-R). Individual immune markers, their trajectories, and overall variability were compared in ALS versus control participants; ALS participants were also stratified by clinical progression rates and assessed similarly across progression groups. Finally, a novel, lagged linear regression model correlated the rate of immune changes to subsequent downstream ALSFRS-R changes.

FINDINGS: Numerous immune markers were dysregulated in ALS versus control participants, with altered levels, trajectories, or variability in immune populations and surface markers. ALS participants had increased immune variability relative to control participants; within ALS participants, faster progressors overall had decreased marker variability. Finally, natural killer (NK) cell numbers, NK cell subpopulations, and NK cell surface markers were significantly associated with downstream ALS progression.

CONCLUSIONS: The immune system is dysregulated in ALS and more consistently dysregulated in faster ALS progression, and immune dysregulation occurs upstream of clinical changes. These findings suggest that the immune system is a causal factor of ALS progression in human patients.

FUNDING: CReATe Consortium, NIH, Target ALS, DoD, ALSA.}, } @article {pmid40287045, year = {2025}, author = {Dudzisz, K and Wandzik, I}, title = {Antisense oligonucleotides: A promising advancement in neurodegenerative disease treatment.}, journal = {European journal of pharmacology}, volume = {999}, number = {}, pages = {177644}, doi = {10.1016/j.ejphar.2025.177644}, pmid = {40287045}, issn = {1879-0712}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Neurodegenerative Diseases/genetics/drug therapy/therapy ; Animals ; Clinical Trials as Topic ; }, abstract = {Antisense oligonucleotides (ASOs) are a class of therapeutics designed to modulate gene expression and have shown promise in the treatment of various neurodegenerative diseases. As of March 2025, four ASO-based therapies have received approval for the treatment of neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and hereditary transthyretin amyloidosis (ATTR). These approvals underscore the therapeutic potential of ASOs as effective treatments for neurodegenerative diseases by addressing specific genetic abnormalities. This is best demonstrated by clinical studies in more than a dozen ASOs, which could pave the way for the development of new therapeutics soon. Moreover, the ongoing extended clinical studies, which target presymptomatic carriers, have significant potential to cure familial ALS based on the SOD1 gene mutation. This review provides an update on clinical trials, highlighting promising results and the challenges encountered.}, } @article {pmid40288591, year = {2025}, author = {Servi, R and Akkoç, RF and Aksu, F and Servi, S}, title = {Therapeutic potential of enzymes, neurosteroids, and synthetic steroids in neurodegenerative disorders: A critical review.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {251}, number = {}, pages = {106766}, doi = {10.1016/j.jsbmb.2025.106766}, pmid = {40288591}, issn = {1879-1220}, mesh = {Humans ; *Neurosteroids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Steroids/therapeutic use ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Neurodegenerative disorders present a significant challenge to healthcare systems, mainly due to the limited availability of effective treatment options to halt or reverse disease progression. Endogenous steroids synthesized in the central nervous system, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG), and allopregnanolone (ALLO), have been identified as potential therapeutic agents for neurodegenerative diseases. Neurosteroids such as ALLO, DHEA, and PROG, as well as their synthetic analogs like Ganaxolene, Fluasterone, and Olexoxime, offer promising effects for conditions such as Alzheimer's disease (AD) and depression. Moreover, Brexanolone and Ganaxolone are synthetic steroids approved for the treatment of postpartum depression and epilepsy, respectively. Neurosteroids such as ALLO are crucial in modulating GABAergic neurotransmission and reducing neuroinflammation. These compounds enhance the activity of GABA-A receptors, leading to increased inhibitory signaling in the brain, which can help regulate mood, cognition, and neuroprotection. Small clinical trials and observational studies indicate that ALLO may have cognitive benefits, but no large-scale, definitive meta-analysis confirms a 20 % improvement in AD patients. Mitochondrial dysfunction plays a vital role in the pathogenesis of numerous neurological diseases due to the high-energy demand and sensitivity of neurons to oxidative stress. Reduced mitochondrial function leads to amyloid-beta plaques and tau tangles accumulation in AD. In Parkinson's disease (PD), mitochondrial dysfunction resulting from the PINK1 or Parkin genes leads to energy deficiencies and the accumulation of toxic byproducts. Mutations in genes such as SOD1, C9orf72, and TDP-43 have been associated with mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS). Moreover, studies on these neurodegenerative diseases suggest that inflammation is not merely a consequence of neurodegeneration but is also an essential factor in this process. Many neurological disorders involve multifaceted interactions between genetics, the environment, and immune responses, making it difficult to pinpoint their exact causes. Future research aims to overcome these hurdles through genetic advances, regenerative medicine, and personalized therapies. Cutting-edge technologies such as artificial intelligence and high-throughput screening are expected to accelerate drug discovery and improve diagnostic accuracy. Increasing collaboration between interdisciplinary fields such as bioinformatics, neuroscience, and immunology will lead to innovative treatment strategies. This comprehensive review discusses the therapeutic effects of enzymes, neurosteroids, and synthetic steroids in different neurodegenerative diseases, particularly AD, PD, ALS, and MS. Potential challenges in the therapeutic use of neurosteroids, such as the limited bioavailability and off-target effects of synthetic steroids, are also discussed, and an up-to-date and comprehensive review of the impact of these steroids on neurodegenerative disorders is presented.}, } @article {pmid40288877, year = {2025}, author = {Alcaraz, MR and Montemurro, M and Pisano, PL and Lombardi, JM and Bortolato, SA}, title = {Functional data analysis, a comprehensive framework for processing non-quadrilinear and low-selective data provided by four-way liquid chromatography analysis.}, journal = {Analytica chimica acta}, volume = {1356}, number = {}, pages = {344044}, doi = {10.1016/j.aca.2025.344044}, pmid = {40288877}, issn = {1873-4324}, abstract = {The chemometric treatment of higher-order chromatographic (LC) data often crashes due to two main effects: the chromatographic band shifts/warpings across samples and quasi-full overlaps between component signals, affecting their analytical selectivities. From a chemometric point of view, these phenomena have independent effects, although they can jointly contribute to the failure of the algorithms: 1) data multilinearity breaking, leading to the poor performance of multilinear decomposition algorithms, and 2) linear dependence between the analytes signals, causing the failure of folded models. Under this scenario, making chemometric processing feasible involves defining specific experimental conditions that minimize these effects or increasing the number of instrumental ways to deal with selectivity lost. This work presents the Functional Aligned of Pure Vectors (FAPV) algorithm for restoring four-way chromatographic data multilinearity and bearing the spectral overlap trouble. Simulated and experimental four-way data were used to test the FAPV analytical efficiency, covering a wide range of chromatographic artifacts. Based on a multi-injection procedure, the experimental case implied the chromatographic determination of two analytes with uncalibrated interferents in aqueous samples. Both data systems were subjected to FAPV and then processed by PARAFAC. Therefore, a comprehensive comparison was made with the most widely used chemometric models for non-multilinear chromatographic data (MCR-ALS and PARAFAC2). Moreover, the performance of the FAPV approach was compared with commonly used alignment procedures, e.g., correlation-optimized warping. The results (c.a. REPs of 10 % in both analytes from the experimental case) show the efficiency of the FAPV algorithm in solving the troubles observed in chromatographic/spectral data.}, } @article {pmid40290120, year = {2025}, author = {Hong, Y and Song, Y and Wang, W and Shi, J and Chen, X}, title = {Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.}, journal = {Genes & diseases}, volume = {12}, number = {4}, pages = {101437}, pmid = {40290120}, issn = {2352-3042}, abstract = {Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.}, } @article {pmid40290679, year = {2025}, author = {Li, ZY and Li, T and Cai, HQ}, title = {Overview of serrated polyposis syndrome from pathophysiology, diagnosis, and management.}, journal = {World journal of clinical oncology}, volume = {16}, number = {4}, pages = {103343}, pmid = {40290679}, issn = {2218-4333}, abstract = {This editorial discusses Thompson et al's original article, which is published in the most recent edition of the World Journal of Clinical Oncology and sheds critical light on the intertwined issues of health anxiety and work loss in individuals diagnosed with serrated polyposis syndrome (SPS). SPS is rare, characterized by the development of multiple serrated colorectal polyps. This editorial provides an overview of SPS, including its pathophysiology, clinical presentation, diagnostic criteria, management strategies, and the psychosocial impact. SPS is linked to molecular alterations, which drive carcinogenesis. Colonoscopy and histological analysis are used for diagnosis. Genetic testing is also considered where there is a family history. Quality of life can be greatly impacted by the psychosocial effects of SPS, especially health anxiety. Further understanding of the molecular mechanisms and creating individualized surveillance are required.}, } @article {pmid40290690, year = {2025}, author = {Cao, YK and Yang, SL and Wei, ZQ}, title = {Is the use of a transanal drainage tube effective in treating anastomotic leakage for mid-low rectal cancer.}, journal = {World journal of clinical oncology}, volume = {16}, number = {4}, pages = {99801}, pmid = {40290690}, issn = {2218-4333}, abstract = {BACKGROUND: Anastomotic leakage (AL) is a severe surgical complication for mid-low rectal cancers. The efficacy of transanal drainage tube (TDT) has rarely been reported.

AIM: To evaluate the efficacy of TDT after AL.

METHODS: A retrospective analysis was conducted on 68 patients with mid-low rectal cancer who underwent laparoscopic low anterior resection (LAR) and developed ALs. Leakage were identified using imaging studies and digital rectal examinations when local abscesses or systemic infections were present. In each patient, the leakage site was determined using the index finger and a drainage tube was inserted transanally to drain the abscesses and exudates outside the anus. The clinical outcomes of the patients following transanal drainage were analyzed.

RESULTS: A total of 43 patients received TDT treatment, while 25 patients did not receive TDT treatment. Among the patients in the TDT group, 9 required reoperation compared to 12 in the non-TDT group. In the TDT group, 76.74% of the patients were able to restore intestinal continuity, whereas only 40% of the patients in the non-TDT group achieved restored intestinal continuity. In the TDT group, 48.48% of patients developed LAR syndrome (LARS), whereas in the non-TDT group, 90% of patients developed LARS. The median drainage time was 7 days, the median postoperative hospital stay was 21 days, the median fasting time was 6.5 days, and the median hospitalization cost was 109205.93 RMB.

CONCLUSION: TDT use lowered reoperation rate but did not increase hospitalization expenses. After ≥ 1 year of follow-up, its use improved intestinal patency rate and reduced the incidence of LARS.}, } @article {pmid40294721, year = {2025}, author = {Natala, SR and Habas, A and Stocking, EM and Orry, A and Abagyan, R and Makale, MT and Wrasidlo, W}, title = {Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {124}, number = {}, pages = {130259}, doi = {10.1016/j.bmcl.2025.130259}, pmid = {40294721}, issn = {1464-3405}, mesh = {*Toll-Like Receptor 2/antagonists & inhibitors/metabolism ; Humans ; *Drug Design ; *Toll-Like Receptor 9/antagonists & inhibitors/metabolism ; *Small Molecule Libraries/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Structure-Activity Relationship ; Animals ; Dose-Response Relationship, Drug ; }, abstract = {Inflammation is a key driver of the onset and progression of neurodegenerative diseases and cancer and can be caused by aggregated proteins, injured neurons or synapses, dysregulation of inflammatory control mechanisms, and other factors. Tolllike receptors (TLRs) are important mediators of inflammatory pathways, and their activation leads to pro-inflammatory cytokine release by immune cells in the periphery or in the central nervous system (CNS). TLR2 and TLR9 are implicated in the inflammatory pathogenesis of CNS degenerative diseases such as Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). They are also held to be important in the etiology of certain malignancies like inflammatory pancreatic ductal adenocarcinoma and glioblastoma. Inactivation of TLR2/9 in animal models of neurodegeneration has reduced pathological markers and diminished neuronal loss, while in animal models of cancer it has suppressed tumors. Therefore, TLR2 and TLR9 may be potential targets for the treatment of neurodegenerative disorders and cancers. We identified for the first time a key binding locus in TLR2/9 TIR domain which guided reversible covalent drug (RCD) design of a novel, first-in class series of dual TLR2/9 antagonists. Sub-micromolar antagonist concentrations potently inhibited TLR2 and TLR9 signaling induced by TLR2/9 specific agonists. Importantly, this series of antagonists did not discernably activate other TLRs and exhibited favorable in-vitro ADME and safety. The analogs described here may help realize effective TLR2/9 antagonism as a viable therapeutic strategy for inflammation driven CNS diseases and various malignancies with an inflammatory etiology.}, } @article {pmid40295049, year = {2025}, author = {Keul, J and Sperling, S and Rohde, V and Ninkovic, M}, title = {Advantages and Disadvantages of Drug Combination Treatment: Riluzole, Metformin and Dexamethasone Effect on Glioblastoma Cell.}, journal = {Anticancer research}, volume = {45}, number = {5}, pages = {1813-1823}, doi = {10.21873/anticanres.17561}, pmid = {40295049}, issn = {1791-7530}, mesh = {Humans ; *Glioblastoma/drug therapy/pathology/metabolism/genetics ; *Metformin/pharmacology/administration & dosage ; *Dexamethasone/pharmacology/administration & dosage ; Cell Line, Tumor ; *Riluzole/pharmacology/administration & dosage ; *Brain Neoplasms/drug therapy/pathology/metabolism ; Cell Movement/drug effects ; Cell Survival/drug effects ; *Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Matrix Metalloproteinase 2/metabolism ; Drug Synergism ; Cell Proliferation/drug effects ; }, abstract = {BACKGROUND/AIM: In glioblastoma multiforme (GBM), a deadly brain tumor, glucose is one of the main fuels for accelerated growth. Patients with GBM are also exposed to excess glucose through hyperglycemia in diabetes mellitus. In addition, dexamethasone (Dex), a corticosteroid commonly administered for controlling cerebral oedema, causes additional excess glucose. Therefore, targeting glucose metabolism is an attractive therapeutic intervention for GBM treatment. We have recently shown that riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), has an effect on some detrimental Dex-induced metabolic changes in GBM. Therefore, we examined the effect of the combination of metformin (Met), widely used to treat type 2 diabetes, and Ril on GBM cells.

MATERIALS AND METHODS: The 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability of U87MG after treatment with Ril, Met, Ril plus Met (Ril+Met) and the addition of Dex to this co-treatment. Cell migration was assessed by the xCELLigence system, matrix metalloproteinase 2 (MMP2) activation by zymography assay and gene expression by real-time polymerase chain reaction (RT-PCR).

RESULTS: Co-treatment with Ril and Met was effective in killing GBM cells and reducing the expression of genes involved in glucose and stem cell metabolism. Furthermore, combination of Ril and Met reduced MMP2 activation. But co-administration increased the migration of U87MG cells. The addition of Dex to this combination reversed the unfavorable effects of Ril+Met on cell migration.

CONCLUSION: Ril+Met co-treatment had a positive effect in terms of GBM cell death, decreased expression of genes involved in glucose metabolism and stemness, and reduced MMP2 activation. Disadvantage of Ril+Met treatment was increased cell migration. Taken together, these drug combinations may also allow the reduction of the concentration of Dex to minimize its side effects.}, } @article {pmid40295933, year = {2025}, author = {Yu, SF and Michon, M and Lingappa, AF and Paulvannan, K and Solas, D and Staats, K and Ichida, J and Dey, D and Rosenfeld, J and Lingappa, VR}, title = {An ALS assembly modulator signature in peripheral blood mononuclear cells: implications for ALS pathophysiology, therapeutics, and diagnostics.}, journal = {Clinical proteomics}, volume = {22}, number = {1}, pages = {16}, pmid = {40295933}, issn = {1542-6416}, support = {IL-2023-C4-L1//Target ALS/ ; W81XWH2210721//DOD CDMRP/ ; }, abstract = {Assembly modulators are a new class of allosteric site-targeted therapeutic small molecules, some of which are effective at restoring nuclear localization of TDP-43 in ALS cellular models, and which display efficacy in a variety of ALS animal models. These compounds have been shown to bind selectively to a small subset of protein disulfide isomerase (PDI), a protein implicated in ALS pathophysiology. The targeted subset of PDI is found within a novel, transient and energy-dependent multi-protein complex that includes other important members of the ALS interactome, such as TDP-43, RanGTPase, and selective autophagy receptor p62/SQSTM1. We demonstrate here that a similar multi-protein complex drug target is present in PBMCs as isolated by energy-dependent drug resin affinity chromatography (eDRAC) and characterized by mass spectrometry and by Western blot (WB). Signature alterations in the composition of the multi-protein complex in PBMCs from ALS patients compared to PBMCs from healthy individuals were identified by WB of eDRAC bound proteins, thereby extending earlier literature suggesting PBMC dysfunction in ALS. Changes in the PBMC drug target in ALS patients compared to healthy individuals include diminished p62/SQSTM1 and appearance of a 17 kDa post-translationally modified form of RanGTPase. These changes are not readily apparent from analysis of whole cell extracts, as the individual protein components within the drug target multi-protein complex comprise only small percentages of the total of those component proteins in the extract. Furthermore, whole blood from ALS patients shows a distinctive degradation of total RanGTPase not observed in blood from healthy individuals. This degradation appears to be rescued by treatment of whole blood from ALS patients for 72 h with ALS-active assembly modulator small molecules. Our findings are consistent with the hypothesis that ALS is fundamentally a disorder of homeostasis that can be detected early, prior to disability, in blood by the methods described, and restored to the healthy state by assembly modulator drug treatment.}, } @article {pmid40298821, year = {2025}, author = {Bortolotti, M and Polito, L and Battelli, MG and Bolognesi, A}, title = {Xanthine Oxidoreductase: A Double-Edged Sword in Neurological Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {40298821}, issn = {2076-3921}, abstract = {Non-communicable neurological disorders are the second leading cause of death, and their burden continues to increase as the world population grows and ages. Oxidative stress and inflammation are crucially implicated in the triggering and progression of multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and even stroke. In this narrative review, we examine the role of xanthine oxidoreductase (XOR) activities and products in all the above-cited neurological diseases. The redox imbalance responsible for oxidative stress could arise from excess reactive oxygen and nitrogen species resulting from the activities of XOR, as well as from the deficiency of its main product, uric acid (UA), which is the pivotal antioxidant system in the blood. In fact, with the exception of stroke, serum UA levels are inversely related to the onset and progression of these neurological disorders. The inverse correlation observed between the level of uricemia and the presence of neurological diseases suggests a neuroprotective role for UA. Oxidative stress and inflammation are also caused by ischemia and reperfusion, a condition in which XOR action has been recognized as a contributing factor to tissue damage. The findings reported in this review could be useful for addressing clinical decision-making and treatment optimization.}, } @article {pmid40299102, year = {2025}, author = {Zhang, G and Huang, S and Wei, M and Wu, Y and Wang, J}, title = {Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects.}, journal = {Neurochemical research}, volume = {50}, number = {3}, pages = {155}, pmid = {40299102}, issn = {1573-6903}, support = {2023JJB140089//Guangxi Youth Science Foundation Project/ ; 82201694//the National Natural Scientific Foundation of China/ ; 2022AC21033//Guangxi Science and technology base and talent project/ ; 2022KY0349//Guangxi university young and middle-aged teachers' basic ability improvement project/ ; }, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Glutamate Plasma Membrane Transport Proteins/metabolism ; Glutamic Acid/metabolism ; }, abstract = {Excitatory amino acid transporters (EAATs) are pivotal regulators of glutamate homeostasis in the central nervous system and orchestrate synaptic glutamate clearance through transmembrane transport and the glutamine‒glutamate cycle. The five EAAT subtypes (GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, and EAAT5) exhibit spatiotemporal-specific expression patterns in neurons and glial cells, and their dysfunction is implicated in diverse neurological pathologies, including epilepsy, amyotrophic lateral sclerosis (ALS), schizophrenia, depression, and retinal degeneration. Mechanistic studies revealed that astrocytic GLT-1 deficiency disrupts glutamate clearance in ALS motor neurons, whereas GLAST genetic variants are linked to both epilepsy susceptibility and glaucomatous retinal ganglion cell degeneration. Three major challenges persist in ongoing research: ① subtype-specific regulatory mechanisms remain unclear; ② compensatory functions of transporters vary significantly across disease models; and ③ clinical translation lacks standardized evaluation criteria. The interaction mechanisms and dynamic roles of EAATs in neurological disorders were systematically investigated in this study, and an integrated approach combining single-cell profiling, stem cell-based disease modeling, and drug screening platforms was proposed. These findings lay the groundwork for novel therapeutic strategies targeting glutamate homeostasis.}, } @article {pmid40300682, year = {2025}, author = {Li, Z and Xing, J}, title = {Role of sirtuins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic potential.}, journal = {International journal of biological macromolecules}, volume = {310}, number = {Pt 4}, pages = {143591}, doi = {10.1016/j.ijbiomac.2025.143591}, pmid = {40300682}, issn = {1879-0003}, mesh = {Humans ; *Sirtuins/metabolism/genetics ; *Reperfusion Injury/metabolism/drug therapy/pathology ; Animals ; *Brain Ischemia/metabolism/drug therapy/pathology ; }, abstract = {The high incidence and mortality rate of cardiac arrest (CA) establishes it as a critical clinical challenge in emergency medicine globally. Despite continuous advances in advanced life support (ALS) technology, the prognosis for patients experiencing cardiac arrest remains poor, with cerebral ischemia and reperfusion injury (CIRI) being a significant determinant of adverse neurological outcomes and increased mortality. Sirtuins (SIRTs) are a class of highly evolutionarily conserved NAD[+]-dependent histone deacylenzymes capable of regulating the expression of various cytoprotective genes to play a neuroprotective role in CIRI. SIRTs mainly regulate the levels of downstream proteins such as PGC 1-α, Nrf 2, NLRP 3, FoxOs, and PINK 1 to inhibit inflammatory response, attenuate oxidative stress, improve mitochondrial dysfunction, promote angiogenesis, and inhibit apoptosis while reducing CIRI. Natural active ingredients are widely used in regulating the protein level of SIRTs in the body because of their multi-components, multi-pathway, multi-target, and minimal toxic side effects. However, these naturally active ingredients still face many challenges related to drug targeting, pharmacokinetic properties, and drug delivery. The emergence and vigorous development of new drug delivery systems, such as nanoparticles, micromilk, and exosomes, provide strong support for solving the above problems. In the context of the rapid development of molecular biology technology, non-coding RNA (NcRNA), represented by miRNA and LncRNA, offers great potential for achieving gene-level precision medicine. In the context of multidisciplinary integration, combining SIRTs proteins with biotechnology, omics technologies, artificial intelligence, and material science will strongly promote the deepening of their basic research and expand their clinical application. This review describes the major signaling pathways of targeting SIRTs to mitigate CIRI, as well as the current research status of Chinese and Western medicine and medical means for the intervention level of SIRTs. Meanwhile, the challenges and possible solutions in the clinical application of targeted drugs are summarized. In the context of medical and industrial crossover, the development direction of SIRTs in the future is discussed to provide valuable reference for basic medical researchers and clinicians to improve the clinical diagnosis and treatment effects of CIRI.}, } @article {pmid40304918, year = {2025}, author = {Anjum, F and Alsharif, A and Bakhuraysah, M and Shafie, A and Hassan, MI and Mohammad, T}, title = {Discovering Novel Biomarkers and Potential Therapeutic Targets of Amyotrophic Lateral Sclerosis Through Integrated Machine Learning and Gene Expression Profiling.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {2}, pages = {61}, pmid = {40304918}, issn = {1559-1166}, support = {KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Machine Learning ; Receptors, Nicotinic/genetics/metabolism ; Gene Expression Profiling ; Biomarkers/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; Transcriptome ; Membrane Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has multiple factors that make its molecular pathogenesis difficult to understand and its diagnosis and treatment during the early stages difficult to determine. Discovering novel biomarkers in ALS for diagnostic and therapeutic potential has become important. Consequently, bioinformatics and machine learning algorithms are useful for identifying differentially expressed genes (DEGs) and potential biomarkers, as well as understanding the molecular mechanisms and intricacies of diseases such as ALS. To achieve the aim of the present study, six datasets obtained from the Gene Expression Omnibus (GEO) were utilized and analyzed using an integrative bioinformatics and machine learning approach. Log transformation was done during data preprocessing, RMA normalization was performed, and the batch effect was corrected. Differential expression analysis identified 206 DEGs that were significantly associated with different biological processes, including muscle function, energy metabolism, and mitochondrial membrane activity. Functional enrichment analysis highlighted pathways, including those related to prion disease, Parkinson's disease, and ATP synthesis via chemiosmotic coupling. We employed a multi-step machine learning framework incorporating random forest, LASSO regression, and SVM-RFE to identify robust biomarkers. This approach identified three key genes, CHRNA1, DLG5, and PLA2G4C, which could be explored as promising biomarkers for ALS after further validation. The internal validation, including principal component analysis (PCA) and ROC-AUC analysis, demonstrated strong diagnostic potential of these hub genes, achieving an AUC of 0.96. This work highlights the utility of bioinformatics and machine learning in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.}, } @article {pmid40309514, year = {2025}, author = {Li, V and Huang, Y}, title = {Oligonucleotide therapeutics for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {1}, pages = {1-11}, pmid = {40309514}, issn = {2750-6665}, support = {R44 DC018463/DC/NIDCD NIH HHS/United States ; R44 DC018762/DC/NIDCD NIH HHS/United States ; }, abstract = {Recently there has been a surge in interest involving the application of oligonucleotides, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), for the treatment of chronic diseases that have few available therapeutic options. This emerging class of drugs primarily operates by selectively suppressing target genes through antisense and/or RNA interference mechanisms. While various commercial medications exist for delivering oligonucleotides to the hepatic tissue, achieving effective delivery to extra hepatic tissues remains a formidable challenge. Here, we review recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and 2'-O-hexadecyl (C16)-conjugation that work to extend the applicability of siRNAs and ASOs to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.}, } @article {pmid40309800, year = {2025}, author = {Manai, AL and Caria, P and Noli, B and Contini, C and Manconi, B and Etzi, F and Cocco, C}, title = {VGF and Its Derived Peptides in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, pmid = {40309800}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration in the neurons of the frontal cortex, spinal cord, and brainstem, altering the correct release of neurotransmitters. The disease affects every muscle in the body and could cause death three to five years after symptoms first occur. There is currently no efficient treatment to stop the disease's progression. The lack of identification of potential therapeutic strategies is a consequence of the delayed diagnosis due to the absence of accurate ALS early biomarkers. Indeed, neurotransmitters altered in ALS are not measurable in body fluids at quantities that allow for testing, making their use as diagnostic tools a challenge. Contrarily, neuroproteins and neuropeptides are chemical messengers produced and released by neurons, and most of them have the potential to enter bodily fluids. To find out new possible ALS biomarkers, the research of neuropeptides and proteins is intensified using mass spectrometry and biochemical-based assays. Neuropeptides derived from the proVGF precursor protein act as signaling molecules within neurons. ProVGF and its derived peptides are expressed in the nervous and endocrine systems but are also widely distributed in body fluids such as blood, urine, and cerebrospinal fluid, making them viable options as disease biomarkers. To highlight the proVGF and its derived peptides' major roles as ALS diagnostic biomarkers, this review provides an overview of the VGF peptide alterations in spinal cord and body fluids and outlines the limitations of the reported investigations.}, } @article {pmid40311013, year = {2025}, author = {Xu, Z and Yi, W and Guan, L and Tang, J and Feng, D and Zou, Y}, title = {Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {10}, pages = {1898-1908}, doi = {10.1021/acschemneuro.5c00045}, pmid = {40311013}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; Phosphorylation ; Mutation/genetics ; Protein Aggregates/genetics ; *Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is closely related to ubiquitin-positive inclusions formed by transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43). Previous experiments identified that the ALS-linked familial variant, N352S (asparagine substituted by serine), and subsequent phosphorylation of S352 (S352p) are associated with the aggregation of TDP-43. However, the underlying molecular mechanisms are still not fully understood. By performing all-atom explicit-solvent replica exchange molecular dynamics (REMD) simulations with a total simulation time of 100.8 μs, we scrutinized the impact of the N352S mutation and its phosphorylation variant S352p on the conformational ensembles of the TDP-43342-366 dimer. Our simulation results show that both the N352S and S352p variants could promote the formation of unstructured conformation and impede the formation of β-structure and helix content, and the inhibitive effect of S352P is more obvious. Further analyses suggest that the H-bonding and hydrophobic interaction among TDP-43342-366 peptides, as well as the R361-E362 salt bridge, are attenuated by N352S and S352p variants. Additional MD simulations show that N352S and S352p variants reduce the structural stability of the hydrophobic region and lower the number of H-bonds and contacts of two hydrophobic clusters, thus possessing a destabilization effect on the TDP-43282-360 protofibrils. Our results unmask the molecular mechanism of the N352S mutation and its phosphorylation variant S352p toward the inhibition of TDP-43342-366 aggregation and prove the protofibril-destabilizing effects of these two variants, which may be helpful for designing drugs for the treatment of ALS.}, } @article {pmid40312429, year = {2025}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {Author Correction: The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {15297}, doi = {10.1038/s41598-025-95009-7}, pmid = {40312429}, issn = {2045-2322}, } @article {pmid40313114, year = {2026}, author = {Zhou, M and Zheng, M and Liang, S and Li, M and Ma, J and Zhang, S and Song, X and Hu, Y and Lyu, Y and Ou, X and Yue, C}, title = {Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {4}, pages = {1409-1427}, pmid = {40313114}, issn = {1673-5374}, abstract = {The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.}, } @article {pmid40314217, year = {2026}, author = {Ju, T and Zhang, Y and Liu, L and Zhao, X and Li, X and Liu, C and Sun, S and Wu, LA}, title = {The role of gut microbiota-mitochondria crosstalk in neurodegeneration: Underlying mechanisms and potential therapies.}, journal = {Neural regeneration research}, volume = {21}, number = {6}, pages = {2238-2253}, pmid = {40314217}, issn = {1673-5374}, abstract = {Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis, which refers to the crosstalk between the gut and the central nervous system. More importantly, mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain. Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases. Mitochondria are essential for meeting the host's substantial neuronal metabolic demands, maintaining excitability, and facilitating synaptic transmission. Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases. Therefore, this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration, as well as the existing potential therapeutic strategies for neurodegenerative disorders. These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases, and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases. However, this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases, such as Huntington's disease and Multiple sclerosis, and the potential therapeutic strategies were translated into clinical trials, which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.}, } @article {pmid40314791, year = {2025}, author = {Iuzzolino, VV and Scaravilli, A and Carignani, G and Senerchia, G and Pontillo, G and Dubbioso, R and Cocozza, S}, title = {Mapping motor and extra-motor gray and white matter changes in ALS: a comprehensive review of MRI insights.}, journal = {Neuroradiology}, volume = {67}, number = {7}, pages = {1683-1696}, pmid = {40314791}, issn = {1432-1920}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *White Matter/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; *Gray Matter/diagnostic imaging/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, yet with substantial clinical variability. Furthermore, beyond motor symptoms, ALS patients also show non-motor features, reflecting its classification as a multi-system disorder. The identification of reliable biomarkers is a critical challenge for improving diagnosis, tracking disease progression, and predicting patient outcomes. This review explores macro- and microstructural alterations in ALS, focusing on gray matter (GM) and white matter (WM) as observed through Magnetic Resonance Imaging (MRI). This approach synthesizes not only the expected involvement of motor areas but also highlights emerging evidence that these changes extend to extra-motor areas, such as the frontal and temporal lobes, underscoring the complex pathophysiology of ALS. The review emphasizes the potential of MRI as a non-invasive tool to provide new biomarkers by assessing both GM and WM integrity, a key advancement in ALS research. Additionally, it addresses existing discrepancies in findings and stresses the need for standardized imaging protocols. It also highlights the role of multi-modal MRI approaches in deepening our understanding of ALS pathology, emphasizing the importance of combining structural and diffusion MRI techniques to offer more comprehensive insights into ALS progression, ultimately advancing the potential for personalized treatment strategies and improving patient outcomes.}, } @article {pmid40324960, year = {2025}, author = {Simkins Lead, T and Shefner, JM and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and van Eijk, RP}, title = {Application of the ENCALS predictive survival model in assessing the effect of the 24/44 inclusion criteria in FORTITUDE-ALS.}, journal = {Journal of neuromuscular diseases}, volume = {12}, number = {5}, pages = {679-682}, pmid = {40324960}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/drug therapy/diagnosis ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; }, abstract = {FORTITUDE-ALS was a study evaluating reldesemtiv in people living with ALS. Post-hoc analysis identified larger treatment effects in those with symptom onset ≤24 months and baseline ALSFRS-R ≤ 44 (24/44 criteria). Using the ENCALS risk score (RS), we analyzed how the 24/44 criteria changed the eligible population. Of the 272 participants meeting the 24/44 criteria, 73% had very short to intermediate RS compared to 18% not meeting the criteria. Though the 24/44 criteria enriched the FORTITUDE-ALS population with rapidly progressing patients, they did not completely exclude all patients with a very long predicted survival.}, } @article {pmid40326914, year = {2025}, author = {Vasta, R and Ombelet, F and Hobin, F and Manera, U and Ammar, AC and Caravaca Puchades, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Holmdahl, O and Ingre, C and Lamaire, N and McDermott, C and Mac Domhnaill, É and McDonough, H and McFarlane, R and Mouzouri, M and Sarah, OM and Povedano Panadés, M and Sennfält, S and Shaw, P and Terrafeta Pastor, C and van den Berg, LH and van Eijk, RPA and Veldink, JH and Weemering, DN and Van Damme, P and Chiò, A}, title = {Real-world prognostic role of riluzole use in ALS: a multi-center study from PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {50-60}, doi = {10.1080/21678421.2025.2472889}, pmid = {40326914}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality/diagnosis ; Male ; Female ; Middle Aged ; *Neuroprotective Agents/therapeutic use ; Retrospective Studies ; Aged ; Prognosis ; Disease Progression ; Adult ; Kaplan-Meier Estimate ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) remains an incurable disease, with limited treatment options, and riluzole is the most widely available drug. We evaluated survival in a large cohort of patients with ALS, comparing those treated with riluzole to those who were not.

METHODS: Using data from the PRECISION-ALS database, we retrospectively analyzed patients with ALS who were treated with 100 mg of riluzole daily at the time of diagnosis. ALSFRS-R slope from onset to diagnosis (ΔFRS) was calculated. Based on the ΔFRS distribution, we defined fast progressors as patients having a ΔFRS > 1.17, intermediate progressors as those with 1.17 > ΔFRS > 0.31 and slow progressors as those with a ΔFRS < 0.31 points per month. We used Kaplan-Meier curves and Cox proportional hazards model to explore the association of riluzole use with patient survival since diagnosis.

RESULTS: Out of the 5842 patients with available riluzole data, 4847 (82.9%) received riluzole. The overall survival significantly differed between patients treated and not treated with riluzole (HR 0.70, 95%CI 0.69, 0.79), independently of sex, site of onset, age at onset and diagnostic delay. Patients treated with riluzole exhibited a 7 month longer median survival than those who did not receive riluzole (17.6 months, IQR 9.7, 29.9 vs 10.7 months, IQR 4.3, 23.4; p = 2 × 10[-16]). The relationship between riluzole use and extended survival varied across ΔFRS strata, being only evident among fast progressors (HR = 0.50, 95% 0.40, 0.63).

CONCLUSIONS: Treatment with riluzole is an independent prognostic factor in ALS. The extended survival related to riluzole use was only evident among fast-progressing patients.}, } @article {pmid40326917, year = {2025}, author = {van Eijk, RPA and Weemering, DN and Opie-Martin, S and van Unnik, JWJ and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, É and McDonough, H and Manera, U and McDermott, CJ and McFarlane, R and Mouzouri, M and Ombelet, F and Povedano Panadés, M and Sennfält, S and Shaw, PJ and Terrafeta Pastor, C and Van Damme, P and Vasta, R and Veldink, JH and Al-Chalabi, A and van den Berg, LH}, title = {Natural history of the revised ALS functional rating scale and its association with survival: the PRECISION-ALS Extant Study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {30-40}, doi = {10.1080/21678421.2024.2443985}, pmid = {40326917}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Disease Progression ; Aged ; Longitudinal Studies ; Cohort Studies ; Adult ; Severity of Illness Index ; Survival Rate/trends ; }, abstract = {OBJECTIVE: To characterize the natural history of the revised ALS functional rating scale (ALSFRS-R) over a 24-month period following initial assessment, and to assess its associations with survival.

METHODS: Longitudinal ALSFRS-R measurements and survival data were obtained from seven population-based, European cohorts. Different models for the ALSFRS-R trajectory were evaluated, including tests for linearity and between-cohort differences. We employed a joint modeling framework to factor in mortality, thereby aiming to derive a more precise estimate of the population's rate of decline, while simultaneously delineating its relationship with survival.

RESULTS: In total, 7,030 patients were included who produced 31,746 ALSFRS-R measurements during a follow-up period of 10,285 person-years. There was substantial evidence for a non-linear time trend within all cohorts (all p < 0.001), with faster progression rates at the beginning of follow-up. The average rate over 24 months was 0.89 points per month; 95% of the patients had a rate between 0.04 and 1.96. Overall, two components of the ALSFRS-R trajectory were found to be associated with survival: (1) the actual value of the ALSFRS-R total score and (2) the rate of change at any given time (both p < 0.001).

CONCLUSIONS: Functional loss in ALS follows a decelerating trajectory, where the current functional status and the rate of change have a direct impact on the patient' s probability of survival. Given the pivotal role of the ALSFRS-R in drug development, these results help to separate treatment benefit from the disease's natural trajectory and to estimate the impact on survival.}, } @article {pmid40333935, year = {2025}, author = {Vanderlinden, G and Carron, C and Van Weehaeghe, D and De Vocht, J and Ombelet, F and Masrori, P and De Weerdt, C and James, RE and Evans, LT and Schroeder, FA and Hooker, JM and Koole, M and Kranz, JE and Gilbert, TM and Van Damme, P and Van Laere, K}, title = {Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {7}, pages = {1350-1359}, pmid = {40333935}, issn = {2328-9503}, support = {//Association for Frontotemporal Degeneration/ ; //Target ALS/ ; //Eikonizo Therapeutics/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Middle Aged ; Female ; Male ; *Positron-Emission Tomography/methods ; Aged ; *Histone Deacetylase 6/metabolism ; *Frontotemporal Dementia/diagnostic imaging/metabolism ; *Brain/diagnostic imaging/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism/etiology ; }, abstract = {OBJECTIVE: [[18]F]EKZ-001 is a positron emission tomography (PET) tracer targeting histone deacetylase 6 (HDAC6), an enzyme responsible for intracellular transport and clearance of misfolded proteins. HDAC6 modulation is a promising treatment strategy in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Apart from motor symptoms, people with ALS (pwALS) can show a variable degree of cognitive impairment as part of the ALS-frontotemporal spectrum disorder (ALS-FTSD). This work assessed [[18]F]EKZ-001 binding in pwALS with variable involvement of FTSD.

METHODS: Twenty-four pwALS (13M/11F, 61 ± 10 years) and 12 healthy controls (HC) (6M/6F, 58 ± 3 years) were included. Thirteen pwALS were cognitively normal (ALS-CN), and eleven pwALS presented with FTSD (ALS-FTSD) ranging from mild cognitive or behavioral impairment to FTD, according to their performance on the Edinburgh cognitive and behavioral ALS screen (ECAS). All subjects underwent dynamic PET-MR imaging with arterial sampling, and regional distribution volumes (VT) were calculated using a Logan graphical analysis.

RESULTS: [[18]F]EKZ-001 VT was significantly lower in pwALS compared to HC. For ALS-CN, the largest reduction was found in the brainstem. For ALS-FTSD, reductions were more widespread in both gray and white matter. No differences in VT were found between pwALS with and without a C9orf72 mutation. [[18]F]EKZ-001 VT was not correlated with ECAS scores, age, or disease duration.

INTERPRETATION: [[18]F]EKZ-001 binding is lower throughout the brain in pwALS compared to HC. This may be related to a compensatory mechanism to repair intracellular transport defects in ALS or to reduced HDAC6 enzyme availability for [[18]F]EKZ-001 binding due to sequestration of HDAC6 within protein aggregates.}, } @article {pmid40344633, year = {2025}, author = {Tang, S and Shi, J and Li, X and Yang, M and Li, C and Zhang, D and Yang, S and Mei, C and Luo, Z and Zhang, L and Zhang, W and Zhang, C and Zhu, C and Ma, X and Xia, R and Chen, Y and Zhang, J and Chen, Q and Chen, S and Xie, Q and Yu, F}, title = {Development and Breeding of Herbicide-Resistant Sorghum for Effective Cereal-Legume Intercropping.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {27}, pages = {e2503083}, pmid = {40344633}, issn = {2198-3844}, support = {YZGG-04//Sorghum Seed Industry Innovation and Improved Joint Research Project of Shanxi Province/ ; 2023YFD1200700//National Key R&D Program of China/ ; 2023YFF1001400//National Key R&D Program of China/ ; 32222010//National Natural Science Foundation of China/ ; 32430077//National Natural Science Foundation of China/ ; }, mesh = {*Sorghum/genetics/drug effects/growth & development ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Edible Grain/genetics/drug effects ; *Plant Breeding/methods ; Acetolactate Synthase/genetics ; Imidazoles/pharmacology ; }, abstract = {Weeds bring a serious challenge to crop production, and herbicides is the most effective and economic way to manage it in field. Sorghum is a critical crop for staple food, fodder, and biofuel. However, the lack of herbicide-resistant sorghum germplasm severely impedes its production. Here, we conducted a large-scale screening and identified 13 sorghum mutant lines resistant to imidazolinone (IMI) herbicides. Two unique mutation sites in SbALS (acetolactate synthase), thus namely Sbals-1 (A93T) and Sbals-2 (S624N) are discovered, both enhance sorghum tolerance to imazamox. Notably, under high concentrations of imazamox, sbals-1 presented a superior growth phenotype and elevated SbALS activity than sbals-2, a difference that can be attributed to the predicted protein structures. Breeding with Sbals, both grain- and grass-type sorghum, shows great weed control and field performance. The herbicide imazamox resistance is further evaluated in a soybean population for sorghum-soybean strip intercropping, identifying 123 highly resistant soybean varieties. Field intercropping tests indicated health growth of both soybean and sorghum lines post-imazamox treatment, which enhance field clearance of weed. This study, therefore, provides valuable insights not only for herbicide-resistant sorghum breeding but also for the successful implementation of efficient and sustainable cereal-legume intercropping systems.}, } @article {pmid40346952, year = {2025}, author = {Çelik, F}, title = {Xenon in ALS Treatment: What Are We Waiting for?.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {5}, pages = {e70435}, pmid = {40346952}, issn = {1755-5949}, } @article {pmid40347374, year = {2025}, author = {Varshney, V and Gabble, BC and Bishoyi, AK and Varma, P and Qahtan, SA and Kashyap, A and Panigrahi, R and Nathiya, D and Chauhan, AS}, title = {Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {62}, number = {11}, pages = {14683-14705}, pmid = {40347374}, issn = {1559-1182}, mesh = {Humans ; *Exosomes/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; Early Diagnosis ; Animals ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.}, } @article {pmid40350531, year = {2025}, author = {Woo, TG and Han, J and Kim, Y and Hwang, YJ and Lee, M and Kang, SM and Park, S and Ji, Y and Chung, YH and Baek, S and Shin, E and Minju-Kim, and Jang, H and Shin, YJ and Kwon, Y and Kim, BH and Park, BJ}, title = {Inhibition of SOD1 trimerization is a novel drug target for ALS disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {21}, pmid = {40350531}, issn = {2047-9158}, support = {RS-2024-00399681//Ministry of Science and ICT, South Korea/ ; RS-2024-00339289//Ministry of Science and ICT, South Korea/ ; RS-2023-00258714//Korea Drug Development Fund/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics/antagonists & inhibitors ; Animals ; Humans ; Mice ; Mice, Transgenic ; *Protein Multimerization/drug effects ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that begins with motor neuron death in the spinal cord and cerebral cortex, ultimately resulting in death from respiratory distress (breathing failure). About 90% of ALS cases are sporadic, and 10% of ALS cases are of the inherited type with a genetic cause. About 150 different gene mutations have been reported so far. SOD1 is a well-identified gene associated with ALS. Indeed, SOD1 aggregation has been reported in ALS patients, but the mechanism of SOD1 aggregation remains unclear. Our previous work showed that inhibiting SOD1 aggregation with a hit compound (PRG-A-01) could reduce the SOD1-induced cytotoxicity and extend the lifespan of ALS mouse model (SOD1[G93A-Tg]). However, the low bioavailability and rapid degradation of the compound in vivo necessitates the development of a more effective candidate. We generated different derivatives and finally obtained the most potential drug candidate, PRG-A-04.

METHODS: Neuronal cell lines were transfected with the mutant SOD1 expression vector and incubated with PRG-A-04. SOD1 aggregation was examined by SOD1 oligomerization assay, immunofluorescence and dot blot assay. The interaction between GST-conjugated SOD1 recombinant proteins and PRG-A-04 was identified using LC-MS/MS and GST pull-down assay. To check the in vivo therapeutic effect of PRG-A-04, SOD1[G93A-Tg] mice were injected with PRG-A-04; then behavioral test, histological analysis and microarray were performed.

RESULTS: PRG-A-04 demonstrated favorable pharmacokinetics including high bioavailability and significant blood-brain barrier penetration. Indeed, oral administration of PRG-A-04 in ALS mouse model inhibited the aggregation of SOD1 in the spinal cord, protected against neuronal loss, and extended the lifespan of ALS mice by up to 3 weeks. In vitro, PRG-A-04 selectively bound to the mutant form of SOD1, but not the wild type, and efficiently inhibited the aggregation caused by SOD1-G147P (a SOD1 trimer stabilizer).

CONCLUSIONS: Our findings underscore the potential of targeting trimeric SOD1 in ALS treatment, positioning PRG-A-04 as a strong drug candidate for both familial and sporadic ALS.}, } @article {pmid40353466, year = {2025}, author = {Dhasmana, S and Dhasmana, A and Khan, S and Narula, AS and Haque, S and Yallapu, MM and Chauhan, SC}, title = {Excessive Urinary p75ecd is a Potential Indicator of Amyotrophic Lateral Sclerosis: An American Cohort Study.}, journal = {Current neuropharmacology}, volume = {23}, number = {12}, pages = {1621-1630}, pmid = {40353466}, issn = {1875-6190}, support = {U54 MD019970/MD/NIMHD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/urine/diagnosis ; Male ; Female ; Middle Aged ; Biomarkers/urine ; Cohort Studies ; Aged ; Adult ; Neurofilament Proteins/urine ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and rapidly progressive neurodegenerative disease. At present, neurofilament light (NFL) and phosphorylated neurofilament heavy (pNfH) proteins in biological fluids are commonly known prognostic biomarkers, but their levels stabilize over time. Thus, there is a critical gap in the field to identify unique biomarkers that can aid disease diagnosis, progression and monitoring the therapy response.

AIMS: To evaluate the presence of extracellular domain of p75 (p75ecd) in urine of ALS patients and healthy control volunteers in the North American cohort.

METHODS: An enzyme-linked immunoassay (ELISA) and creatinine assay was used to determine the levels of p75ecd and creatinine in the urine of ALS patients and healthy control volunteers respectively. This assay demonstrated clear discrimination in the levels of the p75ecd in the urine samples of ALS patients as compared to healthy individuals.

RESULTS: It was found that the concentration of p75ecd in ALS samples was significantly higher than that of healthy controls group. Additionally, high p75ecd levels were segregated with respect to age, sex, family history, occupation and drug treatment, medication status. Moreover, we observed differential expression patterns among the different stages of the disease. Our results followed the pattern that was observed in the Chinese, and Australian cohort. c Conclusion: Altogether, our results indicate that the development of an efficient system for the detection of elevated levels of p75ecd in the urine could serve as a useful modality for early ALS diagnosis, disease progression, and monitoring the effectiveness of therapeutic interventions.}, } @article {pmid40354799, year = {2025}, author = {Bensimon, G and Leigh, PN and Tree, T and Malaspina, A and Payan, CA and Pham, HP and Klaassen, P and Shaw, PJ and Al Khleifat, A and Amador, MDM and Attarian, S and Bell, SM and Beltran, S and Bernard, E and Camu, W and Corcia, P and Corvol, JC and Couratier, P and Danel, V and Debs, R and Desnuelle, C and Dimitriou, A and Ealing, J and Esselin, F and Fleury, MC and Gorrie, GH and Grapperon, AM and Hesters, A and Juntas-Morales, R and Kolev, I and Lautrette, G and Le Forestier, N and McDermott, CJ and Pageot, N and Salachas, F and Sharma, N and Soriani, MH and Sreedharan, J and Svahn, J and Verber, N and Verschueren, A and Yildiz, O and Suehs, CM and Saker-Delye, S and Muller, C and Masseguin, C and Hajduchova, H and Kirby, J and Garlanda, C and Locati, M and Zetterberg, H and Asselain, B and Al-Chalabi, A and , }, title = {Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial.}, journal = {Lancet (London, England)}, volume = {405}, number = {10492}, pages = {1837-1850}, doi = {10.1016/S0140-6736(25)00262-4}, pmid = {40354799}, issn = {1474-547X}, mesh = {Humans ; Female ; Male ; *Riluzole/administration & dosage/therapeutic use/adverse effects ; Middle Aged ; Double-Blind Method ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Adult ; Aged ; *Interleukin-2/administration & dosage/adverse effects/therapeutic use ; *Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects ; Treatment Outcome ; Drug Therapy, Combination ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS.

METHODS: In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18-76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12-18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete.

FINDINGS: From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2LD (hazard ratio 0·81 [95% CI 0·54-1·22], p=0·33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2LD (0·32 [0·14-0·73], p=0·007), with a significant treatment by CSF-pNFH interaction (1·0003 [1·0001-1·0005], p=0·001). IL-2LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2LD was associated with a significant 48% decrease in risk of death (0·52 [0·30-0·89], p=0·016) in the 70% of the population with low (750-3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1·37 [0·68-2·75], p=0·38).

INTERPRETATION: With this treatment schedule, IL-2LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS.

FUNDING: European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association.}, } @article {pmid40355776, year = {2025}, author = {Hirose, S and Kobatake, Y and Tada, N and Kandeel, M and Itoh, A and Oh-Hashi, K}, title = {NanoBiT-based Analysis of Canine SOD1 Protein Dynamics: Understanding the Role of CCS and Ebselen Derivatives as Potential Therapeutics for Canine Degenerative Myelopathy.}, journal = {Cell biochemistry and biophysics}, volume = {83}, number = {3}, pages = {3945-3958}, pmid = {40355776}, issn = {1559-0283}, support = {KFU241899//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University/ ; }, mesh = {Dogs ; Isoindoles ; *Organoselenium Compounds/chemistry/pharmacology/therapeutic use/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; Animals ; *Azoles/chemistry/pharmacology/therapeutic use/metabolism ; Molecular Docking Simulation ; *Spinal Cord Diseases/drug therapy/veterinary/metabolism ; Mutation ; Humans ; Amyotrophic Lateral Sclerosis/drug therapy ; }, abstract = {Canine degenerative myelopathy (DM) is a progressive neurodegenerative disorder that shares common pathological features with amyotrophic lateral sclerosis (ALS) in humans. Both diseases are linked to mutations in the superoxide dismutase 1 (SOD1) gene. Understanding the molecular differences between wild-type (WT) and mutant SOD1 proteins is critical for developing therapeutic strategies. In this study, we employed the NanoLuc complementation (NanoBiT) reporter system to investigate the expression and functional differences between WT and E40K mutant canine SOD1 to assess the therapeutic potential of copper chaperone for SOD1 (CCS) and ebselen derivatives. E40K cSOD1 displayed significantly reduced luciferase activity compared to WT cSOD1 in all NanoBiT-tagged combinations, indicating altered homodimerization and protein stability. Co-transfection with CCS increased both WT and mutant cSOD1 protein levels and reporter activities, with a more pronounced effect on the E40K mutant. Ebselen treatment enhanced luciferase activity, particularly in E40K cSOD1-expressing cells. Two compounds (compounds 2 and 5) were stronger than the parent compound in improving mutant cSOD1-derived NanoBiT activities. Additionally, molecular docking simulations revealed stronger binding affinities of ebselen and its derivatives to E40K cSOD1, suggesting potential therapeutic benefits. In conclusion, the NanoLuc reporter system offers a valuable tool for screening potential therapeutics for SOD1-linked neurodegenerative diseases. CCS and ebselen derivatives exhibited promising effects on SOD1 activity, providing a basis for future therapeutic strategies targeting both DM and ALS.}, } @article {pmid40360341, year = {2025}, author = {Lin, W and Huang, C and Tan, Z and Xu, H and Wei, W and Wang, L}, title = {Cu[II]-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases.}, journal = {Seminars in nuclear medicine}, volume = {55}, number = {4}, pages = {577-586}, doi = {10.1053/j.semnuclmed.2025.03.008}, pmid = {40360341}, issn = {1558-4623}, mesh = {Humans ; *Oxidative Stress ; *Neurodegenerative Diseases/diagnostic imaging/metabolism/complications ; Animals ; *Copper/chemistry ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism/complications ; Positron-Emission Tomography ; Radioactive Tracers ; *Thiosemicarbazones/chemistry ; }, abstract = {Neurodegenerative diseases, characterized by progressive neuronal degeneration and associated with neuroinflammation and oxidative stress, present significant challenges in diagnosis and treatment. This review explores the potential of copper(II)-bis(thiosemicarbazone) complexes, particularly Cu-ATSM, as a dual-purpose radiopharmaceutical for imaging and therapeutic interventions. Cu-ATSM exhibits unique redox-dependent retention in pathological microenvironments, driven by mitochondrial dysfunction and hyper-reductive states, which enables the noninvasive detection of oxidative stress via positron emission tomography (PET). Preclinical studies demonstrate its efficacy in mitigating neuroinflammation by suppressing glial activation, reducing the secretion of pro-inflammatory cytokines (e.g., TNF-α, MCP-1), and increasing the expression of neuroprotective metallothionein-1 (MT1). Some Clinical research reveals elevated [64]Cu-ATSM uptake in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients, correlating with disease severity and regional oxidative stress markers. Furthermore, Cu-ATSM derivatives show promise in modulating blood-brain barrier (BBB) permeability, enhancing amyloid-β clearance, and restoring copper homeostasis in ALS models. Despite these advances, limitations such as small cohort sizes and heterogeneity in clinical studies underscore the need for larger-scale validation. Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders.}, } @article {pmid40362582, year = {2025}, author = {Kitaoka, Y and Uchihashi, T and Kawata, S and Nishiura, A and Yamamoto, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S and Spigelman, I and Seki, S}, title = {Role and Potential of Artificial Intelligence in Biomarker Discovery and Development of Treatment Strategies for Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, pmid = {40362582}, issn = {1422-0067}, support = {24K13154//Japan Society for the Promotion of Science/ ; 21K10091//Japan Society for the Promotion of Science/ ; 24K13113//Japan Society for the Promotion of Science/ ; 23K09351//Japan Society for the Promotion of Science/ ; 24K13112//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; *Artificial Intelligence ; Proteomics/methods ; Neuroimaging/methods ; Deep Learning ; }, abstract = {Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), present significant challenges owing to their complex pathologies and a lack of curative treatments. Early detection and reliable biomarkers are critical but remain elusive. Artificial intelligence (AI) has emerged as a transformative tool, enabling advancements in biomarker discovery, diagnostic accuracy, and therapeutic development. From optimizing clinical-trial designs to leveraging omics and neuroimaging data, AI facilitates understanding of disease and treatment innovation. Notably, technologies such as AlphaFold and deep learning models have revolutionized proteomics and neuroimaging, offering unprecedented insights into ALS pathophysiology. This review highlights the intersection of AI and ALS, exploring the current state of progress and future therapeutic prospects.}, } @article {pmid40364643, year = {2026}, author = {Wen, X and Lan, T and Su, W and Cao, B and Wang, Y and Chen, Y}, title = {Latest progress and challenges in drug development for degenerative motor neuron diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {5}, pages = {1849-1863}, pmid = {40364643}, issn = {1673-5374}, abstract = {Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions. They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage. The main types include amyotrophic lateral sclerosis, progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy, the pathological processes of which are largely identical, with the main disparity lying in the location of the lesions. Amyotrophic lateral sclerosis is the representative condition in this group of diseases, while other types are its variants. Hence, this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases. Although the precise pathogenesis remains elusive, recent advancements have shed light on various theories, including gene mutation, excitatory amino acid toxicity, autoimmunology, and neurotrophic factors. The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis: riluzole, edaravone, AMX0035, and tofersen, with the latter being the most recent to receive approval. However, following several phase III trials that failed to yield favorable outcomes, AMX0035 has been voluntarily withdrawn from both the US and Canadian markets. This article presents a comprehensive summary of drug trials primarily completed between January 1, 2023, and June 30, 2024, based on data sourced from clinicaltrials.gov. Among these trials, five are currently in phase I, seventeen are in phase II, and eleven are undergoing phase III evaluation. Notably, 24 clinical trials are now investigating potential disease-modifying therapy drugs, accounting for the majority of the drugs included in this review. Some promising drugs being investigated in preclinical studies, such as ATH-1105, are included in our analysis, and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases. This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs, with the aim of highlighting the latest potentialities for clinical therapy.}, } @article {pmid40374790, year = {2025}, author = {Verma, KK and Gaur, PK and Gupta, SL and Lata, K and Kaushik, R and Sharma, V}, title = {Metabolomics: a new frontier in neurodegenerative disease biomarker discovery.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {21}, number = {3}, pages = {67}, pmid = {40374790}, issn = {1573-3890}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Biomarkers/metabolism/analysis ; *Metabolomics/methods ; Animals ; }, abstract = {BACKGROUND: Neurodegenerative disorders are a group of debilitating diseases affecting the central nervous system, and are characterized by the progressive loss of neurons, leading to declines in cognitive function, movement, and overall quality of life. While the exact causes remain elusive, it's believed that a combination of genetic, environmental, and lifestyle factors contribute to their development. Metabolites, the end products of cellular processes, reflect the physiological state of an organism. By analysing these molecules, researchers can gain a deeper understanding of the underlying metabolic changes associated with neurodegenerative disorders.

AIM OF REVIEW: This review aims to explore the possibilities between metabolites and their association with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS) and Huntington's disease (HD).

Metabolomic studies could potentially illuminate altered biochemical pathways, facilitating earlier detection and treatment of these conditions. Metabolomic investigations have revealed the role of oxidative stress, alterations in glucose and fat metabolism, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and alterations in myelin composition in neurodegenerative disorders. The common metabolic biomarkers identified includes glutamate, taurine, uric acid, branched chain amino acids, acylcarnitine, creatinine, choline, with some more amino acids and lipids. Metabolomics offers valuable insights into disease mechanisms and potential therapeutic targets by identifying biochemical and metabolic alterations, but still there are several aspects to be explored for accurate mapping of metabolites with specific pathway involved in the disease.}, } @article {pmid40381165, year = {2025}, author = {Esperante, I and Banzan, C and Munuera, JZ and Lima, A and Hunt, H and De Kloet, ER and Deniselle, MCG and De Nicola, AF and Meyer, M}, title = {The Selective Glucocorticoid Receptor Modulator Cort125329 Decreases Neuroinflammation and Gliosis and Enhances Myelination in the Wobbler Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {9}, pages = {12252-12269}, pmid = {40381165}, issn = {1559-1182}, support = {PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; AFDN grant//CORCEPT Therapeutics/ ; 20020170100224BA)//Universidad de Buenos Aires/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/complications ; *Receptors, Glucocorticoid/metabolism ; *Gliosis/drug therapy/pathology/complications/metabolism ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/pathology/complications/metabolism ; *Myelin Sheath/drug effects/metabolism ; Mice ; Motor Neurons/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; Male ; }, abstract = {The Wobbler mouse is a genetic model of familial amyotrophic lateral sclerosis. Wobblers show spinal cord neurodegeneration associated with gliosis, neuroinflammation, and demyelination. Like human neurodegenerative diseases, Wobblers show high levels of corticosterone in the blood and the nervous system. The role of glucocorticoids in neuropathology is suggested by the observation that pathological signs attenuate with treatment with glucocorticoid receptor (GR) antagonists/modulators. In the present study, we demonstrated in 5-month-old clinically afflicted Wobbler mice that the selective GR modulator CORT125329 decreased motoneuron degeneration, astro- and microgliosis, and levels of pro-inflammatory factors (HMGB1, toll-like receptor 4, tumor necrosis factor α, and its receptor). In addition, CORT125329 increased the acetylcholine-producing enzyme choline acetyltransferase, the neurotrophin brain-derived neurotrophic factor, and their cellular colocalization. Furthermore, the increased oligodendrocyte number and a healthier myelin ultrastructure are consistent with the enhanced axonal myelination after CORT125329 treatment. Finally, the high expression of immunoreactive protein and mRNA levels of aquaporin4 in Wobblers was decreased by CORT125329 treatment, implying this water channel is a glucocorticoid target involved in neuropathology. The beneficial effects of CORT125329 correlated with enhanced motor behavioral performance and trophic changes of the forelimbs. In conclusion, our results support further preclinical and clinical studies on GR modulators in sporadic amyotrophic lateral sclerosis.}, } @article {pmid40381433, year = {2025}, author = {Begh, MZA and Zehravi, M and Bhuiyan, MAK and Molla, MR and Raman, K and Emran, TB and Ullah, MH and Ahmad, I and Osman, H and Khandaker, MU}, title = {Recent advances in stem cell approaches to neurodegeneration: A comprehensive review with mechanistic insight.}, journal = {Pathology, research and practice}, volume = {271}, number = {}, pages = {156013}, doi = {10.1016/j.prp.2025.156013}, pmid = {40381433}, issn = {1618-0631}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; }, abstract = {The progressive nature of neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, presents substantial problems because current treatments are still obscure. Stem cell-based treatments are emerging as a viable solution to address the significant gaps in treating these severe diseases. This study provides a comprehensive analysis of the latest advancements in stem cell research, focusing on the treatment of NDs. Various types of stem cells, such as adult, induced pluripotent, and embryonic stem cells, and their potential applications in immunomodulation, neurotrophic factor release, and neuronal development are also discussed. Recent clinical studies reveal outcomes, challenges, and solutions, with advancements in disease-specific neural cell production, gene editing, and improved stem cell transplantation transport strategies. The review discussed future perspectives on developing more effective stem cell-based interventions. Biomaterials are being used for cell distribution and personalized medicine techniques to improve treatment outcomes, while exploring stem cell treatments for NDs and identifying areas for further research.}, } @article {pmid40384011, year = {2025}, author = {Changqing, L and Leying, Y and Caiyun, M and Hebao, W and Laiguo, H and Xiaojiang, Z}, title = {Causal Relationships Between the Gut Microbiota, Inflammatory Cytokines, and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70571}, pmid = {40384011}, issn = {2162-3279}, support = {//Philosophy and Social Sciences Foundation of the Anhui Higher Education Institutions of China/ ; //Provincial Quality Engineering Project of Higher Education Institutions of Anhui Province/ ; //Natural Science Foundation of the Higher Education Institutions of Anhui Province/ ; 202310367042//National College Students Innovation and Entrepreneurship Training Program/ ; //innovation and entrepreneurship training program for college students/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/microbiology ; Humans ; Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics/physiology ; *Cytokines/metabolism/genetics ; Genome-Wide Association Study ; Inflammation ; }, abstract = {BACKGROUND: The relationship between gut microbiota (GM) and amyotrophic lateral sclerosis (ALS) is well-documented. However, the causal nature of this association and the potential mediating role of inflammatory cytokines (ICs) have yet to be elucidated.

METHODS: We performed Mendelian randomization (MR) analyses utilizing data derived from genome-wide association studies (GWAS) of GM, ICs, and ALS. Initially, we conducted bidirectional two-sample MR analysis to determine the causal relationships between GM, ICs, and ALS. Subsequently, a two-step MR mediation analysis was performed to investigate the role of ICs as mediators. The primary statistical approach was the inverse variance weighted (IVW) method.

RESULTS: Through MR analysis, we identified one positive causal relationship and three negative causal relationships between GM and ALS. There was one positive association and one negative association between ICs and ALS. In addition, ICs do not appear to mediate the pathway from GM to ALS.

CONCLUSION: This study established a causal relationship between GM, ICs, and ALS, suggesting that ICs do not function as mediators in the pathway from GM to ALS. These findings provide new perspectives on potential ALS prevention and treatment strategies.}, } @article {pmid40384575, year = {2025}, author = {Vogt, C and Weber, M and Schneider, U and Neuwirth, C}, title = {Quinine Sulfate for Muscle Cramps in Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind Crossover Trial.}, journal = {Muscle & nerve}, volume = {72}, number = {2}, pages = {267-273}, doi = {10.1002/mus.28440}, pmid = {40384575}, issn = {1097-4598}, support = {//Swiss ALS foundation/ ; //Hänseler AG/ ; }, mesh = {Humans ; *Quinine/therapeutic use ; Double-Blind Method ; *Muscle Cramp/drug therapy/etiology ; Male ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Female ; Cross-Over Studies ; Middle Aged ; Aged ; Adult ; Treatment Outcome ; Muscle Relaxants, Central/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: Many patients with amyotrophic lateral sclerosis (ALS) experience muscle cramps during the course of the disease. This study aimed to evaluate the efficacy of orally administered quinine sulfate for muscle cramps in ALS patients.

METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial in ALS patients experiencing daily muscle cramps. After a two-week run-in period, patients were assigned to receive 250 mg quinine sulfate once daily, followed by a placebo or vice versa. Each treatment period lasted 2 weeks and was followed by a 4-week washout period. Patients used a daily diary to rate muscle cramp intensity on the numeric rating scale (NRS) and record muscle cramp frequency. The primary outcome measure was change in cramp intensity; coprimary outcome measures were number of muscle cramps during daytime and nighttime.

RESULTS: Data from four women and three men were included in the analysis, all of whom reported a notable reduction in cramp intensity and frequency, leading them to continue the medication. Quinine sulfate was well-tolerated, with two patients reporting mild tinnitus. Cramp intensity was significantly reduced by 48% (p = 0.042). Further, the number of daytime muscle cramps declined significantly (p = 0.024).

DISCUSSION: Our findings suggest the potential efficacy of quinine sulfate in reducing muscle cramp intensity and frequency in ALS patients. However, the small sample size (n = 7) limits generalizability. Larger, multicenter studies are needed to confirm these results and fully assess its safety, serious adverse events, and therapeutic potential.}, } @article {pmid40385805, year = {2025}, author = {Moutinho, A and Fontes, J and Ferreira, L and Lopes, J and Martins, F and Mega, S and Gil, M and Barros, F and Correia, AM}, title = {Sepsis Alerts in the Pre-hospital Setting: An Observational Retrospective Study of Emergency Medical Services' Response in Portugal (2020-2023).}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82528}, pmid = {40385805}, issn = {2168-8184}, abstract = {Background Sepsis is a life-threatening condition that demands prompt recognition and intervention to enhance patient outcomes. Early identification and timely treatment, particularly in the prehospital setting, are essential. Objective This study aims to characterize sepsis pre-alerts issued by the Portuguese Emergency Medical Services (EMS) early warning system between May 2020 and December 2023, focusing on adult patients. It provides an overview of the alert system and examines associated clinical data, therapeutic interventions, and hospital referrals. Methods A retrospective analysis was conducted on sepsis pre-alerts from the Portuguese EMS database. Data collected included patient demographics, comorbidities, National Early Warning Score (NEWS), interventions administered, and outcomes. Results A total of 537 sepsis alerts were identified, with a median patient age of 83 years. The majority of patients had significant cardiovascular and neurological comorbidities. The average NEWS was 11.74. Advanced Life Support (ALS) or Integrated Life Support (ILS) teams were required in 76.9% (N=413) of cases. Interventions included intravenous fluid administration in 49.3% (N=265), oxygen therapy in 46.2% (N=248), and vasopressor use in 3.9% (N=14). Conclusions Effective prehospital sepsis management is crucial for improving patient outcomes. Challenges such as delayed hospital transfers, often due to regional constraints, highlight the need for enhanced integration between EMS and hospital care. Future efforts should focus on optimizing early sepsis management, fostering collaboration between EMS and hospital teams, and exploring the feasibility of prehospital antibiotic administration.}, } @article {pmid40388191, year = {2025}, author = {De Marchi, F and Lombardi, I and Bombaci, A and Diamanti, L and Olivero, M and Perciballi, E and Tornabene, D and Vulcano, E and Ferrari, D and Mazzini, L}, title = {Recent therapeutic advances in the treatment and management of amyotrophic lateral sclerosis: the era of regenerative medicine.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {7}, pages = {773-789}, doi = {10.1080/14737175.2025.2508781}, pmid = {40388191}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Regenerative Medicine/methods ; Genetic Therapy/methods ; Stem Cell Transplantation/methods ; Animals ; }, abstract = {INTRODUCTION: Despite decades of research, effective disease-modifying treatments for Amyotrophic Lateral Sclerosis (ALS) remain scarce. The emergence of regenerative medicine presents a new frontier for ALS treatment.

AREAS COVERED: This review is based on a comprehensive literature search using PubMed, Scopus and clinical trials databases on the recent therapeutic advancements in ALS, giving focus to regenerative medicine. The article includes coverage of stem cell-based therapies, including mesenchymal, neural and induced pluripotent stem cells; all of which may offer potential neuroprotective and immunomodulatory effects. Gene therapy, particularly antisense oligonucleotides targeting ALS-related mutations, has gained traction, with tofersen becoming the first FDA-approved genetic therapy for ALS. The article also covers emerging approaches such as extracellular vesicles, immune-modulating therapies, and bioengineering techniques, including CRISPR-based gene editing and cellular reprogramming, that hold promise for altering disease progression.

EXPERT OPINION: While regenerative medicine provides hope for ALS patients, significant challenges remain. Biomarkers will play a crucial role in guiding personalized treatment strategies, ensuring targeted interventions. Future research should prioritize optimizing combinatory approaches, integrating different therapy strategies to maximize patient outcomes. Although regenerative medicine is still in its early clinical stages, its integration into ALS treatment paradigms could redefine disease management and alter its natural course.}, } @article {pmid40389086, year = {2025}, author = {Pu, K and Yang, S and Sheng, R and Chen, J and Dai, Y and Wood, IC and Zhong, Z and Xu, S}, title = {Chuanxiong-Danggui herb pair alleviated cognitive deficits of APP/PS1 mice by promoting mitophagy.}, journal = {Journal of ethnopharmacology}, volume = {350}, number = {}, pages = {119988}, doi = {10.1016/j.jep.2025.119988}, pmid = {40389086}, issn = {1872-7573}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice, Inbred C57BL ; *Mitophagy/drug effects ; *Cognitive Dysfunction/drug therapy ; Mice ; *Alzheimer Disease/drug therapy/pathology ; Amyloid beta-Protein Precursor/genetics ; Hippocampus/drug effects/pathology/metabolism ; Mice, Transgenic ; Male ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Presenilin-1/genetics ; Cell Line ; Dendritic Spines/drug effects ; Maze Learning/drug effects ; }, abstract = {Disruption of receptor-mediated mitophagy contributes to neuronal damage in Alzheimer's disease (AD). Chuanxiong-Danggui herb pair (CDHP) is classic herbal pair applied to treating neurodegenerative diseases including AD, Amyotrophic Lateral Sclerosis, Parkinson's disease. Though studies have demonstrated the neuroprotective effects of CDHP, the underlying mechanisms by which CDHP attenuates neuronal impairment of AD remains to be elucidated.

AIM OF THE STUDY: The objective of this work was to investigate the anti-AD mechanism of CDHP in APP/PS1 mice.

MATERIALS AND METHODS: Behavioral assessments were conducted on C57BL/6J and APP/PS1 mice following CDHP treatment, alongside an evaluation of neuronal morphology in the hippocampal region. In vitro, HT-22 cells were induced by Aβ25-35 before being treated with CDHP. The mechanisms of CDHP were investigated using transmission electron microscopy, Golgi staining, immunofluorescence, and Western blot analysis.

RESULTS: Results from the passive avoidance test and the Morris water maze (MWM) indicated that CDHP significantly mitigated cognitive deficits of APP/PS1 mice, accompanied by a reduction of pathological damage in the CA1 and CA3 regions of hippocampus. Further testing found that a significant reduction in dendritic spines density was rescued by CDHP. Synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) were elevated in the CDHP group, while β-amyloid (Aβ) plaques deposition was significantly reduced. Simultaneously, CDHP markedly inhibited neuronal apoptosis through a decrease of the levels of Cleaved Caspase-12 and enhanced expression of Bcl-2/Bax, both in vivo and in vitro. Additionally, CDHP improved mitochondrial morphology and function in the AD model by decreasing abnormal mitochondria and increasing the expression of COXIV. Transmission electron microscopy (TEM) revealed that clear mitophagy-autophagosomes were nearly absent in APP/PS1 mice, while the expression of p62 and LC3B were elevated following CDHP treatment. Furthermore, CDHP increased the expression of the FUNDC1 and PGAM5 in APP/PS1 mice and AD-like cell models.

CONCLUSION: These findings suggest that CDHP mitigated cognitive dysfunction in APP/PS1 mice by enhancing mitophagy to reduce neuronal injury.}, } @article {pmid40389171, year = {2025}, author = {Das, D and Das, A and Bhattacharya, K and Koch, KP and Deuri, DJ and Saikia, D and Chanu, NR and Deka, S}, title = {Xanthones as neuroprotective agents: A comprehensive review of their role in the prevention and treatment of neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {109}, number = {}, pages = {102772}, doi = {10.1016/j.arr.2025.102772}, pmid = {40389171}, issn = {1872-9649}, mesh = {*Xanthones/therapeutic use/pharmacology/chemistry ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/prevention & control ; Animals ; }, abstract = {Over the recent years, numerous research efforts have been focused toward xanthones, a class of heterocyclic compounds characterized by a three-ring core structure and a diverse range of biological activities. Despite extensive studies, no xanthone-based molecule has successfully progressed through clinical trials to reach pharmaceutical applications. Xanthones belong to the class of secondary metabolites that exist naturally, found in various plant species, and their structural diversity has been further expanded through synthetic modifications to enhance their pharmacological efficacy. This review provides a comprehensive description of the therapeutic potential of xanthone derivatives within the scope of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuroinflammation. Existing literature has been rigorously examined to highlight the pharmacological relevance of xanthones in these disorders. Additionally, the pathophysiological aspects of each disease are discussed in detail to establish a mechanistic understanding of how xanthone derivatives may exert neuroprotective effects. Furthermore, the SAR of xanthones is explored to elucidate key molecular features responsible for their bioactivity, providing insights into rational drug design. By synthesizing and critically analyzing the existing research, this review is focused in highlighting the therapeutic relevance of xanthones in neurodegenerative diseases and their potential as lead candidates for further drug development.}, } @article {pmid40389989, year = {2025}, author = {Noh, MY and Oh, SI and Kim, YE and Cha, SJ and Sung, W and Oh, KW and Park, Y and Mun, JY and Ki, CS and Nahm, M and Kim, SH}, title = {Mutations in NEK1 cause ciliary dysfunction as a novel pathogenic mechanism in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {59}, pmid = {40389989}, issn = {1750-1326}, support = {RS-2023-00265515//Ministry of Science and ICT/ ; RS-2023-00265515//Ministry of Science and ICT/ ; 24-BR-02-04//Ministry of Science and ICT/ ; 25-BR-04-01//Ministry of Science and ICT, South Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *NIMA-Related Kinase 1/genetics/metabolism ; *Cilia/metabolism/pathology/genetics ; Mutation/genetics ; Female ; Male ; Middle Aged ; Motor Neurons/metabolism ; Fibroblasts/metabolism ; Adult ; }, abstract = {BACKGROUND: Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear.

METHODS: We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand the disease contribution of NEK1 variants in ALS, we performed a series of functional studies using patient fibroblasts focusing on primary cilia and microtubule-related phenotypes. In addition, these findings were validated in iPSC-derived motor neurons (iPSC-MNs).

RESULTS: NIMA-related kinase 1 (NEK1), a gene encoding a serine/threonine kinase involved in cell cycle regulation, has been identified as a risk gene for amyotrophic lateral sclerosis (ALS). Here, we report that mutations in NEK1 cause primary ciliary abnormality, cell cycle re-entry, and disrupted tubulin acetylation in ALS. We analyzed the whole-exome sequences of 920 Korean patients with sporadic ALS and identified 16 NEK1 variants in 23 patients. We found that two novel variants, p.E853Rfs*9 and p.M1?, reduced NEK1 expression, resulting in loss-of-function (LOF) and one synonymous splicing variant (p.Q132=) exhibited an aberrant isoform lacking exon 5. All three NEK1 variants exhibited abnormal primary ciliary structure, impaired sonic hedgehog signaling, and altered cell-cycle progression. Furthermore, the ALS-linked variants induced intracellular calcium overload followed by Aurora kinase A (AurA)-histone deacetylase (HDAC)6 activation, resulting in ciliary disassembly. These defects were restored by treatment with the intracellular Ca[2+] chelator, BAPTA. We also found that NEK1 variants cause decreased α-tubulin acetylation, mitochondrial alteration, and impaired DNA damage response (DDR). Notably, drug treatment to inhibit HDAC6 restored the NEK1-dependent deficits in patient fibroblasts. And, we confirmed that data found in patient fibroblasts were reproduced in iPSC-MNs model.

CONCLUSIONS: Our results suggest that NEK1 contributes to ALS pathogenesis through the LOF mechanism, and HDAC6 inhibition provides an attractive therapeutic strategy for NEK1 variants associated ALS treatment.}, } @article {pmid40391540, year = {2025}, author = {Massey, C and Hobson, E and Griffiths, AW and Musson, L and McDermott, C}, title = {Exploring mechanisms of behavior change for healthcare professionals in cough and secretion management in ALS.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {4}, pages = {149-160}, pmid = {40391540}, issn = {1758-2032}, support = {NIHR301648//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Cough/therapy/etiology ; *Health Personnel/psychology ; Female ; Male ; Focus Groups ; Middle Aged ; Qualitative Research ; Adult ; }, abstract = {OBJECTIVES: To explore healthcare professionals' experiences managing cough and secretion problems in Amyotrophic Lateral Sclerosis (ALS).

METHODS: A qualitative study was completed with 23 individuals participating in four focus groups. Data was analyzed using reflexive thematic analysis and COM-B and theoretical domains framework (TDF) behavior change frameworks.

RESULTS: This study found that roles, responsibilities, and expectations needed to be clearly defined and that building relationships was important to support care delivery. Barriers identified included limited access to specialist care, equipment, and opportunities to gain knowledge and skills. A structured clinical assessment was highlighted to enable good-quality care. Data mapped most commonly to the environmental context/resources, knowledge, skills (TDF), and physical capability (COM-B) behavior change domains.

CONCLUSION: Cough and secretion management in ALS is complex due to the multifaceted nature of the disease. This study emphasizes the need for future development of clinical interventions to support care.}, } @article {pmid40395983, year = {2025}, author = {Beckers, J and Van Damme, P}, title = {The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2474796}, pmid = {40395983}, issn = {2769-4127}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two extremes of a neurodegenerative disease spectrum characterised by overlapping genetic, clinical, and neuropathological features. This review covers the intricate relationship between both ALS and FTD and defects in the autophagy and endolysosomal pathway as recent evidence has pointed towards alterations in these pathways as being a root cause of disease pathogenesis. Here, we review the current knowledge on the interplay between ALS/FTD and lysosomebased proteostasis pathways and carefully asses the steps of the autophagy and endolysosomal pathways that are impaired by ALS or FTDcausing variants. Finally, we present a comprehensive overview of therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating the impact of these devastating diseases. Through this review, we aim to enhance the understanding of the pathophysiological mechanisms involving autophagy and/or the endolysosomal system that underlie the ALS-FTD spectrum and underscore the necessity for specific therapeutic approaches that target these shared vulnerabilities.}, } @article {pmid40396445, year = {2025}, author = {Hu, X and Cheng, J and Yuan, R and Zhou, Y and Rao, J and Wan, Y and Li, Y and Zhang, X and Li, R}, title = {Gold nanoparticles: diagnostic and therapeutic applications in neurodegenerative disorders.}, journal = {Journal of drug targeting}, volume = {33}, number = {9}, pages = {1511-1528}, doi = {10.1080/1061186X.2025.2509287}, pmid = {40396445}, issn = {1029-2330}, mesh = {Humans ; *Gold/chemistry/administration & dosage ; *Metal Nanoparticles/chemistry/administration & dosage ; *Neurodegenerative Diseases/drug therapy/diagnosis ; Blood-Brain Barrier/metabolism ; Animals ; Drug Delivery Systems/methods ; }, abstract = {Neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases, pose a significant and escalating health challenge in the context of an ageing population. Gold nanoparticles (GNPs) have emerged as promising agents in the diagnostic and therapeutic realms of NDDs, due to their unique ability to enhance drug delivery across the blood-brain barrier (BBB). This paper presents a comprehensive review of the application of GNPs in the context of NDDs diagnosis and therapy, highlighting their potential to transform patient management. Additionally, we systematically address the critical challenges associated with the use of GNPs in the treatment and diagnosis of NDDs, focusing on pharmacokinetics and metabolism, toxicity, long-term biocompatibility, regulatory challenges and cost-effectiveness. Furthermore, we synthesise ongoing clinical studies to provide a holistic perspective on the current state of research in this field. We also explore the prospective trajectories and clinical translational potential of GNPs, which may usher in a new era in the treatment of NDDs.}, } @article {pmid40400898, year = {2025}, author = {Aziz, S and Anbreen, S and Shahzad, S and Ahmed, MS and Sharma, V and Yang, J and Ali, L}, title = {Investigating nanoparticle's utilization in stem cell therapy for neurological disorders.}, journal = {American journal of stem cells}, volume = {14}, number = {1}, pages = {1-13}, pmid = {40400898}, issn = {2160-4150}, abstract = {Stem cell therapy is a promising area of regenerative medicine, offering potential treatments for various life-threatening disorders. Stem cells are classified based on their differentiation potential into totipotent, pluripotent, and multipotent stem cells. Among them, mesenchymal stem cells (MSCs) are widely used in regenerative medicine due to their tissue regeneration capabilities and ability to differentiate into multiple cell types. Stem cells are being explored for treating neurodegenerative disorders like Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). These conditions result from progressive neuronal degeneration, leading to irreversible damage. Challenges such as cell survival, immune rejection, tumor formation, and ethical concerns related to embryonic stem cells need to be addressed. Nanotechnology is emerging as a tool for enhancing stem cell therapy, improving targeted delivery and effectiveness. Nanoparticles possess the ability to create microenvironments as substrates, facilitate targeted administration, and enable real-time, precise imaging of stem cells. This review explores the integration of stem cells and nanotechnology as regenerative medicine tool for neurodegenerative disease treatment, analyzing current strategies and therapeutic approaches. Integrating nanotechnology with stem cell therapy may significantly improve targeted delivery and enhance regenerative outcomes for neurodegenerative disorders.}, } @article {pmid40403503, year = {2025}, author = {Dhapola, R and Paidlewar, M and Kumari, S and Sharma, P and Vellingiri, B and Medhi, B and HariKrishnaReddy, D}, title = {cGAS-STING and neurodegenerative diseases: A molecular crosstalk and therapeutic perspective.}, journal = {International immunopharmacology}, volume = {159}, number = {}, pages = {114902}, doi = {10.1016/j.intimp.2025.114902}, pmid = {40403503}, issn = {1878-1705}, mesh = {Humans ; *Nucleotidyltransferases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/immunology ; *Membrane Proteins/metabolism ; Animals ; Signal Transduction ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and Frontotemporal Dementia (FTD) share key pathological features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, autophagic dysfunction, and DNA damage. By identifying cytosolic DNA and triggering the type I interferon response, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway regulates neuroinflammation. Dysregulated cGAS-STING signaling has been linked to neuroinflammation and neuronal degeneration across multiple neurodegenerative conditions. In many neurodegenerative disorders, neuroinflammation is mediated by the cGAS-STING pathway. Mitochondrial malfunction and impaired autophagy cause cytosolic DNA buildup in Huntington's, Parkinson's, and Alzheimer's diseases, which activates cGAS-STING and drives chronic inflammation. This pathway is triggered by TDP-43 pathology and nucleic acid dysregulation in ALS and FTD, which leads to neuronal destruction. Both central demyelination and peripheral immunological responses are linked to cGAS-STING activation in multiple sclerosis. Various inhibitors, such as RU.521, H-151, and naturally occurring compounds like metformin, potentially attenuate cGAS-STING-mediated neuroinflammation and associated pathologies. H-151 significantly decreased the expression of pro-inflammatory markers in murine macrophage J774 cells activated with cGAMP: TNF-α by 68 %, IFN-β by 84 %, and CXCL10 by 96 %. cGAS-STING inhibitors target neuroinflammation, offering a disease-modifying approach unlike current symptomatic treatments. However, challenges like blood-brain barrier penetration, off-target effects, and immune suppression hinder clinical translation, necessitating optimized drug delivery and immune modulation. With a focus on its potential for future clinical applications, this review explores the role of the cGAS-STING pathway in neurodegeneration and new treatment approaches.}, } @article {pmid40403957, year = {2025}, author = {Zeng, L and Yang, J and Zhang, C and Zhu, J and Zhong, S and Liu, X and Xie, H and Wang, L and Chen, L and Zhong, M and Hua, F and Liang, W}, title = {Miro1: A potential target for treating neurological disorders.}, journal = {Neuroscience}, volume = {577}, number = {}, pages = {228-239}, doi = {10.1016/j.neuroscience.2025.05.019}, pmid = {40403957}, issn = {1873-7544}, mesh = {Humans ; Animals ; *rho GTP-Binding Proteins/metabolism ; *Nervous System Diseases/metabolism/drug therapy ; *Mitochondria/metabolism ; *Mitochondrial Proteins/metabolism ; Neurons/metabolism ; }, abstract = {The Miro1 protein is a member of the mitochondrial Rho GTPase (Miro) protein family and plays a crucial role in regulating the dynamic processes of mitochondria and participating in cellular movement and mitochondrial transport. In the nervous system, it ensures adequate energy supply for normal neuronal function and synaptic transmission. Additionally, Miro1 actively participates in the regulation of mitochondrial quality control and stress responses within neurons. Its primary function is to sense intracellular stress signals to regulate mitochondrial movement and metabolism, thereby adapting to environmental changes. Multiple studies have indicated that the Miro1 protein is associated with the pathogenesis of various neurological disorders, such as Alzheimer's Disease(AD), Parkinson's Disease(PD), and Amyotrophic Lateral Sclerosis(ALS). This article reviews the mechanistic role of Miro1 in these diseases and summarizes the latest research on its involvement in neurological disorders. These efforts aim to provide unified treatment strategies for certain neurological disorders and explore the potential for treating complex neurological diseases.}, } @article {pmid40405710, year = {2025}, author = {Clift, A and Rowen, D and Knox, L and Griffiths, AW and McDermott, CJ}, title = {A Systematic Review of Attributes Influencing Preferences for Treatments and Interventions in People With Amyotrophic Lateral Sclerosis (ALS).}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {359-382}, pmid = {40405710}, issn = {1097-4598}, support = {//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Patient Preference/psychology ; Quality of Life/psychology ; Patient-Centered Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that has no cure, and treatments predominantly focus on improving quality of life. Patient-centred care is central to bringing about meaningful improvements to quality of life. This review addresses the lack of consolidated evidence on what matters most to people with ALS (pwALS) by synthesizing 44 preference-based studies covering six different treatment and intervention categories. Data-based convergent synthesis identified five overarching factors influencing preferences: ease of use, accessibility, making life easier, autonomy, and safety/reliability. Simplifying and enhancing accessibility of treatment delivery across disease stages aligns with the nature of neurodegenerative disorders such as ALS, where function declines as the disease progresses. The value in perceived and real control reflects the profound impact ALS has on an individual's independence. Safety and reliability are crucial for people with ALS and are recognized as fundamental requirements for quality healthcare. The themes identified in this review can inform the attributes of preference elicitation methods. Systematically varying the levels of these attributes elicits quantitative measures of preferences. These findings can be used to inform and develop healthcare policy and clinical practice in ALS care. Specifically, preferences related to drug treatments can then be integrated into target product profiles (TPPs) to align drug development with the needs and values of pwALS. Integrating patient preferences into clinical practice promotes patient-centred care, increasing both patient satisfaction and treatment effectiveness.}, } @article {pmid40409314, year = {2025}, author = {, and , }, title = {Safety and efficacy of trehalose in amyotrophic lateral sclerosis (HEALEY ALS Platform Trial): an adaptive, phase 2/3, double-blind, randomised, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {24}, number = {6}, pages = {500-511}, doi = {10.1016/S1474-4422(25)00173-5}, pmid = {40409314}, issn = {1474-4465}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; Disease Progression ; Double-Blind Method ; Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Treatment Outcome ; *Trehalose/therapeutic use/adverse effects/administration & dosage ; }, abstract = {BACKGROUND: Trehalose is a disaccharide that activates autophagy pathways in animal models of neurodegenerative diseases, with the potential to catalyse clearance of toxic, misfolded proteins in motor neurons and slow disease progression in amyotrophic lateral sclerosis (ALS). We aimed to evaluate the safety and efficacy of trehalose in individuals with ALS.

METHODS: The HEALEY ALS Platform Trial is a perpetual, adaptive, phase 2/3, randomised, double-blind, multi-regimen trial conducted at 60 geographically diverse sites in the USA. In the current regimen, adults with clinically possible, probable, laboratory-supported probable, or definite ALS, defined by the revised El Escorial criteria, were randomly allocated (3:1), stratified by use of edaravone and riluzole, to receive trehalose 0·75 g per kg intravenously weekly over 24 weeks, or matching placebo. The primary outcome was a composite of the relative rate of disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), and survival over 24 weeks, estimated in a Bayesian shared-parameter model. The study included prespecified stopping rules for futility; interim analyses occurred every 12 weeks. The primary outcome was analysed according to the intention-to-treat principle in all participants in the trehalose group, the placebo group within the regimen, and placebo groups from other contributing regimens; the safety analysis population was comprised of all participants who initiated treatment. This study is registered with ClinicalTrials.gov, NCT05136885.

FINDINGS: Between Feb 21, 2022, and Feb 17, 2023, 1021 participants were screened for the platform trial and 171 were assigned to the trehalose regimen. Of these, 161 participants met eligibility criteria, with 120 randomly allocated to trehalose and 41 to regimen-specific placebo. 164 participants randomly allocated to placebo in other regimens were added for analysis (totalling 205 placebo recipients). The disease rate ratio for change in ALSFRS-R and survival was 0·87 (95% credible interval 0·665-1·102, posterior probability of superiority 0·877). Serious adverse events occurred in 19 (16%) participants in the trehalose group and three (7%) participants in the regimen-only placebo group, leading to premature discontinuations in 14 (12%) versus one (2%), respectively. Fatal treatment-emergent adverse events occurred in seven participants in the trehalose group and none in the regimen-only placebo group. No death was considered related to the trial drug. The most common cause of death was respiratory failure, consistent with the natural history of ALS.

INTERPRETATION: Trehalose was well tolerated but there was no evidence to suggest a difference in ALS disease progression compared with placebo in this study. No statistical benefit was seen in secondary clinical or biomarker measures, suggesting that trehalose at this dosage is unlikely to be efficacious for treatment of ALS.

FUNDING: AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, the Muscular Dystrophy Association, ALS ONE, the Arthur M Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and other community fundraising initiatives and donors. Study drug and partial regimen-related funding was provided by Seelos.}, } @article {pmid40413059, year = {2025}, author = {Lopes, AMDS and Giacomini, S and Ulahannan, A and Darnac, C and Bugeia, S and Gutknecht, G and Colomer-Lahiguera, S and Spurrier-Bernard, G and Latifyan, S and Addeo, A and Michielin, O and Eicher, M}, title = {Acceptability of an Electronic Patient-Reported Outcomes-Based Model of Care to Monitor Symptoms Related to Cancer Treatment with Immune Checkpoint Inhibitors: Results from the IePRO Randomized Controlled Trial.}, journal = {Seminars in oncology nursing}, volume = {41}, number = {4}, pages = {151903}, doi = {10.1016/j.soncn.2025.151903}, pmid = {40413059}, issn = {1878-3449}, mesh = {Humans ; *Neoplasms/drug therapy ; *Patient Reported Outcome Measures ; Female ; Male ; *Immune Checkpoint Inhibitors/adverse effects/therapeutic use ; Middle Aged ; Aged ; Adult ; *Mobile Applications ; Telemedicine ; Aged, 80 and over ; }, abstract = {OBJECTIVES: This study analyzed the acceptability of an electronic patient-reported outcomes measures-based model of care (IePRO MoC) and the usability of its complementary ePROM mobile app to monitor and manage symptoms related to immune checkpoint inhibitors. In this MoC, symptoms reported by patients treated at an outpatient clinic were reviewed by oncology triage nurses who provided symptom management interventions by telephone.

METHODS: As part of a larger intervention trial (ClinicalTrials.gov.NCT05530187) we conducted an abductive, semantic thematic analysis through semistructured interviews of patients participating in the intervention arm. Acceptability was deduced from Sekhon et al's (2017) Theoretical Framework of Acceptability completed with inductively generated themes. Usability analysis was guided by the mHealth App Usability Questionnaire's domains by Zhoul et al (2019).

RESULTS: A total of 17 interviews were performed. The IePRO MoC was reported to be an acceptable intervention. Patients expressed feeling safe and empowered due to continuous monitoring and timely support from nurses. Personalized support motivated patients to use the MoC throughout treatment. Some questioned the predefined response options of the app, and the standardized approach regarding notifications and monitoring requirements. Despite high app usability, some expressed discomfort from being frequently reminded of their illness and being confronted with questions about their sexuality and other intimate themes.

CONCLUSIONS: The feedback loop between patients and nurses facilitated the acceptability of the IePRO MoC. The app's usability further facilitated adherence to the MoC. A more personalized approach regarding the frequency of assessments and the way symptoms are conveyed is recommended to decrease discomfort and support the implementation of similar MoCs in the future.}, } @article {pmid40414239, year = {2025}, author = {Shneider, NA and Harms, MB and Korobeynikov, VA and Rifai, OM and Hoover, BN and Harrington, EA and Aziz-Zaman, S and Singleton, J and Jamil, A and Madan, VR and Lee, I and Andrews, JA and Smiley, RM and Alam, MM and Black, LE and Shin, M and Watts, JK and Walk, D and Newman, D and Pascuzzi, RM and Weber, M and Neuwirth, C and Da Cruz, S and Soriano, A and Lane, R and Henry, S and Mathews, J and Jafar-Nejad, P and Norris, D and Rigo, F and Brown, RH and Miller, S and Crean, R and Bennett, CF}, title = {Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series.}, journal = {Lancet (London, England)}, volume = {405}, number = {10494}, pages = {2075-2086}, pmid = {40414239}, issn = {1474-547X}, support = {75N95023C00015/DA/NIDA NIH HHS/United States ; R01 NS111990/NS/NINDS NIH HHS/United States ; TL1 TR001875/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; R01 NS106236/NS/NINDS NIH HHS/United States ; U24 MH100931/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *RNA-Binding Protein FUS/genetics ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Oligonucleotides, Antisense/therapeutic use/administration & dosage/adverse effects ; Injections, Spinal ; Adult ; *Oligonucleotides/therapeutic use/administration & dosage/adverse effects ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND: Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS.

METHODS: This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8-33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology.

FINDINGS: Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16-45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology.

INTERPRETATION: The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial.

FUNDING: ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.}, } @article {pmid40417702, year = {2025}, author = {Hoang, K and Prayotamornkul, S and Kuo, CY and Jang, H and Shi, L}, title = {Optical imaging of metabolic dynamics in ALS under methionine regulation.}, journal = {Journal of biomedical optics}, volume = {30}, number = {Suppl 2}, pages = {S23906}, pmid = {40417702}, issn = {1560-2281}, support = {R21 NS125395/NS/NINDS NIH HHS/United States ; R01 NS111039/NS/NINDS NIH HHS/United States ; U01 AI167892/AI/NIAID NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; *Methionine/metabolism/pharmacology ; Humans ; *Optical Imaging/methods ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Spectrum Analysis, Raman/methods ; Cytochromes c/metabolism ; Imaging, Three-Dimensional ; Oxidation-Reduction ; }, abstract = {SIGNIFICANCE: Excessive reactive oxygen species (ROS) in dysfunctional mitochondria, combined with inefficient antioxidant defenses, can drive amyotrophic lateral sclerosis (ALS) progression. L-methionine (Met) can neutralize ROS by modulating metabolism and activating antioxidants; however, its impact on ALS remains unknown.

AIM: We aim to investigate the influence of excess Met on cellular metabolism and ROS accumulation and its role in ALS using multimodal optical imaging techniques.

APPROACH: We applied deuterium oxide-probed stimulated Raman scattering imaging to study metabolic changes of lipids, proteins, and cytochrome c and two-photon excitation fluorescence imaging to assess mitochondrial redox state (nicotinamide adenine dinucleotide and flavin adenine dinucleotide ratio) in ALS cellular models under excess Met treatment. With three-dimensional (3D) image reconstruction, we investigated morphological changes of lipid droplets (LDs) and stress granules (SGs) in ALS models.

RESULTS: Excess Met not only promoted syntheses of lipids and unsaturated lipid membranes but also reduced protein synthesis, cytochrome c oxidation, and oxidative stress. Moreover, 3D image reconstruction showed that LDs increased in volume and number to promote cellular repair, whereas SGs decreased in volume but increased in number in response to reduced cellular stress.

CONCLUSIONS: Excess Met offers a protective mechanism against oxidative stress and promotes cellular repair in ALS.}, } @article {pmid40436373, year = {2025}, author = {Vosough, M and Drees, F and Sieber, G and Stach, TL and Beisser, D and Probst, AJ and Boenigk, J and Schmidt, TC}, title = {Integrative Analysis of Nontargeted LC-HRMS and High-Throughput Metabarcoding Data for Aquatic Environmental Studies Using Combined Multivariate Statistical Approaches.}, journal = {Analytical chemistry}, volume = {97}, number = {22}, pages = {11563-11571}, pmid = {40436373}, issn = {1520-6882}, mesh = {Chromatography, Liquid ; Mass Spectrometry ; Multivariate Analysis ; Wastewater/chemistry/analysis ; RNA, Ribosomal, 16S/genetics ; *Water Pollutants, Chemical/analysis ; *High-Throughput Screening Assays ; *DNA Barcoding, Taxonomic ; }, abstract = {Significant progress in high-throughput analytical techniques has paved the way for novel approaches to integrating data sets from different compartments. This study leverages nontarget screening (NTS) via liquid chromatography-high-resolution mass spectrometry (LC-HRMS), a crucial technique for analyzing organic micropollutants and their transformation products, in combination with biological indicators. We propose a combined multivariate data processing framework that integrates LC-HRMS-based NTS data with other high-throughput data sets, exemplified here by 18S V9 rRNA and full-length 16S rRNA gene metabarcoding data sets. The power of data fusion is demonstrated by systematically evaluating the impact of treated wastewater (TWW) over time on an aquatic ecosystem through a controlled mesocosm experiment. Highly compressed NTS data were compiled through the implementation of the region of interest-multivariate curve resolution-alternating least-squares (MCR-ALS) method, known as ROIMCR. By integrating ANOVA-simultaneous component analysis with structural learning and integrative decomposition (SLIDE), the innovative SLIDE-ASCA approach enables the decomposition of global and partial common, as well as distinct variation sources arising from experimental factors and their possible interactions. SLIDE-ASCA results indicate that temporal variability explains a much larger portion of the variance (74.6%) than the treatment effect, with both contributing to global shared space variation (41%). Design structure benefits include enhanced interpretability, improved detection of key features, and a more accurate representation of complex interactions between chemical and biological data. This approach offers a greater understanding of the natural and wastewater-influenced temporal patterns for each data source, as well as reveals associations between chemical and biological markers in an exemplified perturbed aquatic ecosystem.}, } @article {pmid40436457, year = {2025}, author = {Peace, A and White, DA and Hackney, G and Bradburn, M and Norman, P and White, S and Al-Chalabi, A and Baird, W and Beever, D and Cade, J and Coates, E and Cooper, C and Ezaydi, N and Halliday, V and Maguire, C and Shaw, PJ and Stavroulakis, H and Waterhouse, S and Young, TA and McDermott, CJ and , }, title = {Randomised controlled trial with parallel process evaluation and health economic analysis to evaluate a nutritional management intervention, OptiCALS, for patients with amyotrophic lateral sclerosis: study protocol.}, journal = {BMJ open}, volume = {15}, number = {5}, pages = {e096098}, pmid = {40436457}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/economics ; Cost-Benefit Analysis ; Energy Intake ; Ireland ; Nutrition Therapy/methods ; Quality of Life ; United Kingdom ; Equivalence Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating illness that leads to muscle weakness and death usually within around 3 years of diagnosis. People with ALS (pwALS) often lose weight due to raised energy requirements and symptoms of the disease presenting significant challenges to taking adequate oral diet, with those who lose more weight being at a greater chance of earlier death. There is also some evidence to suggest that a higher calorie diet may benefit the disease course in pwALS, but further research is needed.

METHODS AND ANALYSIS: Two armed, parallel group, superiority, open labelled, randomised controlled trial, with internal pilot, to assess the effectiveness of an early high calorie diet on functional outcomes in ALS, comprising two treatment arms: (1) standard care, (2) standard care with additional active management using the OptiCALS complex intervention to achieve a high calorie diet (initially randomised 1:1, then 1:2 following a protocol amendment). Using a food first approach, pwALS will be encouraged and supported to follow a diet that meets an individualised calorie target from food before prescribing oral nutritional supplements. 259 pwALS will be recruited from up to 20 ALS centres across the United Kingdom and Ireland and followed up for a period of 12 months. Primary outcome is functional change measured over 12 months, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Secondary end points include measures of functional health, quality of life, calorie intake and weight, as well as time to gastrostomy and survival. A health economic analysis and process evaluation will also be undertaken. Participant recruitment is expected to complete in September 2025, and participant follow-up is expected to complete in September 2026. The results of this study are expected in March 2027.

ETHICS AND DISSEMINATION: The trial was approved by Greater Manchester-North West Research Ethics Committee, reference 20/NW/0334 on 8 September 2020. We will publish the study findings in peer-reviewed academic journals and present at local, national and international conferences where possible.

TRIAL REGISTRATION NUMBER: ISRCTN30588041.}, } @article {pmid40437235, year = {2025}, author = {Modafferi, S and Farina, S and Esposito, F and Brandi, O and Di Salvio, M and Della Valle, I and D'Uva, S and Scarian, E and Cicio, G and Riccardi, A and Pisati, F and Garbelli, A and Santini, T and Pansarasa, O and Morlando, M and D'Ambrosi, N and Cozzolino, M and Cestra, G and d'Adda di Fagagna, F and Gioia, U and Francia, S}, title = {DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue.}, journal = {Cell death and differentiation}, volume = {32}, number = {12}, pages = {2309-2322}, pmid = {40437235}, issn = {1476-5403}, support = {RIPREI2023_7c8ae10d783c//Istituto Superiore di Sanità (ISS)/ ; PRIN 2020 CXFL4T//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; MNESYS (PE0000006)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041 CN3 RNA//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PNRR-CN3//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2021 DDR&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2016 DDRNA&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; Flagship Project Interomics//Consiglio Nazionale delle Ricerche (National Research Council)/ ; TELORNAGING-835103//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC-IG(21762)//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; AIRC 5×1000//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; GGP17111//Fondazione Telethon (Telethon Foundation)/ ; POR FESR 2014-2020//Regione Lombardia (Region of Lombardy)/ ; Ricerca Corrente 2022 - 2024//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; Humans ; Mice ; *DNA Damage ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Inclusion Bodies/metabolism/drug effects ; Ataxia Telangiectasia Mutated Proteins/metabolism/antagonists & inhibitors ; DNA Repair/drug effects ; DNA Breaks, Double-Stranded/drug effects ; Mutation ; }, abstract = {Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUS[P525L], co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUS[P525L] CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In Drosophila melanogaster, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS CIs include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.}, } @article {pmid40449630, year = {2025}, author = {Vu Trung, K and Abou-Ali, E and Gulla, A and Soares, K and Caillol, F and Paik, WH and Napoleon, B and Halimi, A and Masaryk, V and Bruno, MJ and Pérez-Cuadrado-Robles, E and Bolm, L and Seyfried, S and Petrone, MC and Yilmaz, B and Vollmer, C and Berger, A and Maggino, L and Schemmer, P and Wichmann, D and Karam, E and Dugic, A and Kunovsky, L and Regner, S and Gaujoux, S and Hollenbach, M and , }, title = {Development and validation of the SDLD score: a simplified tool to predict successful endoscopic papillectomy in ampullary lesions.}, journal = {Gastrointestinal endoscopy}, volume = {102}, number = {4}, pages = {602-606}, doi = {10.1016/j.gie.2025.03.1333}, pmid = {40449630}, issn = {1097-6779}, mesh = {Humans ; *Ampulla of Vater/surgery/pathology ; Female ; Male ; Aged ; *Common Bile Duct Neoplasms/surgery/pathology ; Middle Aged ; *Sphincterotomy, Endoscopic ; ROC Curve ; Pancreatic Ducts/pathology ; Logistic Models ; Aged, 80 and over ; *Adenoma/surgery/pathology ; Retrospective Studies ; Cholangiopancreatography, Endoscopic Retrograde ; }, abstract = {BACKGROUND AND AIMS: Endoscopic papillectomy (EP) is the standard treatment for noninvasive ampullary lesions (ALs), whereas advanced cases require surgery. Managing ALs is challenging and may lead to over- or undertreatment. We developed a score to identify the best candidates for endoscopic or surgical treatment.

METHODS: We analyzed 447 patients who underwent EP. The cohort was randomly split into a training set (n = 325) and validation set (n = 122). Logistic regression identified predictors for incomplete resection (R1), which were incorporated into a 4-item score. Performance was assessed using the area under the receiver-operating characteristic curve (AUROC).

RESULTS: Independent predictors for R1 included size ≥30 mm (S), high-grade dysplasia and/or invasive cancer (D), laterally spreading-lesion (L), and bile or pancreatic duct dilation (D), which we named the SDLD score. ALs with 0 to 1 points had the highest complete resection rates (training, 86.0%; validation, 88.5%), whereas ≥2 points significantly increased R1 rates (training, 52.0%; validation, 57.7%; P < .001). The AUROC was 0.792 (training) and 0.708 (validation).

CONCLUSIONS: The SDLD score predicts R1 in EP and aids in treatment decisions.}, } @article {pmid40453369, year = {2025}, author = {Slagt, C and Van Kuijk, SMJ and Bruhn, J and Van Geffen, GJ and Mommers, L}, title = {First Results of Our Local Practice Guide Used During the Late Phase of Resuscitation in Patients with Refractory VF in Out of Hospital Cardiac Arrest.}, journal = {Open access emergency medicine : OAEM}, volume = {17}, number = {}, pages = {203-213}, pmid = {40453369}, issn = {1179-1500}, abstract = {OBJECTIVE: Treatment of refractory ventricular fibrillation (rVF) is a clinical challenge. If rVF is still present after standard advanced life support (ALS) guideline care, including amiodaron administration, other therapeutic options might be necessary. Based on the available evidence and expertise, our Helicopter Emergency Medical Service (HEMS) team developed a local practice guide for the prolonged resuscitation of patients in rVF and implemented this as standard HEMS care in March 2022.

METHODS: This database study contains all patients treated with our local practice guide during out of hospital cardiac arrest (OHCA) with rVF beyond the fifth regular ALS shock-block. This local practice HEMS treatment algorithm consisted of, among others, cessation of epinephrine and alternating administration of esmolol and norepinephrine combined with enoximone. Data were derived from the HEMS database and the treating hospitals. Primary outcome was the return of spontaneous circulation. Secondary outcome was defined as survival to hospital discharge and cerebral performance. This outcome was compared to the literature to analyze for inferiority of treatment.

RESULTS: In a 21-month period, HEMS was 761 times deployed for OHCA. Nineteen patients were treated with the local practice guide, nine patients (47%) were admitted to hospital with return of spontaneous circulation. Median resuscitation time was 22min. Hospital survival with good neurology was achieved in 42% vs 17% as expected. Exact Clopper-Pearson and logistic regression analysis revealed non-inferiority of the local practice guide. Withholding epinephrine was achieved in 84% of patients. A total of 79% and 90% of patients received esmolol and norepinephrine/enoximone mixture, respectively. Alternative defibrillation positions were indicated in 18 patients but applied in only 6 (33%).

CONCLUSION: In patients with persisting VF despite prolonged advanced life support care, a multifaceted bundle of care approach shows promising results and warrants further research. Alternative drug administrations were found to be substantially easier to achieve compared to alternative defibrillation positions.}, } @article {pmid40459635, year = {2025}, author = {Abraham, I and Martin, P and Vaghela, S and Klein, T and Chow, E and Rush, M and Morlock, R and Huang, H}, title = {Budget impact analysis of revumenib for the treatment of relapsed or refractory acute leukemias with a KMT2A translocation in the United States.}, journal = {Journal of managed care & specialty pharmacy}, volume = {31}, number = {7}, pages = {680-693}, pmid = {40459635}, issn = {2376-1032}, mesh = {Humans ; United States ; *Myeloid-Lymphoid Leukemia Protein/genetics ; *Histone-Lysine N-Methyltransferase/genetics ; *Leukemia, Myeloid, Acute/drug therapy/economics/genetics ; Budgets ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/economics/genetics ; Translocation, Genetic ; *Antineoplastic Agents/economics/therapeutic use ; Adult ; Recurrence ; Drug Costs ; Benzamides ; Spiro Compounds ; }, abstract = {BACKGROUND: Acute leukemias (ALs), including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), are heterogeneous diseases characterized by different phenotypic, genetic, and molecular alterations that can guide treatment decisions. ALs harboring lysine methyltransferase 2A gene translocation (KMT2t), previously known as mixed-lineage leukemia, are associated with high rates of relapsed or refractory (R/R) disease. Revumenib, a first-in-class oral menin inhibitor, has shown improved clinical outcomes in patients with R/R KMT2At ALs.

OBJECTIVE: To estimate, using a budget impact model (BIM), the financial impact of introducing revumenib for the treatment of adult patients with R/R KMT2At ALs on the formulary of a hypothetical US 1-million-member commercial health plan.

METHODS: The BIM compared scenarios with or without revumenib and the resulting impact on commercial US third-party payers over a 3-year time horizon. Although no other therapies specifically targeted for R/R KMT2At ALs were approved during BIM development, 11 additional pharmacotherapies for R/R ALs (5 for AML and 6 for ALL, not including revumenib) were included as treatment options in the model. Clinical data included adverse event (AE) rates, duration of treatment, time to subsequent treatment, and survival outcomes. Cost inputs (USD 2024) included in the model comprised drug acquisition and administration, grade 3 or greater AEs, treatment-related supportive care and monitoring, subsequent treatment, and end-of-life costs. The differential cost per member per month (PMPM) was estimated. One-way sensitivity analyses varying the costs of drug acquisition and toxicity by ±20% and scenario analyses varying uptake of revumenib and epidemiology inputs, as well as excluding costs related to supportive care and posttreatment discontinuation, were performed.

RESULTS: An estimated 1.7 adult patients (AML, 1.1; ALL, 0.6) were treatment eligible annually. Estimated 3-year total plan costs without and with revumenib were $2,146,564 and $2,126,919, respectively, for savings of -$19,646. Including revumenib was estimated to yield a differential PMPM cost of -$0.0005 over 3 years. The total number of grade 3 or greater AEs was lower over 3 years (10.82 vs 10.99, respectively) in the plan with revumenib vs without. Sensitivity and scenario analyses validated the robustness of the model.

CONCLUSIONS: The BIM demonstrated that including revumenib in a formulary for adult patients with R/R KMT2At ALs was approximately cost neutral, offering patients access to a targeted treatment with potential for improved clinical outcomes.}, } @article {pmid40460337, year = {2025}, author = {van Unnik, JWJ and Ing, L and Oliveira Santos, M and McDermott, CJ and de Carvalho, M and van Eijk, RPA}, title = {Remote Monitoring of Amyotrophic Lateral Sclerosis Using Digital Health Technologies: Shifting Toward Digitalized Care and Research?.}, journal = {Neurology}, volume = {105}, number = {1}, pages = {e213738}, pmid = {40460337}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; *Telemedicine ; Wearable Electronic Devices ; Videoconferencing ; Digital Technology ; *Biomedical Technology ; Monitoring, Physiologic/methods ; Digital Health ; }, abstract = {Current care and research pathways for amyotrophic lateral sclerosis (ALS) primarily rely on regularly scheduled visits to specialized centers. These visits provide intermittent clinical information to health care professionals and require patients to travel to the clinic. Digital health technologies enable continuous data collection directly from the patient's home, bringing new opportunities for personalized, timely care and a refined assessment of disease severity in clinical trials. In this review, we summarize the state of the art in digital health technologies for remote monitoring of patients with ALS, ranging from televisits through videoconferencing to sensor-based wearable devices. We explore how these technologies can benefit clinical care and advance treatment development. Despite significant progress, real-world adoption of these technologies remains limited. An overview is provided of the key barriers hindering their widespread implementation and the opportunities to advance the field. Significantly, there is an urgent need for harmonization across stakeholders through consensus guidelines and consortia. These efforts are essential to accelerate progress and harness the full potential of digital health technologies to better meet the needs of patients.}, } @article {pmid40462117, year = {2025}, author = {Akif, A and Nguyen, TTM and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Fluids and barriers of the CNS}, volume = {22}, number = {1}, pages = {55}, pmid = {40462117}, issn = {2045-8118}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; R01NS105787//National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS133895-01//National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism/drug effects ; Mice ; *Dementia, Vascular/drug therapy/metabolism ; *Signal Transduction/drug effects ; *Sulfonylurea Compounds/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Carotid Stenosis/complications ; Brain/drug effects/metabolism ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid40464332, year = {2025}, author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Islam, A}, title = {The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment.}, journal = {The European journal of neuroscience}, volume = {61}, number = {11}, pages = {e70156}, doi = {10.1111/ejn.70156}, pmid = {40464332}, issn = {1460-9568}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/drug therapy/metabolism ; Animals ; *Protein Kinases/metabolism ; Protein Kinase Inhibitors/therapeutic use ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.}, } @article {pmid40464500, year = {2025}, author = {Dedoni, S and Avdoshina, V and Olianas, MC and Onali, P}, title = {Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {5}, pages = {28245}, doi = {10.31083/FBL28245}, pmid = {40464500}, issn = {2768-6698}, mesh = {Humans ; *Lysophospholipids/metabolism ; *Nervous System Diseases/physiopathology/metabolism/drug therapy ; Animals ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; }, abstract = {Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.}, } @article {pmid40474686, year = {2025}, author = {Rothstein, J and Genge, A and De Silva, S and Zinman, L and Chum, M and Chio, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Wamil, A and Apple, S}, title = {Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT-1186-A02).}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {433-442}, pmid = {40474686}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration & dosage ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Administration, Oral ; Treatment Outcome ; *Free Radical Scavengers/administration & dosage/adverse effects/therapeutic use ; Adult ; Drug Administration Schedule ; Suspensions ; }, abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is approved in the US for the treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed IV edaravone slows the rate of physical functional decline. This study evaluated whether investigational daily dosing displayed superior efficacy vs. approved on/off dosing of edaravone oral suspension, and assessed safety and tolerability, over 48 weeks in patients with ALS.

METHODS: Study MT-1186-A02 (NCT04569084) was a multicenter, phase 3b, double-blind, parallel group, superiority study that randomized patients to edaravone oral suspension (105-mg dose) administered Once Daily or the same edaravone oral suspension dose administered according to the approved On/Off regimen including placebo to mimic daily drug dosing. Patients had definite or probable ALS, baseline forced vital capacity ≥ 70%, and baseline disease duration ≤ 2 years. The primary endpoint was a combined assessment of function and survival (CAFS) at week 48, which included change in ALS Functional Rating Scale-Revised (ALSFRS-R) and time to death.

RESULTS: CAFS at week 48 indicated Once Daily dosing did not show a statistically significant difference vs. approved on/off dosing (p = 0.777). Both dosing regimens provided comparable change from baseline ALSFRS-R total score to week 48 (least squares mean difference: 0.27 [95% CI -1.43 to 1.97]). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

DISCUSSION: Daily edaravone oral suspension did not show superiority and had equivalent safety and tolerability vs. the approved On/Off regimen, reinforcing the appropriateness of the approved dosing regimen.}, } @article {pmid40475252, year = {2025}, author = {Seyedi Asl, FS and Malverdi, N and Ataei Kachouei, FS and Zarei, F and Ghiabi, S and Baziyar, P and Nabi-Afjadi, M}, title = {Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1569777}, pmid = {40475252}, issn = {2296-2646}, abstract = {Protein misfolding and aggregation in superoxide dismutase 1 (SOD1) are linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 mutations have a significant role in the pathophysiology and fast behavior of protopathic proteins in ALS illness. The E100K mutation may be useful in uncovering the pathogenic mechanism of SOD1 associated with ALS. According to several studies, giving small molecule inhibitors made from polyphenolic flavonoid compounds may be a viable treatment strategy for neurological conditions. Using molecular docking and MD simulations, we have identified a potential flavonoid drug that may successfully inhibit SOD1's amyloidogenic activity. Puerarin, Fisetin, and Peonidin provided intriguing pharmacological hints during the initial screening of flavonoids. The Fisetin-E100K complex had a larger residual energy contribution and substantial binding than other flavonoid compounds. The findings showed that, unlike other materials, Fisetin increased the structural stability, hydrophobicity, and flexibility of the mutant while reducing the amount of β-sheets. Furthermore, to distinguish aggregation in the mutant (unbound/bound) states, we displayed modifications in the free energy landscape (FEL). As a result, Fisetin was identified as having therapeutic potential against the E100K, which might make it a viable pharmacological option for the creation of inhibitors that lower the chance of ALS death.}, } @article {pmid40480222, year = {2025}, author = {Oldani, EG and Reynolds Caicedo, KM and Spaeth Herda, ME and Sachs, AH and Chapman, EG and Kumar, S and Linseman, DA and Horowitz, S}, title = {The effect of G-quadruplexes on TDP43 condensation, distribution, and toxicity.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {8}, pages = {1294-1303.e5}, doi = {10.1016/j.str.2025.05.006}, pmid = {40480222}, issn = {1878-4186}, mesh = {*G-Quadruplexes ; Humans ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; HEK293 Cells ; Oxidative Stress ; Mice ; Animals ; Protein Aggregates ; Protein Binding ; Saccharomyces cerevisiae/metabolism ; RNA/chemistry/metabolism ; }, abstract = {Many proteins implicated in neurodegenerative diseases (e.g., trans-active response DNA binding protein 43 kDa [TDP43]) interact with nucleic acids, including RNA G-quadruplexes (G4s). We here investigate whether RNA G4s play a role in TDP43 condensation in biophysical and cellular models. We find that G4s modulate TDP43 aggregation in vitro and condensation in multiple cell types, including yeast, HEK293T, and motor-neuron-like NSC-34 cells. In yeast cells, treatment with G4s causes increased TDP43 accumulation in cells before cellular death. In HEK293T cells expressing TDP43, incubation with G4-binding small molecules causes an increase in G4 stability that also stabilizes TDP43 and reduces TDP43 condensation induced by proteasomal or oxidative stress. Finally, in NSC-34 cells overexpressing exogenous TDP43, we show that G4s co-localize with TDP43 condensates under stress conditions, and treatment with G4-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest exploring treating protein misfolding diseases by targeting specific RNA structures such as G4s.}, } @article {pmid40480675, year = {2025}, author = {Reitzle, L and Rohmann, JL and Kurth, T and Audebert, HJ and Piccininni, M}, title = {External validation of risk prediction models for post-stroke mortality in Berlin.}, journal = {BMJ open}, volume = {15}, number = {6}, pages = {e089320}, pmid = {40480675}, issn = {2044-6055}, mesh = {Humans ; Male ; Female ; Aged ; Berlin/epidemiology ; Registries ; Risk Assessment/methods ; *Stroke/mortality ; Hospital Mortality ; Aged, 80 and over ; Middle Aged ; Risk Factors ; }, abstract = {OBJECTIVES: Prediction models for post-stroke mortality can support medical decision-making. Although numerous models have been developed, external validation studies determining the models' transportability beyond the original settings are lacking. We aimed to assess the performance of two prediction models for post-stroke mortality in Berlin, Germany.

DESIGN: We used data from the Berlin-SPecific Acute Treatment in Ischaemic or hAemorrhagic stroke with Long-term follow-up (B-SPATIAL) registry.

SETTING: Multicentre stroke registry in Berlin, Germany.

PARTICIPANTS: Adult patients admitted within 6 hours after symptom onset and with a 10th revision of the International Classification of Diseases discharge diagnosis of ischaemic stroke, haemorrhagic stroke or transient ischaemic attack at one of 15 hospitals with stroke units between 1 January 2016 and 31 January 2021.

PRIMARY OUTCOME MEASURES: We evaluated calibration (calibration-in-the-large, intercept, slope and plot) and discrimination performance (c-statistic) of Bray et al's 30-day mortality and Smith et al's in-hospital mortality prediction models. Information on mortality was supplemented by Berlin city registration office records.

RESULTS: For the validation of Bray et al's model, we included 7879 patients (mean age 75; 55.0% men). We observed 763 (9.7%) deaths within 30 days of stroke compared with 680 (8.6%) predicted. The model's c-statistic was 0.865 (95% CI: 0.851 to 0.879). For Smith et al's model, we performed the validation among 1931 patients (mean age 75; 56.2% men), observing 105 (5.4%) in-hospital deaths compared with the 92 (4.8%) predicted. The c-statistic was 0.891 (95% CI: 0.864 to 0.918). The calibration plots of both models revealed an underestimation of the mortality risk for high-risk patients.

CONCLUSIONS: Among Berlin stroke patients, both models showed good calibration performance for low and medium-risk patients and high discrimination while underestimating risk among high-risk patients. The acceptable performance of Bray et al's model in Berlin illustrates how a small number of routinely collected variables can be sufficient for valid prediction of post-stroke mortality.}, } @article {pmid40482593, year = {2025}, author = {Tankisi, H and Jacobsen, AB and Fanella, G and Cengiz, B and Kılınç, H and Matamala, JM and Moreno-Roco, J and Abrahao, A and Zinman, L and Koltzenburg, M and Howells, J and Samusyte, G and Awiszus, F and Bostock, H}, title = {Short-interval intracortical inhibition and facilitation in amyotrophic lateral sclerosis related to disease phenotype.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {176}, number = {}, pages = {2110770}, doi = {10.1016/j.clinph.2025.2110770}, pmid = {40482593}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Evoked Potentials, Motor/physiology ; Transcranial Magnetic Stimulation/methods ; *Neural Inhibition/physiology ; Aged ; *Motor Cortex/physiopathology ; *Phenotype ; Adult ; Electromyography ; }, abstract = {OBJECTIVE: To investigate the relationship between short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF) and amyotrophic lateral sclerosis (ALS) phenotype, using threshold-tracking transcranial magnetic stimulation (TMS).

METHODS: A new paired-pulse TMS protocol was applied to 49 patients with ALS and 49 age-matched healthy controls. Motor evoked potentials (MEPs) were recorded from first dorsal interosseus muscle, while paired pulses were delivered at interstimulus intervals (ISI) of 1.0, 2.5 or 3.0 ms, with stimuli related to the resting motor threshold for a 200 µV MEP. For each ISI, 6 SICI and 3 SICF pulse pairs with different conditioning stimuli were randomised and interleaved with test-alone stimuli.

RESULTS: ALS phenotypes were characterised as Pyramidal (n = 12, with prominent upper motor neuron signs), Classic (n = 20, with limb onset), or Bulbar (n = 17). Compared with healthy controls, Bulbar patients had significantly less inhibition at all ISIs, while SICI in Pyramidal patients was normal, and in Classic patients intermediate. The only SICF abnormalities independent of the changes in SICI were less facilitation in Pyramidal patients at ISIs 1 and 3 ms.

CONCLUSION: Changes in SICI and SICF depend on ALS phenotype.

SIGNIFICANCE: ALS phenotypes should be matched between treatment and placebo arms of clinical trials.}, } @article {pmid40482733, year = {2025}, author = {Ting, CH and Tai, ST and Chang, HY and Huang, PY and Cheng, LF and Lai, HJ and Kuo, YC and Kao, CH and Wang, IF and Tsai, LK}, title = {Baicalein benefits amyotrophic lateral sclerosis via reduction of Intraneuronal misfolded protein.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1869}, number = {8}, pages = {130831}, doi = {10.1016/j.bbagen.2025.130831}, pmid = {40482733}, issn = {1872-8006}, mesh = {*Flavanones/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; *Superoxide Dismutase-1/metabolism/genetics ; Mice ; Protein Folding/drug effects ; *Motor Neurons/drug effects/metabolism/pathology ; Humans ; Mice, Transgenic ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by muscle weakness and atrophy, with limited treatment options. The accumulation of misfolded proteins, such as misfolded superoxide dismutase 1 (mSOD1), contributes significantly to neuronal degeneration in ALS. Therapies targeting misfolded proteins represent a promising strategy. Baicalein, a flavonoid compound with neuroprotective properties, has shown efficacy in clearing misfolded proteins and improving behaviors in rodent models of Alzheimer's and Parkinson's diseases. However, its effects in ALS remain largely unexplored. This study demonstrated that baicalein treatment reduced total and misfolded SOD1 protein levels in both soluble and insoluble fractions of a motor neuron cell line overexpressing mutant SOD1. Baicalein also reduced intracellular SOD1 aggregates in cultured motor neurons transfected with SOD1/G93A, preserving neurite length. In an ALS mouse model expressing the SOD1/G93A transgene, baicalein treatment decreased mSOD1 aggregation, increased spinal motor neuron density, and reduced neuromuscular junction denervation. Furthermore, baicalein partially improved motor behaviors, as assessed by the rotarod test. These findings highlight baicalein's potential as a therapeutic agent for ALS, targeting intraneuronal misfolded proteins to ameliorate pathological changes and preserve motor function.}, } @article {pmid40485494, year = {2025}, author = {Genge, A and Pattee, GL and Sobue, G and Aoki, M and Yoshino, H and Couratier, P and Lunetta, C and Petri, S and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Apple, S and Wamil, A and Kalin, A and Jackson, CE}, title = {Safety Extension Study of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis for up to an Additional 96 Weeks of Treatment.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {450-454}, pmid = {40485494}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America Inc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration & dosage/adverse effects/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; Administration, Oral ; *Free Radical Scavengers/administration & dosage/adverse effects/therapeutic use ; Adult ; Suspensions ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Edaravone intravenous (IV) and oral suspension have been shown to have similar pharmacokinetics, safety, and slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Study MT-1186-A01 indicated that edaravone oral suspension was well-tolerated over 48 weeks, with no new safety concerns identified relative to existing safety data of IV edaravone, including Study MCI186-19. The aim of this study was to assess the long-term safety and tolerability of edaravone oral suspension in patients with ALS.

METHODS: Study MT-1186-A03 (NCT04577404) was a phase 3, open-label, multi-center, extension study that evaluated the long-term safety of edaravone oral suspension over an additional 96 weeks in patients with ALS who have completed the initial 48 weeks of Study MT-1186-A01, for a total of up to 144 weeks of treatment. Patients received a 105-mg dose of edaravone administered in treatment cycles identical to the approved edaravone on/off dosing schedule. Patients had definite, probable, probable-laboratory-supported, or possible ALS.

RESULTS: In Study MT-1186-A03, edaravone oral suspension was well tolerated with no new safety concerns. The most common treatment-emergent adverse events (TEAEs) were fall, muscular weakness, dyspnea, constipation, and dysphagia. These TEAEs were consistent with the safety profile for edaravone from previous clinical trials.

DISCUSSION: These results help establish the long-term safety and tolerability profile of edaravone oral suspension.}, } @article {pmid40485888, year = {2025}, author = {Liu, Y and Ren, Y and Song, P}, title = {Traditional Chinese medicine for intractable and rare diseases: Research progress and future strategies.}, journal = {Intractable & rare diseases research}, volume = {14}, number = {2}, pages = {109-121}, pmid = {40485888}, issn = {2186-3644}, abstract = {Rare diseases have become a global public health challenge due to their low prevalence, difficult diagnosis, and limited treatment options. Intractable diseases are more common but often involve complex mechanisms, treatment with limited efficacy, and high medical costs, placing a heavy burden on patients and healthcare systems. In recent years, traditional Chinese medicine (TCM) has demonstrated unique advantages in the treatment of intractable and rare diseases and has gradually become an important complementary treatment. The current work is a systematic review of the progress of clinical and experimental research on TCM in typical rare diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), mitochondrial encephalomyopathy, aplastic anemia (AA), and Wilson's disease (WD). It focuses on the multi-target therapeutic mechanisms of key Chinese herbal compound formulas, including immune regulation, antioxidative stress, and neuroprotection. The core TCM theories of "syndrome differentiation", "different treatments for the same disease" and the "same treatment for different diseases" are also discussed in the context of personalized medicine. In recent years, China has continuously promoted the development of TCM through a series of national plans and supportive policies, such as the 14th Five-Year Plan for TCM development, funding for key special projects, expedited approval pathways, and expanded coverage by medical insurance. These efforts have provided strong support for the clinical translation of TCM and technological innovation in the field of intractable and rare diseases. Notwithstanding the encouraging advances, the field of Chinese medicine continues to grapple with numerous challenges. In the future, the enhancement of mechanistic studies and quality multicenter clinical trials needs to be promoted while further enhancing policy support and international collaboration to substantiate the scientific basis and clinical value of TCM in the prevention and treatment of intractable and rare diseases.}, } @article {pmid40487949, year = {2025}, author = {Kumar, S}, title = {Nomogram-based strategy to predict relapse-free survival in patients with gastrointestinal stromal tumor using inflammatory indicators.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {5}, pages = {103127}, pmid = {40487949}, issn = {1948-5204}, abstract = {Zhao et al's investigation on the assessment of inflammatory markers prognostic value for relapse-free survival in patients with gastrointestinal stromal tumor (GIST) using a nomogram-based approach is a scientific approach. This study explored the potential of an inflammatory marker-based nomograph model, highlighting the relapse-free survival-associated risk factors prognostic potential in patients with GIST. The author assessed 124 samples from patients with GIST to find an association between inflammatory markers and tumor size in a retrospective study using multivariate regression analysis. Further, a nomogram model was developed to identify the independent risk factors for the prognosis. GIST clinical treatment can use preoperative monocyte/lymphocyte ratio and platelet/lymphocyte ratio for relapse-free survival prognosis as independent factors.}, } @article {pmid40488810, year = {2025}, author = {Kulkarni, SR and Thokchom, B and Abbigeri, MB and Bhavi, SM and Singh, SR and Metri, N and Yarajarla, RB}, title = {The role of L-DOPA in neurological and neurodegenerative complications: a review.}, journal = {Molecular and cellular biochemistry}, volume = {480}, number = {10}, pages = {5221-5242}, pmid = {40488810}, issn = {1573-4919}, mesh = {Humans ; *Levodopa/therapeutic use/pharmacokinetics/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Animals ; Blood-Brain Barrier/metabolism ; *Parkinson Disease/drug therapy/metabolism ; }, abstract = {L-DOPA remains a cornerstone treatment for Parkinson's disease and is increasingly recognized for its role in various neurological and neurodegenerative disorders. As a direct precursor to dopamine, L-DOPA is synthesized from L-tyrosine through the action of tyrosine hydroxylase and is subsequently converted into dopamine via aromatic L-amino acid decarboxylase. Its ability to cross the blood-brain barrier (BBB) makes it a crucial therapeutic agent for restoring dopaminergic neurotransmission, thereby influencing motor function, cognition, and neuroprotection. Beyond Parkinson's, L-DOPA's therapeutic potential extends to neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, multiple sclerosis, Lewy body dementia, and amyotrophic lateral sclerosis, where dopamine modulation plays a critical role. Furthermore, L-DOPA has demonstrated efficacy in neurological disorders including epilepsy, peripheral neuropathy, cerebrovascular diseases, and traumatic brain injury, suggesting broader neurobiological applications. However, long-term use is associated with challenges such as motor fluctuations, dyskinesias, and loss of therapeutic efficacy due to progressive neurodegeneration and alterations in dopaminergic pathways. Recent advancements in drug delivery systems, combination therapies, and nanotechnology, including plant-derived carbon dots, offer promising strategies to enhance L-DOPA's effectiveness while mitigating its limitations. This comprehensive review explores L-DOPA's synthesis, pharmacokinetics, mechanism of action, and its evolving role in neurological diseases, while highlighting ongoing challenges and future directions for optimizing its clinical application.}, } @article {pmid40491248, year = {2025}, author = {Bernsen, S and Fabian, R and Koc, Y and Schumann, P and Körtvélyessy, P and Castro-Gomez, S and Meyer, T and Weydt, P}, title = {Serum Cardiac Troponin T Levels as a Therapy Response Marker in Tofersen-Treated ALS.}, journal = {Muscle & nerve}, volume = {72}, number = {3}, pages = {509-514}, pmid = {40491248}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/drug therapy/genetics ; *Troponin T/blood ; Male ; Female ; Middle Aged ; Aged ; Biomarkers/blood ; *Oligonucleotides/therapeutic use ; Treatment Outcome ; Neurofilament Proteins ; Superoxide Dismutase-1/genetics ; Cohort Studies ; Adult ; Creatine Kinase/blood ; }, abstract = {INTRODUCTION/AIMS: Cardiac troponin T (cTnT) levels are elevated in the majority of persons with amyotrophic lateral sclerosis (ALS) and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study, we assess cTnT levels in SOD1-ALS at baseline and during tofersen treatment.

METHODS: cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1 variants.

RESULTS: cTnT levels increased in the control ALS cohort over time (p < 0.0001) but not in the tofersen group (p = 0.36). Creatine kinase (CK) and CK-MB levels did not show significant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p = 0.0013). A significantly lower fold change in cTnT levels was observed in the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) relative to the control group (median 1.89; IQR 1.35-2.75) (p = 0.0003). Nine (39%) patients treated with tofersen experienced a reduction in cTnT levels.

DISCUSSION: In this study, we describe a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigation.}, } @article {pmid40491620, year = {2025}, author = {Sue, S and Yamazaki, S and Sue, K and Kinoshita, T and Yoshida, K}, title = {Combined Effects of Lung Volume Recruitment Training and Mechanical Insufflation-Exsufflation in a Patient With Advanced Amyotrophic Lateral Sclerosis Receiving Long-Term Mechanical Ventilation: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e83823}, pmid = {40491620}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) degenerates both upper and lower motor neurons. Most patients with ALS require respiratory support due to deterioration of their respiratory muscles. Mechanical insufflation-exsufflation (MI-E) is one option that can help patients with weak cough strength to clear the airway, and it may potentially increase survival time. Another option is lung volume recruitment training (LVRT), a technique commonly used to maintain lung and chest wall flexibility. However, it requires specific equipment, such as one-way valves, to be applied to patients with ALS who undergo invasive mechanical ventilation with tracheostomy. Only limited studies have indicated the effectiveness of LVRT for patients with ALS. Moreover, no study is currently available on the effect of combining LVRT with MI-E. As the disease progresses, treatment options become increasingly limited, making it crucial to explore new therapeutic approaches for patients at the advanced stage. Here, we examined the effects of a combination of LVRT and MI-E in a 74-year-old female patient with ALS who had survived under invasive mechanical ventilation for nine years. We measured tidal volume (TV) and dynamic lung compliance (Cdyn) as respiratory parameters three months before and after the initiation of the combined therapy. Following the intervention, TV improved from 750.15 L/min (standard deviation (SD) ± 34.60) to 859.14 L/min (SD ± 75.63), and Cdyn increased from 24.18 cmH2O (SD ± 2.84) to 26.54 cmH2O (SD ± 2.92). These results suggest that MI-E combined with LVRT may improve lung compliance even in patients with ALS receiving long-term invasive mechanical ventilation.}, } @article {pmid40492022, year = {2025}, author = {Ennis, R and Husted, C}, title = {Case Report: Treating Atrial Fibrillation with the Neubie Direct Current Electrical Stimulation.}, journal = {Medical devices (Auckland, N.Z.)}, volume = {18}, number = {}, pages = {291-295}, pmid = {40492022}, issn = {1179-1470}, abstract = {INTRODUCTION: A novel Neuro-Bio-Electric-Stimulation device (Neubie, Neufit, Austin, Texas, USA) using Direct Current (DC) has been used to treat various neurological conditions (ALS, MS, peripheral neuropathy, chronic pain) and functional limitations such as limited range of motion. One method, called the Master Reset Protocol, is thought to stimulate the vagus nerve system, impacting heart rate, digestion and other vital systems.

PURPOSE: We used the Master Reset Protocol on a subject experiencing paroxysmal Atrial Fibrillation (AFib) to assess whether this treatment might be effective in reversing a cardiac arrhythmia.

SUBJECT AND METHODS: A single subject is reported in this Case Report. The subject is a 62-year-old healthy, athletic male, 6'2″ tall, 165 lbs. with a good diet and is not obese nor has other exacerbating underlying conditions related to heart disease. The subject experiences arrhythmia approximately 1-2 times per month lasting generally 3 or more days per the subject. The Master Reset Method was initiated within 12 hours of arrhythmia onset, and arrhythmia before and after treatment was confirmed through subject observation and confirmed with pulse readings. A total of ten treatments were conducted over 7 months.

RESULTS: Reversal of arrhythmia was confirmed during or within 24 hours of treatment with DC application for all 10 treatments (100%). Two of the more severe cases of AFib required two treatments on the same day with confirmed reversal of AFib.

CONCLUSION: Treatment with Direct Current suggests a good correlation with reversal of arrhythmia. Further studies are planned to determine if similar, regular, treatments can be effective in preventing arrhythmia.}, } @article {pmid40492044, year = {2025}, author = {Roshni, J and Mahema, S and Janakiraman, V and Ahmad, SF and Al-Mazroua, HA and Ahmed, SSSJ}, title = {Effect of bovine milk-derived peptide on SNAP-25 of the neurotransmitter system in treating the sialorrhoea in chronic neurological diseases.}, journal = {Food science and biotechnology}, volume = {34}, number = {11}, pages = {2601-2610}, pmid = {40492044}, issn = {2092-6456}, abstract = {Sialorrhea is a prominent symptom of chronic neurological disorders like amyotrophic lateral sclerosis, Parkinson's disease, motor neuron disease, cerebral palsy, and stroke. Synaptosome-Associated Protein-25 (SNAP-25) plays a key role in triggering involuntary saliva secretion. This study aimed to identify SNAP-25-targeting bovine milk-derived peptides to mitigate sialorrhea, using computational and quantum atomistic simulation approach. Among 8559 bovine milk-derived peptides, 8499 were non-toxic, 7749 non-allergenic, 911 with blood-brain barrier crossing potential, and 175 with cell-penetrating capabilities. Using HAPPENN program, 20 non-hemolytic peptides were screened, while PeptideRanker predicted two physiologically active peptides. Protein-peptide docking followed by de novo structural modeling showed that CMPTFQFFK has a stronger inhibitory affinity (- 7.45 kcal/mol) for SNAP-25 than botulinum toxin. Additionally, dynamic simulations, free energy and quantum chemical studies confirmed the stability of CMPTFQFFK's with SNAP-25. Our study recommends CMPTFQFFK as a potential inhibitor of SNAP-25 for sialorrhea treatment, with further in vitro testing needed to confirm efficacy.}, } @article {pmid40496257, year = {2025}, author = {Ding, LH and Wu, PF and Sun, NZ}, title = {Investigation of clinical outcomes in conservative management of hook fractures: Commentary on recent findings.}, journal = {World journal of orthopedics}, volume = {16}, number = {5}, pages = {106881}, pmid = {40496257}, issn = {2218-5836}, abstract = {This editorial critically evaluates the landmark study by Tanaka and Yoshii, which demonstrated a 100% union rate with conservative management of hamate hook fractures, challenging the historical preference for surgical intervention. In contrast to Scheufle et al's report of 90%-100% failure rates with early surgical approaches, Tanaka and Yoshii's protocol achieved universal healing despite delayed diagnoses in 25% of cases. Central to this success is the systematic integration of high-resolution computed tomography for early diagnosis and dynamic monitoring of trabecular bone regeneration, significantly reducing missed diagnoses and guiding personalized immobilization timelines. The patient-centered strategy-allowing temporary splint removal during low-risk activities-balanced fracture stability with joint mobility preservation, avoiding post-treatment stiffness. However, limitations such as small sample size (n = 16), selection bias, and insufficient long-term functional data (e.g., grip strength, return-to-sport metrics) underscore the need for comparative trials. Emerging trends, including adjunct therapies like low-intensity pulsed ultrasound and biologics (e.g., teriparatide), are proposed to accelerate healing while minimizing immobilization risks. This work redefines conservative fracture management paradigms, emphasizing innovation without compromising efficacy. Overall, this assessment deepens our understanding of the conservative management of hook fractures and provides evidence-based insights for improved clinical decision-making.}, } @article {pmid40496636, year = {2025}, author = {Qiao, H and Cheng, X and Tian, H and Zhao, C and Sun, X and Zhao, J}, title = {Lower cervical C6/C7 andersson lesion with upper cervical C1/C2 fracture in ankylosing spondylitis: a case report and literature review.}, journal = {Frontiers in surgery}, volume = {12}, number = {}, pages = {1568553}, pmid = {40496636}, issn = {2296-875X}, abstract = {Cervical andersson lesions (ALs) are rare in patients with ankylosing spondylitis (AS), and even more rare in patients with simultaneous superior cervical atlantoaxial fracture and dislocation. Here, we present a case of C1 Jefferson fracture (C1 bilateral posterior arch fracture), C2 odontoid, lateral mass, vertebral fracture (nonclassic C2 hangman fracture), traumatic posterior atlantoaxial dislocation (AAD) and C6/C7 AL in a long-standing AS cervical spine. The patient with traumatic AS-related cervical fractures underwent a two-stage surgery. The stage I surgery involved a posterior atlantoaxial reduction and fixation surgery combined with C5/C6/T1/T2 posterior pedicle screw fixation plus C6/C7 decompression. One week later, C6/C7 anterior cervical corpectomy decompression and fusion (ACCF) with long anterior plate stabilization combined with iliac crest bone graft transplantation was performed for stage II surgery. The patient recovery observed during follow-up was satisfactory. Nine-month postoperative radiological images revealed fracture union of the upper and lower cervical spine with optimal reduction of the atlantoaxial segment. In conclusion, lower cervical ALs with simultaneous upper cervical C1/C2 fractures in the AS are very rare. Posterior C1-C2 fixation combined with C6-C7 AL corpectomy/fusion and posterior pedicle screw fixation may offer a desirable alternative approach for this complex case of cervical trauma. During treatment, complete decompression, effective reduction, and potent stabilization can comprehensively improve the clinical prognosis.}, } @article {pmid40497426, year = {2025}, author = {Bao, J and Zhou, J and Xie, Z and Zou, M and Napier, R and Li, J}, title = {CYP99A2 from Aegilops tauschii metabolizes pyroxsulam but not mesosulfuron-methyl, causing different natural sensitivity to two herbicides.}, journal = {Pest management science}, volume = {81}, number = {10}, pages = {6210-6219}, doi = {10.1002/ps.8967}, pmid = {40497426}, issn = {1526-4998}, support = {2021YFD1700100//National Key Research and Development Program/ ; }, mesh = {*Herbicides/pharmacology/metabolism ; *Sulfonylurea Compounds/metabolism/pharmacology ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Herbicide Resistance ; *Plant Proteins/metabolism/genetics ; Acetolactate Synthase/antagonists & inhibitors ; *Poaceae/genetics/metabolism/drug effects/enzymology ; Plant Weeds/drug effects ; }, abstract = {BACKGROUND: Weed tolerance to herbicides poses a major threat to agricultural production. Aegilops tauschii has promising prospects for genetic development; however, the fact that this plant is invasive in China and other countries is often ignored owing to its pronounced adaptability. Among the current acetolactate synthase (ALS) inhibitors, only mesosulfuron-methyl (MM) can control A. tauschii, and pyroxsulam (P) is ineffective. However, a knowledge gap remains regarding differences in sensitivity of A. tauschii to these two ALS inhibitors.

RESULTS: We hypothesized that differences in sensitivity of A. tauschii to the ALS inhibitors MM and P are mediated by metabolic enzymes. Whole-plant experiments showed that the P450s inhibitor 1-Aminobenzotriazole (ABT) significantly increased the sensitivity of A. tauschii to P compared with MM. In A. tauschii, the P metabolism rate was higher than that of MMl, as detected by liquid chromatography with tandem mass spectrometry. Transcriptome sequencing and quantitative real-time polymerase chain reaction identified seven differentially expressed P450s after P and MM treatments, three of which were upregulated after P treatment and were unaffected by MM. AtCYP99A2 reduced plant sensitivity to P by metabolizing P without affecting MM by overexpressing it in Arabidopsis and inducing in vitro protein expression.

CONCLUSION: To the best of our knowledge, this is the first report on P450 involvement in A. tauschii sensitivity to two ALS-inhibitor herbicides. This study deepens current understandings of A. tauschii and facilitates subsequent screening of specific metabolic enzyme inhibitors to be used as synergists in combination with herbicides, which will provide new avenues for weed control. © 2025 Society of Chemical Industry.}, } @article {pmid40498248, year = {2025}, author = {Pahwa, R and Molho, E and Lew, M and Dashtipour, K and Gil, RA and Revilla, FJ and Clinch, T and Qin, P and Isaacson, SH and , }, title = {Long-Term Safety and Efficacy of Repeated Cycles of RimabotulinumtoxinB in the Treatment of Chronic Sialorrhea: Results of the OPTIMYST Trial.}, journal = {Neurology and therapy}, volume = {14}, number = {4}, pages = {1553-1567}, pmid = {40498248}, issn = {2193-8253}, abstract = {INTRODUCTION: Botulinum toxin injections into the salivary glands inhibit saliva production by reducing the release of acetylcholine at the parasympathetic nerve terminals within the salivary gland. The phase 3 study reported here assessed the safety, tolerability, and effectiveness of repeated cycles of rimabotulinumtoxinB (RIMA) injections in adults with troublesome sialorrhea.

METHODS: In this phase 3, open-label multicenter study, 187 adult participants with troublesome sialorrhea due to Parkinson disease (65.8%), amyotrophic lateral sclerosis (13.9%), and other etiologies (20.3%) received up to 4 cycles of RIMA treatment (3500 U every 11-15 weeks).

RESULTS: Participants (69% male, 31% female; mean age 64.1 years) had sialorrhea for a mean of 3.2 years at baseline with a mean Unstimulated Salivary Flow Rate (USFR) of 0.63 ± 0.49 g/min. During the first treatment cycle, RIMA significantly reduced the mean±standard deviation (SD) USFR from baseline to week 4 by - 0.34 ± 0.37 g/min (p < 0.0001), and efficacy was maintained through week 13 (- 0.14 ± 0.29 g/min; p < 0.0001). Reductions were maintained at subsequent injection cycles 2-4, with mean absolute USFRs at weeks 4 and 13 of each cycle similar to those of cycle 1. Most adverse events (AEs) were mild, and the most commonly reported AEs in each cycle that were considered to be treatment-related were dry mouth (≤ 15.5% participants/cycle) and dental caries (≤ 6.0% participants/cycle).

CONCLUSION: This study demonstrates that RIMA 3500 U safely reduces saliva production over repeated treatment cycles through 1 year, thereby supporting its utility in the management of troublesome sialorrhea in adults.

GOV IDENTIFIER: NCT02610868.}, } @article {pmid40499018, year = {2025}, author = {Yadav, V and Singh, R and Chaturvedi, M and Siddhanta, S and Chaturvedi, R}, title = {Multivariate and Machine Learning-Derived Virtual Staining and Biochemical Quantification of Cancer Cells through Raman Hyperspectral Imaging.}, journal = {Analytical chemistry}, volume = {97}, number = {24}, pages = {12660-12668}, doi = {10.1021/acs.analchem.5c01028}, pmid = {40499018}, issn = {1520-6882}, mesh = {*Spectrum Analysis, Raman/methods ; Humans ; *Machine Learning ; Principal Component Analysis ; Multivariate Analysis ; Neural Networks, Computer ; *Hyperspectral Imaging/methods ; Staining and Labeling ; Least-Squares Analysis ; Lipids/analysis ; Algorithms ; Collagen/analysis ; Cell Line, Tumor ; }, abstract = {Advances in virtual staining and spatial omics have revolutionized our ability to explore cellular architecture and molecular composition with unprecedented detail. Virtual staining techniques, which rely on computational algorithms to map molecular or structural features, have emerged as powerful tools to visualize cellular components without the need for physical dyes, thereby preserving sample integrity. Similarly, spatial omics enable the mapping of biomolecules across tissue or cell surfaces, providing spatially resolved insights into biological processes. However, traditional dye-based staining methods, while widely used, come with significant limitations. In this context, Raman spectroscopy offers a robust, label-free alternative for probing molecular composition at a high resolution. We present a novel algorithm that reconstructs super-resolved Raman images by extracting spectral patterns from surrounding pixels, enabling detailed, label-free visualization of cellular structures. By employing Raman spectroscopy in conjunction with chemometric tools such as principal component analysis (PCA), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural network (ANN), we performed a quantitative analysis of key biomolecular components, including collagen, lipids, glycogen, and nucleic acids, and classify the different cancer cell lines with an accuracy of nearly 99%. This approach not only enabled the identification of distinct molecular fingerprints across the different cancer types but also provided a powerful tool for understanding the biochemical variations that underlie tumor heterogeneity. This innovative combination of virtual staining, spatial omics, and advanced chemometrics highlights the potential for more accurate diagnostics and personalized treatment strategies in oncology.}, } @article {pmid40501612, year = {2025}, author = {Bhuiyan, P and Yi, Y and Wei, B and Yan, A and Dong, L and Wei, H}, title = {Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501612}, issn = {2692-8205}, support = {R01 AG061447/AG/NIA NIH HHS/United States ; }, abstract = {Calcium dysregulation, caused by pathological activation of ryanodine receptors, contributes to motor neuron degeneration, motor dysfunction, and muscle weakness in SOD1-G93A transgenic amyotrophic lateral sclerosis (ALS) mice. This study investigates the therapeutic efficacy of intranasally administered dantrolene nanoparticles, a ryanodine receptor antagonist, on motor neuron function, muscle strength, spinal cord degeneration, and survival outcomes. Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) IN-DAN: Intranasal administration of dantrolene in the Ryanodex formulation vehicle (RFV), at a dosage of 5mg/kg, administered daily from ages 90-120 days; 3) IN-VEH: Intranasal administration of RFV alone (as a vehicle control), following the same dosing schedule as the IN-DAN condition. Body weight and general motor function were monitored weekly, with survival recorded daily throughout the treatment period. At the treatment conclusion, neurological function was comprehensively evaluated using a standardized neurological scoring system. Motor coordination and balance were assessed using the balance beam test (beam widths of 12 mm and 6 mm) and the rotarod test. Muscle strength was evaluated by measuring grip force using the Kondziela inverted screen test. After behavioral testing, spinal cord tissues were collected for analysis. The levels of neurofilament light chain (NFL), a skeletal neuron protein, and spinal cord weight were determined to measure spinal cord degeneration. Compared to non-transgenic control mice, SOD1-G93A mice exhibited significantly elevated neurological scores, indicating severely impaired neurological function. This deterioration was robustly and significantly ameliorated by IN-DAN treatment by 90% (P<0.0001). Similarly, ALS mice demonstrated impairments in motor coordination and balance on the beam balance test, with dramatic and significant increases in crossing time and the number of foot slips. These impairments were greatly and significantly mitigated by IN-DAN treatment, by 78% in crossing time (P<0.0001) and 84% in the number of slips (P<0.0001) on the 12 mm-wide beam, but not by the vehicle control. ALS mice demonstrated progressive body weight loss as well, which was similarly reversed by IN-DAN treatment, but not by the vehicle control. Muscle strength, as measured by grip force, was significantly reduced in ALS mice but robustly preserved IN-DAN treatment, which prevented the decrease by 213% (P<0.0001), while the vehicle control had no effect. Spinal cord weight was significantly reduced in ALS mice, a trend reversed by intranasal dantrolene nanoparticle treatment, but not by the vehicle control. Survival analysis revealed that 100% of control mice survived through the 30-day treatment period (up to 120 days of age), while survival in untreated or vehicle-treated ALS mice dropped to 67%. In contrast, ALS mice treated with intranasal dantrolene nanoparticles demonstrated a significantly improved survival rate of 89%. Thus, intranasal dantrolene nanoparticle treatment significantly and robustly improved neurological outcomes in SOD1-G93A ALS mice, inhibiting neurological impairment, motor dysfunction, balance deficits, and muscle weakness. These improvements were associated with a marked inhibition of spinal cord weight loss. Additionally, dantrolene treatment reversed body weight loss and significantly improved survival probability in ALS mice.}, } @article {pmid40505784, year = {2025}, author = {Tang, J and Kang, Y and Chen, Q and Zhang, B and Shang, N and Lan, J and Wu, L and Peng, Y}, title = {TIMP1 inhibits Rac1-mediated ROS production to ameliorate blood-spinal cord barrier disruption in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {213}, number = {}, pages = {106987}, doi = {10.1016/j.nbd.2025.106987}, pmid = {40505784}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; *rac1 GTP-Binding Protein/metabolism ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/genetics ; *Spinal Cord/metabolism/pathology ; *Reactive Oxygen Species/metabolism ; Mice ; Endothelial Cells/metabolism ; Mice, Transgenic ; Humans ; Mice, Inbred C57BL ; Male ; Neuropeptides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of motor neurons, for which therapeutic strategies and pharmacological interventions remain limited. Disruption of the blood-spinal cord barrier (BSCB) has been identified as a significant factor that may exacerbate motor neuron damage. Tissue inhibitor of metalloproteinase-1 (TIMP1), a molecule known for its dual roles in inhibiting matrix metalloproteinase (MMP) activity and exerting cytokine-like effects via receptor interactions, has been demonstrated to ameliorate endothelial barrier damage in various diseases. Here, we explored the potential of TIMP1 to restore BSCB integrity as a strategy to slow the ALS progression. Specifically, the expression of TIMP1 or its mutant variant AlaTIMP1, which lacks MMP-inhibitory activity, in spinal cord microvascular endothelial cells (SCMECs) prior to disease onset significantly reduces BSCB leakage in mice with ALS, thereby alleviating motor function deficits and delaying disease progression. Additionally, TIMP1 expression restores the expression of junctional complexes in SCMECs, as demonstrated in both in vivo and in vitro ALS models. Mechanistic studies revealed that TIMP1 suppresses ALS injury-induced integrin β1 activation independent of MMP inhibition, blocking downstream Rac1 translocation to the membrane to form a complex with NOX2. The inhibition of NOX2 activity reduces ROS-induced cytoskeletal remodeling, consequently stabilizing overall junctional alignment and preserving the BSCB integrity. Overall, our findings elucidate an MMP-independent mechanism through which TIMP1 regulates BSCB integrity in ALS context, suggesting that TIMP1 could serve as a novel tool for the treatment of ALS, particularly for prophylactic treatment in patients with familial ALS.}, } @article {pmid40508048, year = {2025}, author = {Tolochko, C and Shiryaeva, O and Alekseeva, T and Dyachuk, V}, title = {Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms and Treatment Strategies (Part 2).}, journal = {International journal of molecular sciences}, volume = {26}, number = {11}, pages = {}, pmid = {40508048}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/metabolism/therapy/etiology/pathology ; Humans ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/pharmacology ; Motor Neurons/metabolism/pathology/drug effects ; Glutamic Acid/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with damage to motor neurons and leading to severe muscle weakness and, eventually, death. Over the past decade, understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy.}, } @article {pmid40509360, year = {2025}, author = {Chang, B and Huang, J and Xie, Q and Ruan, Y and Liu, R}, title = {Identification, Geographical Traceability, and Thermal Oxidation and Photodegradation Studies of Camellia Oil Based on Raman Spectroscopy.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {11}, pages = {}, pmid = {40509360}, issn = {1420-3049}, support = {2024KY0802, 2023KY0217,XJ21KT29//the Middle-aged and Young Teachers' Basic Ability Promotion Project of Guangxi，The Guilin University of Aerospace Technology School Fund/ ; No. AD25069073//Guangxi Science and Technology Program Project/ ; }, mesh = {*Spectrum Analysis, Raman/methods ; *Plant Oils/chemistry/analysis ; *Camellia/chemistry ; Oxidation-Reduction ; Photolysis ; Carotenoids/chemistry/analysis ; Temperature ; Least-Squares Analysis ; Discriminant Analysis ; }, abstract = {Camellia oil, rich in monounsaturated fatty acids, squalene, tocopherols, and polyphenols, is highly valued for its nutritional benefits. However, its high market value and regional variations have led to frequent adulteration, highlighting the need for rapid, non-destructive methods for authentication, geographical traceability, and quality assessment. This study employed portable Raman spectroscopy combined with Partial Least Squares Discriminant Analysis (PLS-DA) and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to differentiate camellia oil from other edible oils and evaluate its thermal and photo-oxidative stability. PLS-DA, based on VIP-selected spectral variables, effectively distinguished camellia oil, with Raman bands near 1250 cm[-1] and 1650 cm[-1] contributing significantly. A unique peak at 1525 cm[-1], observed in samples from Gongcheng, Guangxi, was associated with carotenoids and served as a potential marker for geographical traceability. MCR-ALS modeling revealed significant reductions in the 1650 cm[-1] and 1525 cm[-1] peaks when temperatures exceeded 150 °C, indicating degradation of unsaturated fatty acids and carotenoids. Under UV exposure, the 1525 cm[-1] peak declined sharply and nearly disappeared after 24 h, suggesting rapid carotenoid degradation via photooxidation. Extended UV treatment also affected the 1650 cm[-1] peak and led to oxidative product accumulation. Overall, this study demonstrates the feasibility of integrating Raman spectroscopy with chemometric analysis for efficient oil classification, traceability, and stability monitoring, offering a valuable tool for food quality control and market supervision.}, } @article {pmid40511876, year = {2025}, author = {Yeole, A and Khanna, L and Doshi, M and Sharma, A and Uttarwar, P and Doshi, S and Kaushik Kumar, R and Venkataramana, N and Parmar, D}, title = {A phase 2, proof-of-concept, placebo-controlled, randomized, multicenter, double-blind study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {794-801}, doi = {10.1080/21678421.2025.2515900}, pmid = {40511876}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Neurofilament Proteins/cerebrospinal fluid/blood ; *Organic Chemicals/administration & dosage/adverse effects/pharmacokinetics ; Proof of Concept Study ; Treatment Outcome ; }, abstract = {Objective: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. Results: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (p > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. Conclusion: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.}, } @article {pmid40513028, year = {2025}, author = {Bromberg, MB}, title = {What Is in the Literature.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {4}, pages = {176-183}, doi = {10.1097/CND.0000000000000526}, pmid = {40513028}, issn = {1537-1611}, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; }, abstract = {This issue of What Is in the Literature focuses on articles over the past year on clinical aspects of motor neuron disease, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Disease-modifying treatment for ALS remains a challenge as 2 formal drug trials did not hold up to retesting. There are new thoughts based on a multistep model to partially explain why ALS develops relatively late in life. New information on fluid biomarkers, sex differences, efficacy of medical marijuana for common symptoms, and cognitive dysfunction are discussed. For the clinic, there are updated guidelines for multidisciplinary management. Other articles address how frequently the topic of sexual health is brought up in the clinic, and insights into how patients view end-of-life issues and quality of life when using tracheal ventilation. PLS has diagnostic challenges and practical aspects, which are reviewed.}, } @article {pmid40517187, year = {2026}, author = {Haro-Martínez, E and Muscolino, E and Moral, N and Duran, J and Fornaguera, C}, title = {Crossing the blood-brain barrier: nanoparticle-based strategies for neurodegenerative disease therapy.}, journal = {Drug delivery and translational research}, volume = {16}, number = {3}, pages = {797-824}, pmid = {40517187}, issn = {2190-3948}, support = {2021 SGR 00537//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 2024-LLAV-00042//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; ICREA Acadèmia 2024//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 202207-31//Fundació la Marató de TV3/ ; PID2020-118699GB-100//Agencia Estatal de Investigación/ ; Not specified//Fundación Ramón Areces/ ; FISDUR-2024//Departament d'Universitats, Recerca i Societat de la Informació/ ; }, mesh = {Humans ; *Blood-Brain Barrier/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Nanoparticles/administration & dosage/chemistry ; Drug Delivery Systems ; Drug Carriers/chemistry ; }, abstract = {Neurodegenerative conditions, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease, represent a critical medical challenge due to their increasing prevalence, severe consequences, and absence of curative treatments. Beyond the need for a deeper understanding of the fundamental mechanisms underlying neurodegeneration, the development of effective treatments is hindered by the blood-brain barrier, which poses a major obstacle to delivering therapeutic agents to the central nervous system. This review provides a comprehensive analysis of the current landscape of nanoparticle-based strategies to overcome the blood-brain barrier and enhance drug delivery for the treatment of neurodegenerative diseases. The nanocarriers reviewed in this work encompass a diverse array of nanoparticles, including polymeric nanoparticles (e.g. micelles and dendrimers), inorganic nanoparticles (e.g. superparamagentic iron oxide nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, selenium and cerium oxide nanoparticles), lipid nanoparticles (e.g. liposomes, solid lipid nanoparticles, nanoemulsions), as well as quantum dots, protein nanoparticles, and hybrid nanocarriers. By examining recent advancements and highlighting future research directions, we aim to shed light on the promising role of nanomedicine in addressing the unmet therapeutic needs of these diseases.}, } @article {pmid40518671, year = {2025}, author = {Val, GD and Gauye, F and Audrain, M and Menant, S and Ratnam, M and Chevalier, E and Ollier, R and Bhatia, D and Seredenina, T and Afroz, T and Pfeifer, A and Kosco-Vilbois, M and Nevoltris, D}, title = {A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {9}, pages = {4360-4380}, pmid = {40518671}, issn = {1525-0024}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology/metabolism/genetics ; *DNA-Binding Proteins/immunology/antagonists & inhibitors/genetics/metabolism ; *Frontotemporal Dementia/therapy/pathology/metabolism/genetics ; Mice ; Disease Models, Animal ; Humans ; *Antibodies, Monoclonal/genetics/administration & dosage/immunology ; *Genetic Vectors/genetics/administration & dosage ; Dependovirus/genetics ; Brain/metabolism/pathology ; }, abstract = {Transactive response DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated as a vectorized full-length antibody (vmAb) and evaluated for brain delivery using adeno-associated virus 9 (AAV9). Among the expression cassettes explored, the selected construct utilized an internal ribosome entry site (IRES), which produced high expression yields in vitro (>200 mg/L) with comparable quality, binding, and functional properties to the conventionally produced mAb. A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid, and brain of mice. In a mouse model of ALS/FTD, treatment with a vmAb reduced the amount of pathological phospho-TDP-43 in neurons by 58% and 68% when expressed using either a ubiquitous promoter or a brain-selective promoter, respectively. This innovative approach sufficiently delivers effective immunotherapy with a single dose and illustrates the enormous potential of using vectorized antibodies to target neuropathology, including TDP-43 in patients suffering from ALS, FTD, and other TDP-43 proteinopathies.}, } @article {pmid40519505, year = {2025}, author = {Funo, K and Fukutake, T and Takeuchi, R and Uzawa, Y}, title = {Importance of Individualized Pressure Settings in Mechanical Insufflation-Exsufflation for Lung Volume Recruitment: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e84211}, pmid = {40519505}, issn = {2168-8184}, abstract = {Lung volume recruitment (LVR) has been proposed as a treatment to maintain respiratory health in patients with neuromuscular diseases who frequently develop restrictive ventilatory impairment due to muscle weakness. LVR applies noninvasive mechanical pressure techniques to maintain and improve pulmonary and chest wall compliance and to preserve vital capacity. Various methods of LVR have been developed, which can be classified into two types: the stacked-breath method and the single-breath method. Mechanical insufflation-exsufflation (MI-E) is one approach categorized under the single-breath method. Although the clinical use of pressure settings in MI-E varies, inspiratory pressure levels around 40 cmH2O are sometimes applied in practice. However, such settings may result in patient discomfort and raise safety concerns. Given the limited clinical guidance available, it may be more appropriate to determine individualized settings based on each patient's impairment level, pulmonary mechanics, and tolerance. This case report describes such an approach to LVR using the single-breath method with MI-E in a patient with amyotrophic lateral sclerosis (ALS). To determine the optimal inspiratory pressure, three parameters were assessed at each pressure level: expiratory volume, subjective perception of lung expansion, and immediate subjective effects following inspiration. As the patient reported discomfort at 30 cmH2O, the final inspiratory pressure was set at 25 cmH2O. This level of inspiratory assistance led to improvements in vocal loudness and alleviated breathlessness during speech. These positive effects contributed to the patient's acceptance of the intervention and its continued use after discharge to home care. This case highlights the importance of tailoring LVR settings to optimize effectiveness, patient comfort, and safety, based on pulmonary mechanics, bedside volume assessment, and patient-reported respiratory status.}, } @article {pmid40522761, year = {2026}, author = {Fan, T and Peng, J and Liang, H and Chen, W and Wang, J and Xu, R}, title = {Potential common pathogenesis of several neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {3}, pages = {972-988}, pmid = {40522761}, issn = {1673-5374}, abstract = {With the gradual advancement of research methods and technologies, various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases. However, current descriptions of these biological processes do not fully explain the onset, progression, and development of these conditions. Therefore, exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research. This review summarizes the potential common pathogeneses of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal lobar dementia, and Lewy body disease. Research findings have indicated that several common biological processes, including aging, genetic factors, progressive neuronal dysfunction, neuronal death and apoptosis, protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis, are involved in the pathogenesis of these six neurodegenerative diseases. Based on current information derived from diverse areas of research, these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases. Furthermore, promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed. Hence, these potential common biological processes may represent only very small, limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases. In clinical treatment, interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases. Therefore, future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks, rather than isolating individual biological processes. Based on this, therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions, as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.}, } @article {pmid40527529, year = {2025}, author = {Cassidy-Seyoum, SA and Adhikari, B and Chheng, K and Chanpheakdey, P and Meershoek, A and Hsiang, MS and von Seidlein, L and Tripura, R and Ley, B and Price, RN and Dysoley, L and Thriemer, K and Engel, N}, title = {Acceptability and feasibility of glucose-6-phosphate dehydrogenase (G6PD) testing using SD Biosensor by village malaria workers in Cambodia: a qualitative study.}, journal = {BMJ global health}, volume = {10}, number = {6}, pages = {}, pmid = {40527529}, issn = {2059-7908}, mesh = {Humans ; Cambodia ; Qualitative Research ; Feasibility Studies ; *Glucosephosphate Dehydrogenase/blood/analysis ; Female ; *Community Health Workers ; *Biosensing Techniques/methods ; Focus Groups ; Male ; *Glucosephosphate Dehydrogenase Deficiency/diagnosis ; *Patient Acceptance of Health Care/statistics & numerical data ; *Malaria, Vivax/drug therapy ; Adult ; Interviews as Topic ; Point-of-Care Testing ; Middle Aged ; Malaria ; Primaquine/therapeutic use ; }, abstract = {INTRODUCTION: Plasmodium vivax is the predominant cause of malaria in the Greater Mekong Subregion. To ensure safe treatment with primaquine, point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing was rolled out in Cambodia at the health facility level, although most malaria patients are diagnosed in the community. The current study aims to explore the acceptability and feasibility of implementing community-level G6PD testing in Cambodia.

METHODS: Semistructured interviews and focus group discussions (FGD) were conducted. Across eight study sites in three provinces, 142 respondents, including policymakers, programme officers, healthcare providers and patients, participated in 67 interviews and 19 FGDs in 2022 and 2023. Data were analysed thematically using an adapted framework derived from Bowen et al's feasibility framework and Sekhon et al's acceptability framework.

RESULTS: All stakeholders attributed value to the intervention. Acknowledging an intervention's different values can help discern policy implications for an intervention's successful implementation. Building and maintaining confidence in the device, end users, infrastructure and health systems were found to be key elements of acceptability. In general, health centre workers and village malaria workers (VMWs) had confidence that VMWs could conduct the test and administer treatment given appropriate initial training, monthly refresher training and the test's repeated use. More is required to build policymakers' confidence, while some implementation challenges, including the test's regulatory approval, stability above 30°C and cost, need to be overcome.

CONCLUSION: Implementation of G6PD testing at the community level in Cambodia is an acceptable and potentially feasible option but requires addressing implementation challenges and building and maintaining confidence among stakeholders.}, } @article {pmid40534528, year = {2025}, author = {Ertural, B and Çiçek, BN and Kurnaz, IA}, title = {RNA Therapeutics: Focus on Antisense Oligonucleotides in the Nervous System.}, journal = {Biomolecules & therapeutics}, volume = {33}, number = {4}, pages = {572-581}, pmid = {40534528}, issn = {1976-9148}, abstract = {RNA therapeutics represent a disruptive technology that has transformed drug discovery and manufacturing, gaining significant prominence during the COVID-19 pandemic. RNA therapeutics encompass diverse molecules like antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), RNA aptamers, and messenger RNAs (mRNAs), which can function through different mechanisms. RNA therapeutics are increasingly used to treat various diseases, including neurological disorders. For example, ASO therapies such as nusinersen for spinal muscular atrophy and eteplirsen for Duchenne muscular dystrophy are successful applications of RNA-based treatment. Emerging ASO treatments for Huntington's disease and amyotrophic lateral sclerosis are also promising, with ongoing clinical trials demonstrating significant reductions in disease-associated proteins. Still, delivery of these molecules remains a pivotal challenge in RNA therapeutics, especially for ASOs in penetrating the blood-brain barrier to target neurological disorders effectively. Nanoparticle-based formulations have emerged as leading strategies to enhance RNA stability, reduce immunogenicity, and improve cellular uptake. Despite these advances, significant hurdles remain, including optimizing pharmacokinetics, minimizing off-target effects, and ensuring sustained therapeutic efficacy. Regulatory frameworks are evolving to accommodate the unique challenges of RNA-based therapies, including ASOs with efforts underway to establish comprehensive guidelines for RNA therapeutics, yet there are also sustainable manufacturing issues that need to be considered for long-term feasibility. By addressing these challenges, RNA therapeutics hold immense potential to revolutionize treatment paradigms for neurological disorders. Looking forward, the future of RNA therapeutics in neurology appears promising but requires continued interdisciplinary collaboration and technological innovation.}, } @article {pmid40536931, year = {2026}, author = {Li, K and Chen, R and Wang, R and Fan, W and Zhao, N and Yang, Z and Yan, J}, title = {Neuroinflammation in neurodegenerative diseases: Focusing on the mediation of T lymphocytes.}, journal = {Neural regeneration research}, volume = {21}, number = {5}, pages = {1864-1889}, pmid = {40536931}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system, leading to a decline in patients' cognitive, motor, and emotional abilities. Neuroinflammation plays a significant role in the progression of these diseases. However, there is limited research on therapeutic approaches to specifically target neuroinflammation. The role of T lymphocytes, which are crucial mediators of the adaptive immune response, in neurodegenerative diseases has been increasingly recognized. This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases. The pathogenesis of neurodegenerative diseases is complex, involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons, and T cells are a key component of these processes. One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells, including microglia, astrocytes, B cells, and natural killer cells. Different subsets of CD4 + T cells, such as Th1, Th2, Th17, and regulatory T cells, can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases. Additionally, CD8 + T cells, which can directly regulate immune responses and kill target cells, also play several important roles in neurodegenerative diseases. Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that, while some patients respond positively, others may not respond as well and may even experience adverse effects. Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system, which can lead to undesirable side effects. However, with new insights into the pathophysiology of neurodegenerative diseases, there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.}, } @article {pmid40540128, year = {2025}, author = {Bonan, L and Bombardi, M and Di Lionardo, A and Vitiello, M and Morresi, S and Longoni, M}, title = {Co-occurence of amyotrophic lateral sclerosis and sarcoidosis: a case report and systematic review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {9}, pages = {4209-4217}, pmid = {40540128}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Male ; Middle Aged ; *Sarcoidosis/complications/diagnosis/drug therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, with 90% of cases being sporadic. Sarcoidosis is an inflammatory disease affecting multiple organs, with neurological complications occurring in 5-10% of patients. Only isolated cases of this extremely rare combination of the two diseases have been reported.

METHODS: We present the case of a 45-year-old man diagnosed with ALS after a 2-year history of progressive upper limb weakness who was incidentally found to be affected by thoraco-abdominal lymphadenopathy. The biopsy confirmed the co-presence of sarcoidosis. We also make a systematic review of the literature of this rare combination.

RESULTS: The patient showed stabilization of the neurological condition and the pneumological disease after administration of immunosuppressive treatment.

CONCLUSION: Our case report and literature review highlight peculiar clinical characteristics of this extremely rare combination of diseases, deepening the understanding of this peculiar phenotype.}, } @article {pmid40541317, year = {2025}, author = {Frecska, E and Kovács, A and Szabo, A}, title = {The protective effect of DMT against neurodegeneration.}, journal = {International review of neurobiology}, volume = {181}, number = {}, pages = {395-420}, doi = {10.1016/bs.irn.2025.04.010}, pmid = {40541317}, issn = {2162-5514}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy/prevention & control ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Receptors, sigma/agonists/metabolism ; *Reperfusion Injury/metabolism/drug therapy ; Sigma-1 Receptor ; }, abstract = {This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of our previous preclinical (in vitro and in vivo) DMT studies aiming at mitigating IRI and related cellular neuropathologies. We conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest. The multiple neuroprotective mechanisms facilitated by DMT may position it as a model molecule for developing pharmacological treatments for neurodegenerative disorders.}, } @article {pmid40547142, year = {2025}, author = {Kumar, S}, title = {Esophageal squamous cell carcinoma susceptibility of activin A receptor type 1C variants in Chinese population.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {6}, pages = {102687}, pmid = {40547142}, issn = {1948-5204}, abstract = {Lin et al's investigation on the association of activin A receptor type 1C (ACVR1C) (transforming growth factor beta type I receptor) single nucleotide polymorphisms (SNPs) with esophageal squamous cell carcinoma (ESCC) risk in the Chinese population is a scientific approach. This study explores the susceptibility of ACVR1C polymorphism towards ESCC in the Chinese population, highlighting the polymorphism's potentiality as an early diagnostic and therapeutic target. The author assessed about a thousand ESCC Chinese patients' samples for ACVR1C SNPs in a hospital-based cohort study using the ligation detection reaction method. Further, the hypothesis was tested using appropriate statistical genetic models and stratified analysis. ACVR1C SNPs can help assess ESCC susceptibility stratification and provide valuable information for individual diagnosis and treatment of ESCC patients. In order to account for confounding variables, find genuine SNP-disease relationships, boost statistical power, and make biological interpretation easier, it is imperative that genetic association studies of ESCC incorporate pertinent clinical aspects.}, } @article {pmid40548824, year = {2025}, author = {Leykam, L and Jonsson, PA and Forsberg, KME and Andersen, PM and Brännström, T and Marklund, SL and Zetterström, P}, title = {SOD1 Protein Content in Human Central Nervous System and Peripheral Tissues.}, journal = {Journal of neurochemistry}, volume = {169}, number = {6}, pages = {e70136}, pmid = {40548824}, issn = {1471-4159}, support = {//Olsson och Olsson Välgörenhetsstiftelse/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Fort Knox Välgörenhetsstiftelse/ ; 2.1.12-1605-14//Umeå University Insamlingsstiftelsen/ ; 2.1.6-452-20//Umeå University Insamlingsstiftelsen/ ; 223-1881-13//Umeå University Insamlingsstiftelsen/ ; 223-2808-12//Umeå University Insamlingsstiftelsen/ ; //Västerbotten Läns Landsting/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; //Neuroförbundet/ ; 2012-3167//Vetenskapsrådet/ ; 2017-03100//Vetenskapsrådet/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; 2012-0262//Swedish brain foundation/ ; 2012-0305//Swedish brain foundation/ ; 2013-0279//Swedish brain foundation/ ; 2016-0303//Swedish brain foundation/ ; 2020-0353//Swedish brain foundation/ ; }, mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/enzymology ; Male ; Female ; *Central Nervous System/enzymology/metabolism ; Middle Aged ; Aged ; Adult ; *Superoxide Dismutase/metabolism ; Muscle, Skeletal/enzymology ; }, abstract = {Gene silencing therapy is an effective treatment for amyotrophic lateral sclerosis (ALS) patients carrying mutations in the superoxide dismutase-1 (SOD1) gene aiming to reduce noxious forms of SOD1 in the central nervous system (CNS). The normal steady-state level of SOD1 protein in human CNS is therefore of interest but is contested. In this work we have analyzed SOD1 protein content, total protein content, and SOD1 enzymatic activity in six areas of the CNS as well as in four peripheral tissues from sporadic and familial ALS patients and non-ALS controls. Our results show that SOD1 in the human CNS constitutes around 100 μg/g wet weight corresponding to about 0.16% of the total protein in the studied areas. Of the peripheral tissues analyzed, kidney and erythrocytes contain roughly equal amounts, liver higher, and skeletal muscle lower levels of SOD1 compared to the CNS. This data shows SOD1 protein levels around 10 times lower compared to previously published figures. However, SOD1 can still be considered an abundant protein considering that > 12 000 proteins are expressed in human cells. There was no difference in SOD1 protein content between sporadic or familial ALS patients and control individuals. The level and activity of SOD1 are not deviating in the areas of the CNS that are most vulnerable to ALS. Instead, insufficient control of SOD1 structure and aggregation could be important factors behind the vulnerability of motor areas to SOD1 proteotoxicity.}, } @article {pmid40550228, year = {2025}, author = {Tiwari, A and Singh, B and Singh, GK and Meena, J and Agrawal, AK and Kumar, S and Modi, G}, title = {Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.}, journal = {ACS applied bio materials}, volume = {8}, number = {7}, pages = {5406-5423}, doi = {10.1021/acsabm.5c00096}, pmid = {40550228}, issn = {2576-6422}, mesh = {*Exosomes/chemistry/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Biocompatible Materials/chemistry ; Drug Delivery Systems ; }, abstract = {Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.}, } @article {pmid40555967, year = {2025}, author = {Ahmed, AB and Draz, ME and Asad, H and Naguib, IA and Edrees, FH}, title = {Innovative Synchronous Spectrofluorometric Method for Assessing a Novel Drug Combination in Amyotrophic Lateral Sclerosis: In Vivo Human Application With Greenness and Sustainability Evaluation.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {40}, number = {6}, pages = {e70222}, doi = {10.1002/bio.70222}, pmid = {40555967}, issn = {1522-7243}, support = {TU-DSPP-2024-49//Taif University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Spectrometry, Fluorescence/methods ; *Celecoxib/analysis/therapeutic use/administration & dosage/blood ; *Ciprofloxacin/analysis/therapeutic use/blood/administration & dosage ; Drug Combinations ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder that causes damage to sensory neurons, then paralysis and death. A novel combination of celecoxib (CXP) and ciprofloxacin (CIP) has recently been used to enhance both motor performance and CNS cell morphology, alterations in the rate of disease progression, quality of life, and survival, which passed phase IIb RCT study. Celecoxib is classified as a non-steroidal anti-inflammatory drug; ciprofloxacin is a fluoroquinolone antibiotic that has a synergistic effect for the treatment of ALS, which is a severe neurological disorder. A new sustainable, simple, sensitive, and environmentally friendly synchronous spectrofluorimetric approach (SSF) was established to simultaneously estimate celecoxib and ciprofloxacin in pure form and biological fluids. The approach depends on synchronous fluorescence spectroscopy, where CXP and CIP were detected at 364 and 438 nm, correspondingly, using Δλ of 80-nm utilizing sodium dodecyl sulphate (SDS) micellar system, which considerably improved synchronous fluorescence intensity. The approach was validated and revealed excellent linearity with concentrations varying from 10 to 10,000 and 5 to 20,000 ng/mL for CXP and CIP; correspondingly, CXP and CIP showed extremely low limits of detection (LODs) 0.58-0.24 ng/mL, which guarantee the sensitivity of the proposed approach. The suggested approach was successfully implemented to analyze the co-administered pharmaceuticals in their pure form and actual human plasma after concurrent oral administration of both drugs, which may be employed in an inquiry on the pharmacokinetics and bioavailability of human plasma to the new coming PrimeC pharmaceutical formulation. Ultimately, the method's remarkable greenness was proved by evaluating its greenness profile using various assessment strategies. The findings revealed that the SSF approach is a sustainable and environmentally friendly analytical approach.}, } @article {pmid40563328, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {40563328}, issn = {2076-3921}, abstract = {Oxidative stress has become a common impetus of various diseases, including neurodegenerative diseases. This review introduces the generation of reactive oxygen species (ROSs) in the nervous system, the cellular oxidative damage, and the high sensitivity of the brain to ROSs. The literature review focuses on the roles of oxidative stress in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Oxidative stress occurs when excessively produced free radicals are beyond the capability of endogenous antioxidants to scavenge, leading to the oxidation of proteins, lipids, and nucleic acids, stimulating neuroinflammatory responses, causing neuronal dysfunction, senescence, and death. The dysfunctional mitochondria and aberrant activities of metabolic enzymes are the major source of ROSs. The high vulnerability of the nervous system to ROSs underlies the critical roles of oxidative stress in neurodegenerative diseases. Gene mutations and other risk factors promote the generation of ROSs, which have been considered a crucial force causing the main pathological features of AD, PD, HD, and ALS. As a result, antioxidants hold therapeutic potential in these neurodegenerative diseases. The elucidation of the pathogenic mechanisms of oxidative stress will facilitate the development of antioxidants for the treatment of these diseases.}, } @article {pmid40563772, year = {2025}, author = {Artioli, G and Guardamagna, L and Succi, N and Guasconi, M and Diamanti, O and Dellafiore, F}, title = {Relational, Ethical, and Care Challenges in ALS: A Systematic Review and Qualitative Metasynthesis of Nurses' Perspectives.}, journal = {Brain sciences}, volume = {15}, number = {6}, pages = {}, pmid = {40563772}, issn = {2076-3425}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to severe functional decline and death, imposing significant physical, emotional, and ethical burdens on patients and healthcare providers. With no curative treatment, ALS care depends on the early and sustained integration of palliative care to address complex and evolving needs. Nurses play a pivotal role in this process, yet their lived experiences remain underexplored. This study aimed to synthesize qualitative evidence on nurses' experiences in ALS care, with a focus on emotional, ethical, and palliative dimensions.

METHODS: A meta-synthesis of qualitative studies was conducted using Sandelowski and Barroso's four-step method. A systematic search across five databases identified eight studies exploring nurses' experiences with ALS care. Thematic synthesis was applied to extract overarching patterns.

RESULTS: Three core themes emerged: (1) Relational Dimension: From challenges to empathy and Trust and mistrust-emphasizing communication barriers and the value of relational trust; (2) Care Dimension: Competence, Palliative care needs, and Rewarding complexity-highlighting the emotional demands of care, the need for timely palliative integration, and the professional meaning derived from ALS care; (3) Ethical Dimension: Medical interventionism and Patient-centered values-exploring dilemmas around life-sustaining treatments, patient autonomy, and end-of-life decisions.

CONCLUSION: Nurses in ALS care face complex emotional and ethical challenges that call for strong institutional support and palliative training. Enhancing palliative care integration from diagnosis, alongside targeted education and psychological support, is crucial to improving care quality and sustaining the well-being of both patients and nurses.}, } @article {pmid40563773, year = {2025}, author = {Swash, M and de Carvalho, M}, title = {Dynamics of Onset and Progression in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {15}, number = {6}, pages = {}, pmid = {40563773}, issn = {2076-3425}, abstract = {This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease's pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised.}, } @article {pmid40565135, year = {2025}, author = {Bono, N and Fruzzetti, F and Farinazzo, G and Candiani, G and Marcuzzo, S}, title = {Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment.}, journal = {International journal of molecular sciences}, volume = {26}, number = {12}, pages = {}, pmid = {40565135}, issn = {1422-0067}, support = {//Italian Ministry of Health (RRC)/ ; T4-AN-09 prog. ZRPOS2//CALabria HUB per Ricerca Innovativa ed Avanzata- CALHUB.RIA "Creazione di Hub delle Sci-enze della Vita"/ ; ZRA124//AriSLA foundation, "Bulb-Omics"/ ; PNRR-MCNT2-2023-12377336//the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics/diagnosis/metabolism ; Humans ; *Genetic Therapy/methods ; *Biomarkers/metabolism ; C9orf72 Protein/genetics ; Animals ; Gene Editing ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches transforming ALS research and clinical management. We explore emerging biomarkers, including the fluid-based markers such as neurofilament light chain, exosomes, and microRNAs in biological fluids, alongside the non-fluid-based biomarkers, including neuroimaging and electrophysiological markers, for early diagnosis and patient stratification. The integration of multi-omics data reveals complex molecular mechanisms underlying ALS heterogeneity, potentially identifying novel therapeutic targets. We highlight current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood-brain barrier. By bridging molecular neuroscience with bioengineering, these technologies promise to revolutionize ALS diagnosis and treatment, advancing toward truly disease-modifying interventions for this previously intractable condition.}, } @article {pmid40566744, year = {2025}, author = {Bai, J and Cheng, K and Zhang, N and Chen, Y and Ni, J and Wang, Z}, title = {Research advances in dysphagia animal models.}, journal = {Animal models and experimental medicine}, volume = {8}, number = {9}, pages = {1579-1589}, pmid = {40566744}, issn = {2576-2095}, support = {82172531//National Natural Science Foundation of China/ ; 2021Y9105//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; }, mesh = {Animals ; *Deglutition Disorders/etiology/physiopathology ; *Disease Models, Animal ; Dogs ; Amyotrophic Lateral Sclerosis/complications ; Parkinson Disease/complications ; Swine ; Stroke/complications ; Humans ; }, abstract = {Dysphagia is a common complication of stroke, Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The construction of animal models of dysphagia is an important way to explore its pathogenesis and treatment. At present, the animal models of dysphagia mainly include rodents, nonhuman primates, and other mammals, such as pigs and dogs. This review systematically summarizes the establishment and evaluation of dysphagia animal models in stroke, PD, and ALS in three kinds of experimental animals, providing a basis for the selection of appropriate animal models of dysphagia.}, } @article {pmid40566837, year = {2025}, author = {Massey, C and Griffiths, AW and McDermott, C and Hobson, E}, title = {How healthcare professionals support cough and secretion management in amyotrophic lateral sclerosis (ALS): a UK national survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {7-8}, pages = {637-648}, doi = {10.1080/21678421.2025.2522401}, pmid = {40566837}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/epidemiology ; *Cough/etiology/therapy ; United Kingdom/epidemiology ; Cross-Sectional Studies ; Male ; Female ; *Health Personnel ; Surveys and Questionnaires ; Middle Aged ; Adult ; }, abstract = {OBJECTIVE: To understand the practices of healthcare professionals supporting people with Amyotrophic Lateral Sclerosis (ALS) to manage cough and secretion issues. This includes utilization of and confidence in assessment and treatment techniques and barriers and enablers of care.

METHODS: An online cross-sectional survey was distributed to UK healthcare professionals involved in cough and/or secretion management care in people with ALS.

RESULTS: A total of 113 responses were analyzed, over half were from physiotherapists (52%). The majority (71%) of respondents reported a role managing saliva and secretions. Just under two thirds (60%) routinely assessed cough and almost all (89%) routinely assessed secretions. Healthcare professionals reported reduced confidence assessing secretions compared with cough and very few (5%) used validated secretion outcome measures. Participants reported lower confidence implementing all treatment strategies than recommending them. Multiple barriers to care were identified, including access to specialist care and equipment, education and skills training and a lack of evidence-based care guidelines.

CONCLUSION: Cough and secretion management is complex and involves numerous professional groups. There is a need for clinical and educational interventions that address knowledge and skill gaps in managing cough and secretion issues, which will help increase healthcare professionals' confidence in assessing and treating these complex problems.}, } @article {pmid40569529, year = {2025}, author = {Shin, M and Ha, T and Lee, S and Li, C and Choi, JH and Choi, JW}, title = {Biohybrid motor neuron spheroid composed of graphene/HUVEC/neural cell for 3D biosensing system to evaluate drug of amyotrophic lateral sclerosis.}, journal = {Nano convergence}, volume = {12}, number = {1}, pages = {29}, pmid = {40569529}, issn = {2196-5404}, support = {RS-2023-00259341//the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT/ ; RS-2024-00344633//the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)/ ; NRF-2022M3H4A1A01005271//the National R&D Program through the NRF funded by the Ministry of Science and ICT/ ; }, abstract = {A 3D motor neuron (MN) spheroid has been developed to investigate neurodegenerative and neuromuscular junction (NMJ) disease. However, core necrosis and reduced neurogenesis, impairing neural network formation, were observed as the MN spheroid matured. In this study, to enhance neural network formation, a biohybrid MN spheroid composed of neural cells/reduced graphene oxide (rGO)/human umbilical vein endothelial cells (HUVECs) was generated for the first time and applied to 3D biosensing system for MNJ disease. By incorporating rGO and HUVECs at the onset of human neural stem cell (hNSC) culture, rGO and HUVECs were evenly distributed within MN spheroid generated by differentiation of hNSC, which improved oxygen- and nutrient- supply by reduction of core necrosis, and enhanced neurogenesis. The fabricated biohybrid MN spheroid improved neural network formation and electrophysiological signal. This method was also applied to generate biohybrid cerebral organoids from human induced pluripotent stem cells (hiPSCs), emphasizing its versatility for diverse 3D neural models. Then, a 3D NMJ biosensing system was fabricated by positioning the biohybrid MN spheroid with muscle bundles to evaluate its utility in neuromuscular disease modeling. Biohybrid MN spheroids generated from induced pluripotent stem cells of sporadic amyotrophic lateral sclerosis (ALS) patients were used to make NMJ. Reduced contraction of the connected muscle bundle due to ALS could be restored by upon treatment with the bosutinib, ALS drug, demonstrating the potential use for drug screening. The method to generate biohybrid spheroid can be applied to generation of various biohybrid brain organoids, and the proposed 3D NMJ biosensing system can be used to drug screening of diverse neuromuscular diseases.}, } @article {pmid40574761, year = {2025}, author = {Yıldız, GN and Çiftçi, B}, title = {Interplay between insomnia, anxiety, and depression.}, journal = {World journal of psychiatry}, volume = {15}, number = {6}, pages = {104796}, pmid = {40574761}, issn = {2220-3206}, abstract = {Insomnia, anxiety, and depression have become critical mental health issues exacerbated by the coronavirus disease 2019 pandemic, highlighting the importance of understanding their interrelationships. This article evaluates the study by Li et al, which investigates the links between insomnia, anxiety, and depression while examining the mediating role of cognitive failures and the moderating effect of neuroticism. The study employed a cross-sectional design with 1011 participants, using validated scales to measure insomnia severity, neuroticism, cognitive failures, and mental health indicators. Li et al found that approximately 40% of participants exhibited symptoms of anxiety, depression, and insomnia, with most cases being mild. The results demonstrated that cognitive failures play a mediating role in the relationship between insomnia and both anxiety and depression. Furthermore, neuroticism moderated the relationship between insomnia and cognitive failures, with a stronger effect observed in individuals with lower levels of neuroticism. These findings underscore the importance of considering personality traits and cognitive processes in understanding mental health outcomes. This study emphasizes the critical need for interventions aimed at reducing cognitive failures and enhancing emotional stability to mitigate the impact of insomnia on mental health. Strategies to improve sleep quality, boost cognitive resilience, and regulate emotional responses could significantly enhance individuals' mental well-being. Moreover, integrating personality assessments into mental health services could facilitate more effective and personalized interventions. This article provides an original perspective on the effects of the coronavirus disease 2019 pandemic on global mental health. The content of the article addresses the complex relationships between sleep disorders, cognitive function losses, and neuroticism in light of data compiled from existing literature and current research. In addition, how these relationships have deepened during the pandemic and the effectiveness of proposed treatment methods for these phenomena are discussed in comparison with previous studies. The arguments in the article offer new perspectives and suggestions aimed at filling gaps in the literature, and make an important contribution to both clinical practice and public health policies. Li et al's study provides a comprehensive framework for understanding the connections between insomnia, cognitive failures, and neuroticism, as well as their influence on anxiety and depression. The findings offer valuable implications for public health strategies, emphasizing the necessity of holistic approaches to address post-pandemic mental health challenges.}, } @article {pmid40575894, year = {2025}, author = {Eliasdottir, OJ}, title = {[Antisense oliconucleotides-potential treatment for familial Amyotrophic lateral sclerosis (ALS).].}, journal = {Laeknabladid}, volume = {111}, number = {7-08}, pages = {311}, doi = {10.17992/lbl.2025.0708.846}, pmid = {40575894}, issn = {1670-4959}, } @article {pmid40575896, year = {2025}, author = {Thorarinsson, BL and Halldorsdottir, KE and Hilmarsson, A and Sveinsson, OA}, title = {[Treatment of familial ALS with the drug tofersen].}, journal = {Laeknabladid}, volume = {111}, number = {7-08}, pages = {314-317}, doi = {10.17992/lbl.2025.0708.848}, pmid = {40575896}, issn = {1670-4959}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis/cerebrospinal fluid ; Treatment Outcome ; Mutation ; Male ; Middle Aged ; Female ; Superoxide Dismutase-1/genetics ; Neurofilament Proteins/cerebrospinal fluid ; Injections, Spinal ; Iceland ; Genetic Predisposition to Disease ; *Oligonucleotides/administration & dosage/therapeutic use ; Adult ; Biomarkers/cerebrospinal fluid ; *Oligonucleotides, Antisense/administration & dosage ; Phenotype ; Hospitals, University ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe and progressive neurodegenerative disorder. We describe four cases of familial ALS based on SOD1 mutations who received intrathecal treatment with the antisense oligonucleotide tofersen at Landspítali University Hospital Iceland. Since initiation of treatment, there has not been any significant deterioration, and three patients have shown signs of cinical improvement. The cerebrospinal fluid concentration of neurofilament light chain (Nf-L), a biomarker of neuronal axonal damage, has decreased to the reference range of healthy individuals. No serious side effects have been observed.}, } @article {pmid40576748, year = {2026}, author = {Gupta, MK and Chauhan, K and Bhardwaj, S and Srivastava, R}, title = {Innovative Interventions: Postbiotics and Psychobiotics in Neurodegenerative Disease Treatment.}, journal = {Probiotics and antimicrobial proteins}, volume = {18}, number = {2}, pages = {2818-2837}, pmid = {40576748}, issn = {1867-1314}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/drug therapy ; *Probiotics/administration & dosage/therapeutic use ; Gastrointestinal Microbiome/drug effects ; Animals ; }, abstract = {Neurodegenerative disorders, including Huntington's disease, Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, create more challenges as the population gets older and there are no curative therapies available. Recent advances in gut microbiome research have spotlighted postbiotics and psychobiotics as innovative therapeutic strategies targeting the gut-brain axis to alleviate neurodegenerative symptoms and slow disease progression. Postbiotics, which are metabolites and cellular components released by probiotic bacteria, and psychobiotics, a class of probiotics with potential mental health benefits, offer novel approaches to neuroprotection. This chapter examines the ways in which postbiotics and psychobiotics modulate inflammation, oxidative stress, neurotrophic factors, and gut barrier integrity to provide neuroprotective effects. We review scientific research that highlights the efficacy of specific microbial strains and their metabolites in enhancing cognitive function and reducing neurodegeneration. In addition, we explore the consequences of diet and specific nutrition on strengthening the therapeutic results of these medications. The purpose of this chapter is to provide a detailed analysis of the existing data supporting the use of postbiotics and psychobiotics in both the prevention and management of neurological diseases. By integrating perspectives from microbiology, neurology, and clinical nutrition, we highlight the potential of these interventions to enhance patient outcomes and quality of life. In addition, we discuss the translational limitations and future research approaches required to successfully transition these microbiome-based treatments from the laboratory to clinical practice, emphasizing the importance of a holistic and personalized approach in combating neurodegenerative diseases.}, } @article {pmid40580336, year = {2025}, author = {Wang, T and Wang, Y and Yang, Y and Wang, S and Wang, X and Feng, H}, title = {Fisetin Attenuates Mutant SOD1 Aggregation in Amyotrophic Lateral Sclerosis via Nrf2-Mediated Autophagy Activation.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {3}, pages = {84}, pmid = {40580336}, issn = {1559-1166}, support = {2020B11//the First Affiliated Hospital of Harbin Medical University Research Innovation Fund/ ; 2020B11//the First Affiliated Hospital of Harbin Medical University Research Innovation Fund/ ; 2020-127//the Health Commission Scientific Research Foundation of Heilongjiang Province of China/ ; 21042240013//2024 Heilongjiang Province Postdoctoral Research Start-up Fund/ ; }, mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Autophagy ; Flavonols ; *Flavonoids/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Animals ; Motor Neurons/metabolism/drug effects ; Humans ; Cell Line ; Sequestosome-1 Protein/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Protein Aggregates ; Protein Aggregation, Pathological ; }, abstract = {Dysregulated autophagy and copper/zinc superoxide dismutase (SOD1) protein aggregation play a crucial role in amyotrophic lateral sclerosis (ALS). Here, we used stably transfected NSC34 motor neuron-like cells: (1) SOD1[G93A] mutants (G93A), (2) wild-type SOD1 (WT) controls, and (3) empty vector (EV) controls to observe the effects of fisetin. Pharmacological autophagy inhibition (Bafilomycin A1, 40 nM) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene silencing (siRNA transfection) were employed to dissect molecular pathways. Protein aggregation dynamics and autophagy markers (LC3, p62/SQSTM1) were quantified through immunofluorescence and immunoblotting. SOD1[G93A] models exhibited impaired autophagic flux evidenced by elevated LC3-II and p62 levels, correlating with increased detergent-insoluble SOD1 aggregates. Fisetin treatment (1-10 μ M) dose-dependently reduced both soluble and aggregated SOD1[G93A] protein, concomitantly with restored autophagic flux. Mechanistically, fisetin promoted nuclear translocation while decreasing cytoplasmic Nrf2. After administration of an autophagy inhibitor and interference with Nrf2, the regulation of fisetin on p62 and mutant hSOD1 protein was inhibited. Our findings demonstrate that fisetin ameliorates mutant SOD1 proteotoxicity through coordinated activation of Nrf2-mediated autophagy pathways, suggesting therapeutic potential for SOD1-associated ALS pathologies.}, } @article {pmid40580685, year = {2025}, author = {Deng, Z and Chen, H and Chen, J and Du, Z and Zhou, W and Yuan, Z}, title = {Multifaceted roles of extracellular vesicles in the interplay of neuroinflammation and neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {7}, pages = {167960}, doi = {10.1016/j.bbadis.2025.167960}, pmid = {40580685}, issn = {1879-260X}, mesh = {Humans ; *Extracellular Vesicles/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; *Neuroinflammatory Diseases/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology ; Biomarkers/metabolism ; Cell Communication ; }, abstract = {Despite advances in understanding neurodegenerative disease mechanisms, effective treatments remain elusive. Extracellular vesicles (EVs), key mediators of intercellular communication within the central nervous system (CNS), are increasingly recognized for their involvement in the pathogenesis of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). In vivo studies demonstrate EVs' crucial role in maintaining CNS homeostasis, modulating neuroinflammatory responses, and influencing tissue repair and regeneration following injury, thereby impacting disease progression and recovery. Their unique properties, including small size and ability to cross the blood-brain barrier (BBB), position them as promising candidates for both biomarkers and therapeutics in CNS diseases. This review delves into the significant impact of neuroinflammation on neurodegenerative conditions, specifically focusing on the multifaceted contributions of EVs and their intricate interplay with the inflammatory landscape. We explore EV biogenesis, cargo composition, diverse roles in neuroinflammation (including intercellular communication and neuroprotection), their potential as biomarkers and drug delivery vehicles across the BBB for diagnosis or treatment of neuroinflammation implemented neurodegenerative diseases.}, } @article {pmid40580876, year = {2025}, author = {García-Toscano, L and Rodríguez-Cueto, C and Furiano, A and Hind, W and de Lago, E and Fernández-Ruiz, J}, title = {Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {189}, number = {}, pages = {118288}, doi = {10.1016/j.biopha.2025.118288}, pmid = {40580876}, issn = {1950-6007}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics/physiopathology/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Male ; Mice, Transgenic ; Mice ; Motor Neurons/drug effects/pathology/metabolism ; Microglia/drug effects/metabolism/pathology ; Spinal Cord/drug effects/pathology/metabolism ; *Cannabinoids/pharmacology ; *DNA-Binding Proteins/genetics/metabolism ; Dose-Response Relationship, Drug ; Motor Activity/drug effects ; Riluzole/pharmacology ; }, abstract = {Plant-derived cannabinoids, including Δ[9]-THC, cannabinol, and Sativex-like combinations, have shown neuroprotection in preclinical ALS models. However, minor phytocannabinoids like cannabidiolic acid (CBDA) remain unexplored. This study evaluated the neuroprotective effects of CBDA, cannabidivarin, CBD, Δ[9]-THC, and Δ[9]-tetrahydrocannabidivarin in Prp-hTDP-43(A315T) transgenic male mice from early symptomatic (day 65) to advanced stages (day 90). CBDA proved the most effective, improving motor coordination (rotarod test) and reducing neuronal cell death, gliosis, microglial reactivity, and pro-inflammatory mediators in the spinal cord. A dose-response study confirmed that 10 mg/kg CBDA improved motor performance and preserved motor neurons, while lower doses were less effective and higher doses caused toxicity. Flow cytometry revealed a shift from an M1 proinflammatory to an M2 anti-inflammatory phenotype in microglial cells after CBDA treatment, mirroring effects in BV2 cells exposed to LPS. Comparing CBDA with riluzole (standard ALS therapy), CBDA showed superior neuroprotection, except for rotarod performance, where no improvement was observed. A combination of CBD and riluzole failed to enhance efficacy and even weakened microglial response benefits. In conclusion, CBDA was the most effective of the five phytocannabinoids studied and outperformed riluzole in ALS models. These findings support further clinical evaluation of CBDA for ALS treatment.}, } @article {pmid40584972, year = {2025}, author = {Khandelwal, N and Sanchirico, M and Ajibade, A and Munshi, K and Vu, M and Engel-Nitz, N and Steiger, C and Anderson, AJ and Karam, C}, title = {Characteristics, Treatment Patterns, Healthcare Resource Utilization, and Costs Among Patients with Multifocal Motor Neuropathy: A US Claims Database Cohort Study.}, journal = {Journal of health economics and outcomes research}, volume = {12}, number = {1}, pages = {261-268}, pmid = {40584972}, issn = {2327-2236}, abstract = {Background: Multifocal motor neuropathy (MMN) is a rare, slowly progressive nerve disorder characterized by asymmetric limb weakness without sensory abnormalities. MMN is often misdiagnosed due to similarities in clinical symptoms with conditions including amyotrophic lateral sclerosis (ALS), making diagnosis and treatment challenging. Objectives: This study assessed patient characteristics, treatment patterns, and the economic burden of MMN in the United States. Methods: Using the Optum Research Database, this retrospective analysis included patients with ≥1 diagnostic or nondiagnostic medical claim with an MMN diagnosis code between 2016 and 2020 (date of first diagnosis-related claim =index date), and continuous enrollment for 12 months preindex and postindex. Patients with MMN within this group were identified using more specific criteria; ≥2 MMN nondiagnostic claims separated by ≥30 days, with no subsequent ALS diagnosis during follow-up. All patients who did not meet these criteria were included in the MMN-mimic cohort. Outcomes included treatment patterns, differential diagnoses, healthcare utilization, and costs. Results: Of 904 patients identified, 37% had MMN and 63% had an MMN-mimic condition. Patients with MMN were significantly younger than patients in the MMN-mimic cohort (mean, 64.9 vs 66.8 years; P = .047). At preindex, significantly more patients with MMN received MMN-related medications than patients in the MMN-mimic cohort (20.5% vs 9.0%, respectively; P < .001). Intravenous immunoglobulin (IVIG) was the most common MMN-related medication. At postindex, more patients with MMN used IVIG (28.0%) compared with preindex (16.4%). In the 12 months preindex and postindex, >70% of patients had ≥1 differential diagnosis. The MMN cohort had higher all-cause total costs than the MMN-mimic cohort (mean preindex, 58 974 v s 48 132, respectively [P = .100]; mean postindex, 74 187 v s 50 652 [P = .002]); they also had significantly higher MMN-related healthcare costs (mean preindex, 23 625 v s 12 890 [P = .011]; mean postindex, 39 521 v s 11 938 [P < .001]). Discussion: This study showed that most patients with initial MMN diagnoses had an alternative disorder after subsequent evaluation/follow-up, and patients with MMN incurred higher costs. Many patients with MMN did not receive IVIG, suggesting that undertreatment or misattribution of diagnosis codes are common. Conclusions: Further education is needed regarding accurate diagnosis of MMN to ensure patient access to guideline-recommended treatment.}, } @article {pmid40585388, year = {2025}, author = {Wang, X and Sun, Y and Han, C and Meng, X and Wen, K and Wu, J and Min, P and Li, K and Zhang, Y}, title = {Research trends of piezoelectric materials in neurodegenerative disease applications.}, journal = {Bioactive materials}, volume = {52}, number = {}, pages = {366-392}, pmid = {40585388}, issn = {2452-199X}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and huntington's disease, pose significant threats to human health, with current treatment options remaining limited. Piezoelectric materials, known for their ability to convert mechanical energy into electrical signals at the nanoscale, hold great promise in the diagnosis and treatment of neurodegenerative diseases due to their excellent electromechanical properties, environmental stability, and sensitivity. This review systematically outlines the working principles and classifications of piezoelectric materials. Subsequently, the recent advances in piezoelectric materials and their applications in the diagnosis and treatment of neurodegenerative diseases are highlighted. Finally, the challenges and perspectives regarding the development of future piezoelectric materials are discussed. This review aims to provide a comprehensive reference for the further application of piezoelectric materials in neurodegenerative diseases.}, } @article {pmid40589142, year = {2025}, author = {Tiwari, R and Paswan, A and Tiwari, G and Reddy, VJS and Posa, MK}, title = {Perspectives on Fecal Microbiota Transplantation: Uses and Modes of Administration.}, journal = {Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology}, volume = {41}, number = {}, pages = {e20250014}, doi = {10.62958/j.cjap.2025.014}, pmid = {40589142}, issn = {1000-6834}, mesh = {*Fecal Microbiota Transplantation/methods ; Humans ; *Gastrointestinal Microbiome ; Feces/microbiology ; *Nervous System Diseases/therapy ; }, abstract = {Fecal microbiota Transplantation (FMT), often referred to as stool transplantation, fecal transfusion, and fecal bacteria therapy, is considered one of the most medical innovations of the 20th century. Fecal microbiota Transplantation entails filtering and dilution of a healthy donor's feces before injecting it into the recipient's digestive system. In China, it was first administered orally in the fourth century for diarrhea and food poisoning under the name "Yellow Soup." It has recently been widely employed in a variety of clinical settings, including cases of Clostridium difficile infection that are recurring and resistant. By replacing the unhealthy intestinal microbiota with a healthy bacterial community, the FMT treatment aims to enhance the intestinal flora. It also looks at neurological conditions where alterations in gut microbiota are prevalent. We have discussed FMT in the context of its use in conditions affecting the nerve system, such as neurological and other conditions (multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, epilepsy, Amyotrophic lateral sclerosis, Tourette syndrome, neuropathic pain, Huntington's diseases, etc.), as well as the role of gut microbiota in many neurological disorders.}, } @article {pmid40590340, year = {2025}, author = {Takahashi, F and Genge, A and Hirai, M and Selness, D and Todorovic, V and Wamil, A and Sasson, N and Apple, S and Ushirogawa, Y and , }, title = {Analysis of Long-Term Function and Survival of Edaravone Oral Suspension-Treated Patients With Amyotrophic Lateral Sclerosis Using PRO-ACT Data as Historical Placebo Controls.}, journal = {Muscle & nerve}, volume = {72}, number = {4}, pages = {586-596}, pmid = {40590340}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality/physiopathology ; *Edaravone/administration & dosage/therapeutic use ; Male ; Female ; Middle Aged ; Administration, Oral ; Aged ; *Free Radical Scavengers/administration & dosage/therapeutic use ; Treatment Outcome ; *Neuroprotective Agents/administration & dosage ; Suspensions ; Adult ; }, abstract = {INTRODUCTION/AIMS: On/Off dosing of intravenous (IV) edaravone and edaravone oral suspension was US Food and Drug Administration (FDA)-approved for Amyotrophic Lateral Sclerosis (ALS) treatment. Placebo-controlled trials showed that IV edaravone slows the rate of physical functional decline in patients with ALS. Here, the impact of edaravone oral suspension on function and survival was assessed.

METHODS: Edaravone oral suspension was investigated in clinical trials MT-1186-A01/A02/A03/A04. Patients from Studies MT-1186-A02/A04 (prespecified analysis) and Studies MT-1186-A01/A02/A03/A04 (post hoc analysis) were propensity score matched 1:1 on 10 baseline variables with historical Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) placebo patients (not receiving active investigational treatment in their trials) to assess the impact of edaravone oral suspension on function and survival.

RESULTS: In the prespecified analysis, 78 edaravone oral suspension-treated patients from Studies MT-1186-A02/A04 demonstrated a survival benefit versus 78 matched PRO-ACT placebo patients (p = 0.005). Baseline risk-adjusted hazard ratio showed an 84% decreased risk of death in edaravone oral suspension versus PRO-ACT placebo patients (p = 0.005). ALS Functional Rating Scale-Revised (ALSFRS-R) total score change from baseline at Week 48 was -8.4 points for edaravone oral suspension versus -14.1 points for PRO-ACT placebo patients (p < 0.001). In the post hoc analysis, patients from Studies MT-1186-A01/A02/A03/A04 (n = 210) propensity score matched to PRO-ACT placebo patients (n = 210) showed statistically significantly longer time to death and smaller ALSFRS-R change from baseline at Week 48; restricted mean survival time showed a 7.3-month improvement (p < 0.001).

DISCUSSION: This suggests edaravone oral suspension significantly increases survival time and decreases physical functional decline versus PRO-ACT placebo patients.}, } @article {pmid40594383, year = {2025}, author = {Bernardi, S and Vitolo, S and Gabellini, C and Marchese, M and Ferraro, E}, title = {Trimetazidine stimulates intracellular Ca[2+] transients and zebrafish locomotor activity in spinal neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {22854}, pmid = {40594383}, issn = {2045-2322}, support = {GSA23C003//Telethon Foundation/ ; AFM 23771//AFM-TELETHON/ ; P2022LSW98//PRIN 2022 PNRR/ ; }, mesh = {Animals ; Zebrafish/physiology ; *Calcium/metabolism ; Animals, Genetically Modified ; *Motor Neurons/drug effects/metabolism ; *Locomotion/drug effects ; *Trimetazidine/pharmacology ; *Spinal Cord/drug effects/cytology/metabolism ; *Calcium Signaling/drug effects ; }, abstract = {The metabolic modulator trimetazidine (TMZ) is an antianginal recently found to improve skeletal muscle performance in mice models of sarcopenia and of amyotrophic lateral sclerosis (ALS). The mechanism underlying the effect of TMZ on locomotor activity has been proposed to rely on its ability to enhance metabolic efficiency with a consequent improvement of myogenesis and of neuromuscular junction (NMJ) and muscle function. However, although promising and therefore under clinical trials, the mechanism of action of TMZ has not been clearly disclosed; here we hypothesized that it might involve the modulation of neuronal Ca[2+] flows. We studied the effect of TMZ on Ca[2+] dynamics in vivo, by using the transgenic zebrafish line Tg(neurod1:GCaMP6f) in which the neuronal expression of the Ca[2+] indicator GCaMP allows to visualize Ca[2+] dynamics in neurons of zebrafish larvae. By this elegant tool, we demonstrated, for the first time, that TMZ promotes an increase of intracellular Ca[2+] transients in zebrafish spinal neurons likely enhancing motor neuron firing, which correlates with enhanced motor performance induced by this drug. Even though elevated intracellular Ca[2+] levels have often been associated to neurotoxicity, it is unclear if the neuronal excitability features in some neuro-muscular disorders are compensatory or pathological. Therefore, this newly reported effect of TMZ which transiently and selectively enhances spinal neuron firing deserves to be further detailed and taken into account when the possible repurposing of this drug is proposed for the treatment of neuro-muscular disorders.}, } @article {pmid40597943, year = {2025}, author = {Duan, Q and Li, C and Wei, C and Wang, Q and Wang, B and Sun, L and He, Y and Qin, J and Huang, X}, title = {Botulinum toxin type A for amyotrophic lateral sclerosis lower limb spasm: two case reports.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {263}, pmid = {40597943}, issn = {1471-2377}, support = {No.2024AFD137//the Natural Science Foundation of Hubei Province (Joint Fund Program)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Male ; *Botulinum Toxins, Type A/therapeutic use/administration & dosage ; Middle Aged ; *Neuromuscular Agents/therapeutic use/administration & dosage ; *Lower Extremity/physiopathology ; *Muscle Spasticity/drug therapy/etiology ; *Spasm/drug therapy/etiology ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) often experience spasticity, which can severely affect their ability to perform basic activities like standing and walking, potentially diminishing their already compromised quality of life. Botulinum toxin type A (BTX-A) is a first-line drug for spastic management. However, there are limited reports on its effectiveness in reducing muscle tone among ALS patients, with scarcely any related research conducted in China. We conducted the clinical observation and follow-up study through the relevant ethical post (ChiCTR2200061794). Clinical registration was on July 2, 2022. All participants provided written informed consent.

CASE PRESENTATION: We report two cases of middle-aged male patients, both diagnosed with ALS, who presented with symptoms such as limb stiffness and walking limitation due to increased muscle tone in the lower limbs. Based on the spasticity of the patient's lower limbs, the corresponding target muscles were selected for BTX-A treatment under ultrasound guidance, and the patients were evaluated on relevant functional scales before injection (baseline, T0) and at three follow-up visits (T1: 2 weeks, T2: 4 weeks, T3: 8 weeks).

CONCLUSION: Appropriate BTX-A injected into the target muscles could effectively depress the spasticity of ALS patients without apparent side effects.}, } @article {pmid40602529, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Mendoza et al's "Association between use of antihypertensives and treatment of actinic keratoses: A TriNetX population-based study".}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {4}, pages = {e157-e158}, doi = {10.1016/j.jaad.2025.03.105}, pmid = {40602529}, issn = {1097-6787}, } @article {pmid40602557, year = {2025}, author = {Rodriguez-Romano, A and Gonzalez-Valdivieso, J and Moreno-Martinez, L and Vázquez Costa, JF and Osta, R and Rico, P}, title = {Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1[G93A] mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.}, journal = {International journal of biological macromolecules}, volume = {319}, number = {Pt 4}, pages = {145645}, doi = {10.1016/j.ijbiomac.2025.145645}, pmid = {40602557}, issn = {1879-0003}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Hydrogels/chemistry ; Mice ; *Muscular Atrophy/drug therapy/pathology/metabolism ; Disease Models, Animal ; *Alginates/chemistry ; Signal Transduction/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Superoxide Dismutase-1/genetics ; Inflammation/drug therapy/pathology ; Motor Neurons/drug effects/metabolism ; *Neuroprotection/drug effects ; Neuroprotective Agents/pharmacology ; Mice, Transgenic ; Muscle, Skeletal/drug effects/pathology/metabolism ; Borates ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.}, } @article {pmid40602832, year = {2025}, author = {Abgueguen, E and Tortarolo, M and Rouviere, L and Marcuzzo, S and Camporeale, L and Henriques, A and Pasetto, L and Culley, GR and Bonetto, V and Marian, A and Lejeune, BL and Visbecq, A and Lauria, G and Kabashi, E and Callizot, N and Bendotti, C and Miniou, PY}, title = {Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.}, journal = {Life science alliance}, volume = {8}, number = {9}, pages = {}, pmid = {40602832}, issn = {2575-1077}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Motor Neurons/drug effects/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; Zebrafish ; Humans ; Unfolded Protein Response/drug effects ; Mice, Transgenic ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Cytoplasm/metabolism ; Mitochondria/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; Spinal Cord/metabolism ; }, abstract = {A pathological hallmark of ALS is the abnormal accumulation of misfolded proteins (e.g., TDP-43) and enlarged endoplasmic reticulum (ER), indicating ER stress. To resolve this stress, cells initiate the Unfolded Protein Response (UPR). However, unresolved stress leads to apoptosis. In ALS, UPR activation fails to resolve proteostasis impairment. UPR activation modulators, among them Sephin1, reduce protein aggregates and improve motor neuron survival in ALS models. We demonstrate that following glutamate intoxication, Sephin1 increases motor neuron survival by reducing mitochondria ROS production and extranuclear TDP-43. Sephin1 reduces abnormal splicing because of TDP-43 nuclear loss of function following oxidative stress. In SOD1[G93A] mice, Sephin1 treatment decreases TDP-43 in triton-insoluble fraction, improving motor neuron survival in spinal cord. Sephin1 improves motor neurons survival, motor function and survival of mutated TDP-43 transgenic zebrafish. Sephin1 improves motor neuron survival in ALS models by reducing TDP-43 cytoplasmic mislocalization and its toxicity. These findings open new therapeutic opportunities for Sephin1 in neurodegenerative pathologies with TDP-43 proteinopathy, including ALS.}, } @article {pmid40605360, year = {2025}, author = {De Wel, B and Mobach, T and Pfeffer, G and Jewett, G}, title = {Tofersen Treatment Normalizes Neurofilament Levels in Autosomal Recessive SOD1 Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/cjn.2025.10350}, pmid = {40605360}, issn = {0317-1671}, } @article {pmid40605998, year = {2025}, author = {Qin, H and Hussain, L and Liu, Z and Yan, X and Awwad, FA and Butt, FM and Salaria, UA and Ismail, EAA}, title = {Optimizing deep learning models to combat amyotrophic lateral sclerosis (ALS) disease progression.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251349719}, pmid = {40605998}, issn = {2055-2076}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, poses a significant challenge for targeted treatment development. Accurate prediction of its progression is crucial for this endeavor.

METHODS: This study investigated deep learning methods for ALS progression prediction using the publicly available PRO-ACT dataset. Initially, machine learning models (XGBoost, LightGBM) and a deep learning sequential model were evaluated with default parameters, using R-squared (R2) and Root Mean Squared Error (RMSE) as performance metrics.

RESULTS: Notably, the deep learning model demonstrated superior predictive performance with default settings (RMSE: 4.565, R2: 0.716), followed by XGBoost (RMSE: 4.625, R2: 0.709) and LightGBM (RMSE: 4.596, R2: 0.716). Subsequently, hyperparameter optimization significantly enhanced the deep learning model's performance, achieving the highest prediction accuracy (RMSE: 4.511, R2: 0.718). Slight improvements were also observed for XGBoost (RMSE: 4.532, R2: 0.715) and LightGBM (RMSE: 4.551, R2: 0.716). Furthermore, the optimized XGBoost model demonstrated exceptional classification performance in distinguishing between bulbar and limb onset ALS, with a sensitivity of 100%, specificity of 97.44%, accuracy of 97.96%, F1-score of 95.96%, Matthews Correlation Coefficient (MCC) of 94.12%, and an Area Under the Curve (AUC) of 0.9550. Feature importance analysis with optimized XGBoost identified ZBTB2P1 as the most influential feature, followed by RNF181, with WASH9P being the least influential among the top eight.

CONCLUSIONS: These findings convincingly demonstrate the potential of optimized XGBoost and deep learning for ALS progression prediction and classification, particularly with optimized parameters. This approach offers significant potential for early risk stratification, personalized treatment planning, enhanced prognostic communication, diagnostic support, streamlined disease monitoring, and improved clinical decision-making, ultimately contributing to better patient outcomes and potentially reducing ALS-related mortality.}, } @article {pmid40606671, year = {2025}, author = {Zhan, X and Xuan, T and Chen, X and He, J and Ren, Y and Meng, Y and Chen, G and Li, H}, title = {Case Report: A case of ALS type 6 associated with a FUS gene variant and right limb muscle weakness and atrophy as the initial symptom.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1578249}, pmid = {40606671}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. This degeneration results in increasing muscle weakness, ultimately culminating in respiratory failure and death. Mutations in the fused in sarcoma (FUS) gene have been identified as a significant cause of ALS. Here, we present the case of a 40-year-old woman who exhibited right limb muscle weakness and atrophy as her initial symptom. Whole genome sequencing revealed a mutation in the FUS gene, specifically c.1450_1456delinsCCC (p.Tyr484Profs*44), leading to a diagnosis of ALS type 6 (ALS6). The c.1450_1456delinsCCC (p.Tyr484Profs*44) mutation is a frameshift mutation resulting from a non-triplet base deletion in the coding region of the FUS gene. This mutation is novel and has not been previously reported in China or internationally. Furthermore, the onset of muscle weakness and atrophy exclusively in the ipsilateral limb is very rare among ALS patients, and we have found no related reports. This case report aims to enhance medical professionals' understanding of the complexities associated with ALS caused by FUS gene mutations and the onset of ALS symptoms, thereby facilitating more accurate clinical diagnosis and treatment.}, } @article {pmid40610071, year = {2025}, author = {Selvaraj, C and Vijayalakshmi, P and Desai, D and Manoharan, J}, title = {Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.}, journal = {Advances in protein chemistry and structural biology}, volume = {146}, number = {}, pages = {1-34}, doi = {10.1016/bs.apcsb.2024.11.008}, pmid = {40610071}, issn = {1876-1631}, mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Autophagy ; *Protein Aggregation, Pathological/metabolism/therapy/pathology ; *Protein Aggregates ; }, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.}, } @article {pmid40612293, year = {2025}, author = {Bayleyegn Derso, T and Mengistu, BA and Demessie, Y and Fenta, MD and Getnet, K}, title = {Neural stem cells in adult neurogenesis and their therapeutic applications in neurodegenerative disorders: a concise review.}, journal = {Frontiers in molecular medicine}, volume = {5}, number = {}, pages = {1569717}, pmid = {40612293}, issn = {2674-0095}, abstract = {The idea of using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.}, } @article {pmid40614949, year = {2025}, author = {Sarkar, SK and Gubert, C and Hannan, AJ}, title = {The microbiota-inflammasome-brain axis as a pathogenic mediator of neurodegenerative disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {176}, number = {}, pages = {106276}, doi = {10.1016/j.neubiorev.2025.106276}, pmid = {40614949}, issn = {1873-7528}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/immunology/microbiology ; *Inflammasomes/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Brain/metabolism/immunology ; *Receptors, Purinergic P2X7/metabolism ; }, abstract = {In various neurodegenerative disorders, inflammation and associated inflammasome activation play an important role. The most prevalent and extensively researched inflammasomes are NLRP3 inflammasomes, which are triggered by pathogens or danger signals mediating inflammatory reaction. Extracellular ATP also activates NLRP3 by stimulating the purinergic receptor P2X7 (P2X7R). Central and peripheral cells, including those in the gut, have been shown to have activated inflammasomes during pathological changes co-occurring with inflammation in various neurodegenerative disorders. Gut injury or dysfunction is increasingly recognised as one of the peripheral pathogenic characteristics of many neurodegenerative disorders, and has been found to associate with changes in gut microbes. In this article, we review data from preclinical and clinical studies regarding the involvement of the NLRP3 inflammasome and the purinergic receptor P2X7R in the pathophysiology of major CNS disorders involving neurodegeneration, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and the most common form of motor neuron disease, amyotrophic lateral sclerosis (ALS). We also scrutinise the relationship of the NLRP3 inflammasome to intestinal microbiota alterations in these diseases. Both the NLRP3 inflammasome and P2X7R have been shown to play important roles in the pathogenesis and progression of these neurodegenerative diseases. However, most studies have focused on central nervous system (CNS) pathology, particularly within the brain, with comparatively less attention given to their contribution to gut pathology. Additionally, changes in the microbial ecosystems of the intestine have also been implicated in these disorders. However, the association between gut microbiota alterations and inflammasome activity in the pathology of these neurodegenerative disorders remains poorly understood. Therefore, further investigation is urgently needed to explore the microbiota-inflammasome-brain axis in these neurodegenerative conditions, in order to better understand their contribution to disease pathogenesis and progression, and identify novel therapeutic targets and new approaches to prevention and treatment.}, } @article {pmid40620684, year = {2025}, author = {Chen, P and Wang, F and Ling, B and Zhu, Y and Lin, H and Huang, J and Wang, X}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: Emerging Therapies for Neurodegenerative Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {8547-8565}, pmid = {40620684}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Mesenchymal Stem Cells/cytology ; *Extracellular Vesicles/metabolism/transplantation ; Biomarkers/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative diseases are a group of chronic diseases characterized by a gradual loss of neurons that worsens over time and dysfunction. These diseases are extremely harmful, not only affecting the physical health of the patients, but also having a serious impact on their quality of life. They mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), etc. Their pathogenesis is complex, and it is difficult for the existing treatments to effectively slow down the progression of the disease. In recent years, Mesenchymal Stem Cells (MSCs) have received widespread attention for their anti-inflammatory, immunomodulatory and neuroprotective properties. In this context, MSC-derived Extracellular Vesicles (MSC-EVs) have demonstrated unique therapeutic potential as a cell-free therapeutic strategy. MSC-EVs are rich in bioactive substances such as proteins, lipids, mRNAs and miRNAs, which can pass through the blood-brain barrier and be targeted to the diseased area to regulate neuronal survival, synaptic plasticity and neuroinflammatory responses. In addition, compared with stem cell therapy, MSC-EVs have the advantages of low immunogenicity, easy storage and transportation, and avoiding ethical controversies. However, their clinical application still faces challenges: standardized isolation and purification techniques have not been unified, vesicle loading efficiency and targeting need to be further optimized, and long-term safety needs to be systematically evaluated. This review focuses on the role of MSC-EVs in the development of neurological diseases and explores their possible dual roles, both favorable and unfavorable, in the context of neurological diseases. In addition, this review provides a review of current studies on EVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases and provides a comprehensive review of the prospects and challenges of MSC-EVs in clinical applications.}, } @article {pmid40621723, year = {2026}, author = {Anani, T and Pradat-Peyre, JF and Delbot, F and Desnuelle, C and Rolland, AS and Devos, D and , and Pradat, PF}, title = {Feature selection using metaheuristics to predict annual amyotrophic lateral sclerosis progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {62-77}, doi = {10.1080/21678421.2025.2522399}, pmid = {40621723}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Disease Progression ; Male ; Female ; Middle Aged ; *Machine Learning ; Aged ; Cohort Studies ; Predictive Value of Tests ; Prognosis ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease with no curative treatment and affecting motor neurons, leads to motor weakness, atrophy, spasticity and difficulties with speech, swallowing, and breathing. Accurately predicting disease progression and survival is crucial for optimizing patient care, intervention planning, and informed decision-making.

METHODS: Data were gathered from the PRO-ACT database (4659 patients), clinical trial data from ExonHit Therapeutics (384 patients) and the PULSE multicenter cohort aimed at identifying predictive factors of disease progression (198 patients). Machine learning (ML) techniques including logistic/linear regression (LR), K-nearest neighbors, decision tree, random forest, and light gradient boosting machine (LGBM) were applied to forecast ALS progression using ALS Functional Rating Scale (ALSFRS) scores and patient survival over one year. Models were validated using 10-fold cross-validation, while Kaplan-Meier estimates were employed to cluster patients according to their profiles. To enhance the predictive accuracy of our models, we performed feature selection using ANOVA and differential evolution (DE).

RESULTS: LR with DE achieved a balanced accuracy of 76.05% on validation (ranging from 68.6% to 79.8% per fold) and 76.33% on test data, with an AUC of 0.84. With Kaplan-Meier's estimates, we identified five distinct patient clusters (C-index = 0.8; log-rank test p value ≤0.0001). Additionally, LGBM predictions for ALSFRS progression at 3 months yielded an RMSE of 3.14 and an adjusted R[2] of 0.764.

CONCLUSION: This study showcases the potential of ML models to provide significant predictive insights in ALS, enhancing the understanding of disease dynamics and supporting patient care.}, } @article {pmid40622676, year = {2025}, author = {Wei, Y and Li, D and Yang, R and Liu, Y and Luo, X and Zhao, W and Yang, H and Chen, Z and Shen, C and Wang, Y and Huang, Z}, title = {TIA1-mediated stress granules promote neurodegeneration by sequestering HSP70 mRNA in C9orf72 mice.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {12}, pages = {4482-4494}, doi = {10.1093/brain/awaf248}, pmid = {40622676}, issn = {1460-2156}, mesh = {Animals ; *T-Cell Intracellular Antigen-1/metabolism/genetics ; *HSP70 Heat-Shock Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mice ; *Stress Granules/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Humans ; Mice, Knockout ; RNA, Messenger/metabolism ; Male ; Motor Neurons/metabolism/pathology ; Motor Cortex/metabolism/pathology ; Disease Models, Animal ; Female ; Nerve Degeneration/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with progressive loss of motor neurons in the central nervous system. Recent studies have reported that there are mutations at the T-cell antigen-1 (TIA1) domain site in some ALS patients. TIA1 is a key component of stress granules (SGs), but its role and mechanism in ALS pathogenesis remain unclear. In this study, we found that TIA1 was upregulated in the motor cortex of post-mortem ALS patients as well as in the motor cortex neurons of C9orf72-poly-Gly-Ala (GA) mice (ALS mice). TIA1 knockout in the CNS [TIA1Nestin-conditional knockout (CKO) mice] alleviated motor neuron loss, neuroinflammation and motor dysfunction in C9orf72-poly-GA mice. Mechanistically, RNA sequencing combined with the C9orf72-ALS/frontotemporal dementia patient single nucleus RNA-sequencing database revealed that mRNA of heat shock protein 70 (HSP70) family member genes such as HSPa1b were upregulated in the motor cortex of TIA1Nestin-CKO ALS mice. We further found that TIA1-mediated SG formation was increased during ALS pathogenesis, leading to HSP70 mRNA being sequestered into SGs. This reduced HSP70 expression, impairing the degradation of poly-GA aggregates by the UBQLN2-HSP70 pathway and exacerbating C9orf72-ALS progression. Taken together, these findings highlight a previously unrecognized role of TIA1-mediated SGs in promoting ALS pathogenesis by sequestering HSP70 mRNA, suggesting potential therapeutic targets for ALS treatment.}, } @article {pmid40624208, year = {2025}, author = {Tavares, M and Lúcio, MJ and Borges, J and Carriço, F and Guimarães, MJ and Drummond, M}, title = {The impact of obstructive sleep apnea and the prognostic role of level III polysomnography at the onset of amyotrophic lateral sclerosis.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {29}, number = {4}, pages = {235}, pmid = {40624208}, issn = {1522-1709}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/physiopathology/mortality ; *Polysomnography ; *Sleep Apnea, Obstructive/diagnosis/physiopathology/therapy ; Male ; Female ; Middle Aged ; Prognosis ; Cross-Sectional Studies ; Aged ; Noninvasive Ventilation ; Adult ; }, abstract = {PURPOSE: Sleep disturbances are considered an early manifestation of Amyotrophic lateral sclerosis (ALS). However, sleep-disordered breathing (SDB) in ALS remains underexplored. The primary outcome of this study is to describe the clinical, functional and polygraphic characteristics of ALS patients with baseline SDB and to compare those with and without obstructive sleep apnea (OSA) in level III polysomnography (PSG) at diagnosis. Secondary outcomes included identification of baseline factors predictive of non-invasive ventilation (NIV) initiation/death during follow-up and assessing the role of level III PSG performed at the initial clinical evaluation in ALS prognosis regarding timing to NIV initiation and death.

METHODS: A cross-sectional study was conducted on 74 patients between September 2023 and September 2024. For the primary outcome, only patients that exhibited baseline SDB were included (45 patients). The population (45) was divided into 2 groups: Group 1 (n = 26; obstructive apnea/hypopnea index ≥ 5) and Group 2 (n = 19; obstructive apnea/hypopnea index < 5). For the secondary outcomes, all 74 patients were included regardless of sleep events.

RESULTS: Patients with OSA had a higher baseline body mass index (p = 0.03) and lower nocturnal average oxygen saturation (p = 0.03). A lower forced vital capacity (p < 0.001) and higher transcutaneous carbon dioxide (p = 0.005) at baseline were predictive of timing to NIV initiation.

CONCLUSIONS: Our study highlights the importance of performing respiratory functional testing and transcutaneous carbon dioxide assessment in ALS prognosis, regarding timing to NIV initiation. Although level III PSG is vital in the diagnosis and treatment of SDB, further studies are needed to clarify its role at disease onset and identify additional potentially predictors of timing to NIV initiation/death in ALS patients.}, } @article {pmid40625110, year = {2025}, author = {Luo, Y and Xiong, S and Ehdaie, A and Sun, H and Yang, G and Luo, D and Li, J and Wang, X and Zhang, Z and Cai, L and Liu, H and Shehata, M}, title = {Predictive Parameters for Impending Steam Pops During High-Power Short-Duration Ablation for Atrial Fibrillation.}, journal = {Pacing and clinical electrophysiology : PACE}, volume = {48}, number = {8}, pages = {836-842}, doi = {10.1111/pace.70003}, pmid = {40625110}, issn = {1540-8159}, support = {20240216//Liu Hanxiong Famous Doctor Studio of Chengdu/ ; 2024NSFSC1709//the Natural Science Foundation of Sichuan Province/ ; CSY-YN-01-2023-041//Scientific Research Project of The Third People's Hospital of Chengdu/ ; }, mesh = {Humans ; *Atrial Fibrillation/surgery ; Male ; Female ; Retrospective Studies ; *Catheter Ablation/adverse effects/methods ; Middle Aged ; *Steam ; Aged ; }, abstract = {BACKGROUND: High-power short-duration (HPSD) radiofrequency ablation (RFA) for atrial fibrillation (AF) treatment carries the risk of steam pops (SPs) due to rapid tissue heating. However, methods to predict impending SP during HPSD-RFA remain undefined.

OBJECTIVE: This study aims to establish a quantitative criterion for predicting SPs during HPSD-RFA.

METHODS: Retrospective analysis was performed on 489 patients undergoing HPSD-RFA for AF, focusing on corresponding RFA parameters in those who experienced SPs.

RESULTS: Among 1943 ablation lesions (ALs) delivered in 18 patients with SPs, 24 ALs had SP occurrence. Tip temperature, RFA duration, and ablation index were not significantly different between SP ALs and non-SP ALs. The mean contact force was significantly higher in SP ALs (12 g vs. 9, p < 0.001). All SPs adhered to the following criteria: impedance drop ≥8Ω during the first 4 s of RFA, impedance variability <5Ω within the first 4 s of RFA (24/24 vs. 79/247, p < 0.001), no events in the posterior wall of the left atrium, impedance drop ≥12Ω within 4-12 s. By halting delivery of RFA early with this finding in approximately five ALs per patient, the risk of SP complications could be significantly mitigated.

CONCLUSION: Monitoring impedance trends in the initial 4 s of HPSD-RFA can effectively predict impending SP occurrences. Automated algorithms should be developed to halt RFA delivery in this setting.}, } @article {pmid40629698, year = {2025}, author = {Murdock, BJ and Park, J and Jang, DG and Zhao, B and Teener, SJ and Webber-Davis, IF and Zhao, L and Feldman, EL and Goutman, SA}, title = {In Vitro Modeling of Natural Killer Cell Cytotoxicity to Inform Personalized ALS Therapeutics.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {10}, pages = {2036-2044}, pmid = {40629698}, issn = {2328-9503}, support = {R01NS127188/NH/NIH HHS/United States ; //Peter R. Clark Fund for ALS Research/ ; R01NS120926/NH/NIH HHS/United States ; //Coleman Discovery Fund/ ; 20-IIA-431//ALS Association/ ; //Scott L. Pranger/ ; R01TS000339/ACL/ACL HHS/United States ; R01 TS000339/TS/ATSDR CDC HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //Sinai Medical Staff Foundation/ ; AL200064//U.S. Department of Defense/ ; //Hiller and Novak Families/ ; //NeuroNetwork for Emerging Therapies at the University of Michigan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy ; *Killer Cells, Natural/drug effects/immunology ; Female ; Male ; *Piperidines/pharmacology ; Middle Aged ; Aged ; *Pyrimidines/pharmacology ; Precision Medicine/methods ; Adult ; *Cytotoxicity, Immunologic/drug effects ; *Protein Kinase Inhibitors/pharmacology ; }, abstract = {OBJECTIVE: Natural killer (NK) cells might contribute to motor neuron death in amyotrophic lateral sclerosis (ALS) through direct cytotoxicity, a process that could be inhibited with the FDA-approved JAK/STAT pathway inhibitor, tofacitinib. This study aimed to verify that tofacitinib can suppress NK cell cytotoxicity, investigate if immune cell profiles can predict responsiveness to tofacitinib, and assess the role of NK cell cytotoxicity in ALS progression.

METHODS: Primary NK cells were isolated from peripheral blood samples of ALS participants and healthy controls. NK cells were then co-cultured with target cancer cells, with or without tofacitinib, to assess their cytotoxic activity. Flow cytometry was used to generate immune profiles for each participant, based on 154 immune markers, to explore correlations with NK cell cytotoxicity and response to tofacitinib. The potential association between NK cell cytotoxicity and disease severity, as measured by the revised ALS Functional Rating Scale, was also assessed. All analyses were stratified by age and sex.

RESULTS: Tofacitinib effectively reduced the cytotoxicity of primary NK cells isolated from the blood of ALS participants (n = 80) and healthy controls (n = 71), with immune cell profiles correlating with the response to tofacitinib. However, NK cell cytotoxicity was lower in ALS participants compared to healthy controls and showed no association with ALS progression.

INTERPRETATION: These findings confirm that tofacitinib suppresses NK cell cytotoxicity, and that immune profiling may help identify treatment responder groups. However, further research is needed to fully understand the role and timing of NK cell activity in ALS pathogenesis.}, } @article {pmid40640025, year = {2026}, author = {Kim, S and Yang, M and Ku, B and Cha, E and Seo, W and Son, I and Kang, H and Kim, D and Song, B and Yang, CS and Kim, S}, title = {Corrigendum to "Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial" [J. Ethnopharmacol. 320 (2023) 116670].}, journal = {Journal of ethnopharmacology}, volume = {356}, number = {}, pages = {120239}, doi = {10.1016/j.jep.2025.120239}, pmid = {40640025}, issn = {1872-7573}, } @article {pmid40640528, year = {2025}, author = {McGuigan, A and Blair, HA}, title = {Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.}, journal = {CNS drugs}, volume = {39}, number = {9}, pages = {903-912}, pmid = {40640528}, issn = {1179-1934}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; Mutation ; *Oligonucleotides/therapeutic use/adverse effects/pharmacology ; *Oligonucleotides, Antisense/therapeutic use/adverse effects ; }, abstract = {Tofersen (QALSODY[®]) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.}, } @article {pmid40640892, year = {2025}, author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH}, title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {82}, pmid = {40640892}, issn = {1750-1326}, support = {RS-2024-00348451//Korea Dementia Research Center/ ; }, mesh = {Humans ; *Microglia/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Biomarkers/metabolism ; Animals ; }, abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.}, } @article {pmid40640965, year = {2025}, author = {Wright, K and Warren, F and Bucci, S and Dunn, BD and Jones, S and O'Mahen, H and Taylor, RS and Medina-Lara, A}, title = {A study protocol for a randomized controlled feasibility trial of behavioural therapy for interepisode bipolar symptoms (STABILISE).}, journal = {Pilot and feasibility studies}, volume = {11}, number = {1}, pages = {97}, pmid = {40640965}, issn = {2055-5784}, support = {NIHR302220//National Institute for Health and Care Research/ ; }, abstract = {BACKGROUND: In between episodes of (hypo) mania and major depression, people with bipolar disorder can experience ongoing low mood or mood instability, and these may also be present as part of cyclothymic disorder. This is a phase II evaluation of an adapted form of behavioural therapy (STABILISE) for inter-episode bipolar symptoms. The study aims to establish the feasibility and acceptability of the therapy and research procedures, including an economic component, to inform a future definitive trial.

METHODS: Patients will be randomised 1:1 to either Treatment as Usual (control arm) or Treatment as Usual plus STABILISE intervention (intervention arm). Follow up points will be at 14, 30 and 52 weeks post eligibility confirmation, with 30 weeks as the primary end point. We aim to recruit 60 individuals meeting diagnostic criteria for a Bipolar Spectrum Disorder, and reporting ongoing bipolar symptoms (low mood or mood instability) outside of a manic or severe depressive episode. Feasibility and acceptability will be examined through recruitment and retention rates, completion rates for the candidate primary outcome measures (PHQ9, ALS-SF, QoL.BD and BRQ) and feedback from participants on their experience of study participation and therapy. Proceeding to a definitive trial will be indicated if the following criteria are met: (i) trial participation is deemed, or can be made, sufficiently safe; (ii) recruitment rate indicates that larger-scale recruitment would be feasible (recruitment rate of at least two participants per month within at least one site, with mitigation plan if overall target sample size not met); (iii) for candidate primary outcome measure follow up data is available at 30 weeks from at least 75% of participants, or from between 55 and 74% with clear plan for improvement.

DISCUSSION: This study is a randomised, controlled feasibility trial that builds on an initial case series of the STABILISE approach. The findings will be used to establish whether a future, definitive trial is feasible and to refine the research procedures and therapy protocol.

TRIAL REGISTRATION: ISRCTN18207465. Registered 13th March 2024, https://www.isrctn.com/ISRCTN18207465 .}, } @article {pmid40642215, year = {2025}, author = {Ahmed, Z and Samaddar, S and Hassieb, M and Sadek, R and Morozova, V and Begum, S}, title = {Multi-path direct current spinal stimulation extended survival in the SOD1-G93A model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1594169}, pmid = {40642215}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the spinal cord and brain. We have developed a novel non-invasive approach, MultiPath-DCS, which utilizes direct current stimulation at multiple sites along the neural axis to provide simultaneous spinal and peripheral stimulation targeted at the affected limbs. MultiPath-DCS modulates the excitability of spinal cord neurons. This effect is significant for ALS, as motor neuron hyperexcitability is a fundamental characteristic of the disease.

METHODS: This study used a transgenic mouse model of ALS (SOD1-G93A). Anodal-MultiPath-DCS was applied with six electrodes: three on the spine (centered on T13 and with an anodal polarity), two on the sciatic nerves (one on each nerve), and one on the abdomen. Mice were divided into two groups (stimulated vs. unstimulated or sham-stimulated). The stimulated animals received stimulation for one hour a day, three times a week, for three weeks. Survival was calculated from the onset of the disease and birth until the animal's endpoint. We also performed various electrophysiological and molecular experiments to uncover the mechanism of action.

RESULTS: We demonstrated molecular changes induced by anodal MultiPath-DCS, including (a) reduced expression of mutant SOD1 protein, (b) decreased expression of elevated NKCC1, (c) reduced phosphorylated tau, (d) increased expression of HSP70, and (e) increased expression of LC3B. Additionally, we found that treatment with Anodal-MultiPath-DCS (anode on the spinal column) reduces long-term neuronal spinal excitability, slows the progression of muscle weakness, and extends the lifespan of stimulated mice. The mean survival time in the control group was 12.4 days. In comparison, the mean survival time in the stimulated group was 21.6 days using a therapeutic stimulation paradigm, representing a 74% increase in survival from disease onset. Spinal motor neuron survival showed a 54% increase in stimulated compared to non-stimulated groups.

DISCUSSION: Combined, this data provides evidence that Anodal-MultiPath-DCS reduces hyperexcitability and enhances the clearance of misfolded proteins by modulating autophagy and proteolytic systems. By decreasing spinal excitability and clearing toxic proteins from motor neurons, Anodal-MultiPath-DCS promotes survival and could serve as a disease-modifying intervention for ALS.}, } @article {pmid40646945, year = {2025}, author = {Davì, F and Iaconis, A and Cordaro, M and Di Paola, R and Fusco, R}, title = {Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40646945}, issn = {2304-8158}, abstract = {In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.}, } @article {pmid40651399, year = {2025}, author = {Ma, Y and Wu, S and Liu, H and Ren, C and Xie, Y and Deng, G and Yao, S and Wang, X and Qin, C}, title = {Sodium lignosulfonate alkylates based-biosurfactants for efficient remediation of oily sludge.}, journal = {Journal of environmental management}, volume = {391}, number = {}, pages = {126553}, doi = {10.1016/j.jenvman.2025.126553}, pmid = {40651399}, issn = {1095-8630}, mesh = {*Sewage/chemistry ; *Surface-Active Agents/chemistry ; *Lignin/analogs & derivatives/chemistry ; Spectroscopy, Fourier Transform Infrared ; Biosurfactants ; }, abstract = {An alkylated sodium lignosulphonate (ALS) was prepared for highly efficient thermal washing treatment of oily sludge. The ALS was characterized for their chemical structure and surface activity. Furthermore, ALS was used as a thermal cleaning agent to treat oily sludge under different conditions to obtain an optimal thermal washing process. Finally, the oily sludge before and after thermal washing were characterized to explore its structural and compositional changes. Results obtained from the Fourier Transform Infrared spectroscopy (FT-IR) and Two-dimensional Heteronuclear Single Quantum Coherence(2D-HSQC) confirmed the successful grafting of fatty acid chains(C12) onto the LS molecules. ALS was an ideal surfactant with suitable HLB value and excellent surface tension reduction, foaming and emulsification properties. The optimum thermal washing process for oily sludge was: thermal washing temperature 30 °C, ALS concentration 1.5 g/L.}, } @article {pmid40652712, year = {2025}, author = {Brüge, A and Ponimaskin, E and Labus, J}, title = {Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.}, journal = {Pharmacological reviews}, volume = {77}, number = {5}, pages = {100071}, pmid = {40652712}, issn = {1521-0081}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Serotonin/metabolism ; Receptors, Serotonin/metabolism ; *Serotonin Agents/therapeutic use/pharmacology ; Molecular Targeted Therapy ; }, abstract = {More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.}, } @article {pmid40653481, year = {2025}, author = {Marabita, M and Marchioretti, C and Aravamudhan, A and Zito, S and Falconieri, A and Zuccaro, E and Andreotti, R and Gambarotto, L and Metti, S and Tonellato, M and Adami, V and Park, KH and Gunthorpe, MJ and Large, CH and Marasco, A and Vianello, S and Rosati, J and Belluzzi, E and Pozzuoli, A and Biz, C and Ruggieri, P and Basso, M and Poletti, A and Alvaro, G and Sorarù, G and Bonaldo, P and Rossetto, O and Pilati, N and Pennuto, M}, title = {Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {153}, pmid = {40653481}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; *Shaw Potassium Channels/agonists/metabolism/genetics ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Mice ; Phenotype ; Muscle, Skeletal/metabolism/drug effects/pathology ; Male ; Mice, Inbred C57BL ; Female ; Superoxide Dismutase-1/genetics ; }, abstract = {Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.}, } @article {pmid40659018, year = {2025}, author = {Yang, EJ}, title = {Combined Herbal Medicine (<italic>Achyranthes bidentata</italic>, <italic>Gastrodia elata</italic>, and <italic>Chaenomeles sinensis</italic>) Increases Anti-Inflammatory and Anti-Oxidative Effects in a Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Pharmacology}, volume = {}, number = {}, pages = {1-14}, doi = {10.1159/000547388}, pmid = {40659018}, issn = {1423-0313}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons, finally leading to death by respiratory failure. However, no effective drug is available for treating patients with ALS owing to the complex pathological mechanisms. Herbal medicines are globally known for the effects of their multiple bioactive components and lack of adverse effects. This study investigated the effects of a combined herbal medicine formulation containing Achyranthes bidentata Blume, Gastrodia elata Blume, and Chaenomeles sinensis Koehne extracts on motor function and to analyze the underlying biological mechanisms in the gastrocnemius and tibia anterior muscles and spinal cord of hSOD1G93A mice.

METHODS: Rotarod and footprint analyses were performed to examine motor function. The biological mechanisms were examined using Western blot and immunohistochemistry analyses of the muscles and spinal cord in hSOD1G93A mice.

RESULTS: Herbal medicine treatment improved motor function in hSOD1G93A mice by reducing the expression of inflammation-related proteins (glial fibrillary acidic protein and CD11b) and oxidative stress-related proteins (heme oxygenase 1 and ferritin) in the gastrocnemius and tibia anterior muscles and spinal cord. It also regulated autophagy in the muscles and spinal cord of hSOD1G93A mice.

CONCLUSION: Collectively, these findings suggest that the herbal medicine formulation reported herein may facilitate management of diseases with complex pathological mechanisms, such as ALS, or those with unclear pathological mechanisms.}, } @article {pmid40660446, year = {2026}, author = {Singh, D}, title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.}, journal = {Current drug safety}, volume = {21}, number = {2}, pages = {94-107}, doi = {10.2174/0115748863375490250626163609}, pmid = {40660446}, issn = {2212-3911}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles ; *Mitochondrial Diseases/drug therapy ; }, abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.}, } @article {pmid40665048, year = {2025}, author = {Imam, F and Saloner, R and Vogel, JW and Krish, V and Abdel-Azim, G and Ali, M and An, L and Anastasi, F and Bennett, D and Pichet Binette, A and Boxer, AL and Bringmann, M and Burns, JM and Cruchaga, C and Dage, JL and Farinas, A and Ferrucci, L and Finney, CA and Frasier, M and Hansson, O and Hohman, TJ and Johnson, ECB and Kivimaki, M and Korologou-Linden, R and Ruiz Laza, A and Levey, AI and Liepelt-Scarfone, I and Lu, L and Mattsson-Carlgren, N and Middleton, LT and Nho, K and Oh, HS and Petersen, RC and Reiman, EM and Robinson, O and Rothstein, JD and Saykin, AJ and Shvetcov, A and Slawson, C and Smets, B and Suárez-Calvet, M and Tijms, BM and Timmers, M and Vieira, F and Vilor-Tejedor, N and Visser, PJ and Walker, KA and Winchester, LM and Wyss-Coray, T and Yang, C and Bose, N and Lovestone, S and , }, title = {The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.}, journal = {Nature medicine}, volume = {31}, number = {8}, pages = {2556-2566}, pmid = {40665048}, issn = {1546-170X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; R01 AG057911/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; T32 MH135853/MH/NIMH NIH HHS/United States ; RF1 AG057471/AG/NIA NIH HHS/United States ; R01 AG061800/AG/NIA NIH HHS/United States ; R01 AG057339/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; R01 TS000341/TS/ATSDR CDC HHS/United States ; T32 MH020016/MH/NIMH NIH HHS/United States ; R01 AG053960/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; RF1 AG062553/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; U01 AG045390/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; R01 AG064227/AG/NIA NIH HHS/United States ; RF1 AG057470/AG/NIA NIH HHS/United States ; R01 AG083740/AG/NIA NIH HHS/United States ; R01 AG056477/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Proteomics/methods ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Drug Discovery ; *Aging/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.}, } @article {pmid40669676, year = {2025}, author = {Su, X and Tan, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {DAPK1 induces motor neuron apoptosis in hSOD1[G93A]-linked amyotrophic lateral sclerosis via regulating the Xiap/JNK pathway.}, journal = {Molecular and cellular neurosciences}, volume = {134}, number = {}, pages = {104029}, doi = {10.1016/j.mcn.2025.104029}, pmid = {40669676}, issn = {1095-9327}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Apoptosis ; *Death-Associated Protein Kinases/metabolism/genetics ; *Motor Neurons/metabolism ; *X-Linked Inhibitor of Apoptosis Protein/metabolism ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; *MAP Kinase Signaling System ; MicroRNAs/metabolism/genetics ; Male ; Female ; Mice ; Middle Aged ; }, abstract = {Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1[G93A]-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.}, } @article {pmid40671688, year = {2025}, author = {Masegosa, VM and Fritz, E and Corvalan, D and Rojas, F and Garcés, P and Navarro, X and Bloms-Funke, P and van Zundert, B and Herrando-Grabulosa, M}, title = {Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {2887-2900}, pmid = {40671688}, issn = {1948-7193}, mesh = {Animals ; *Astrocytes/metabolism/drug effects ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Frontotemporal Dementia/metabolism/pathology ; Mice ; Rats ; Culture Media, Conditioned/pharmacology ; *Neuroprotective Agents/pharmacology ; *Receptors, GABA/metabolism ; Cells, Cultured ; Mice, Transgenic ; Spinal Cord/drug effects/metabolism ; Nerve Degeneration/metabolism ; Superoxide Dismutase-1/genetics ; *KCNQ2 Potassium Channel/agonists/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a continuous spectrum of aggressive neurodegenerative diseases affecting primarily motoneurons (MNs) and cortical frontotemporal neurons. Noncell autonomous mechanisms contribute to ALS/FTD, wherein astrocytes release toxic factor(s) detrimental to MNs. Because of the multifactorial nature of ALS, single-pathway-focused therapies have limited effectiveness in improving ALS. Therefore, novel combinatorial therapies are currently being pursued. Here, we evaluated whether the simultaneous activation of two complementary targets, the voltage-gated potassium channels 7.2/3 (Kv7.2/3) and the mitochondrial translocator protein (TSPO), by a novel synthesized compound (GRT-X) is an effective neuroprotective treatment in ALS in vitro models. We exposed primary rat ventral spinal cord neuronal cultures and rat spinal cord organotypic cultures to astrocyte-conditioned medium derived from primary mouse ALS astrocytes expressing mutant human SOD1 (SOD1[G93A]-ACM) or from human-induced pluripotent stem cell (iPSC)-derived astrocytes carrying an ALS-causing mutation in SOD1 (SOD1[D90A]-ACM) or an ALS/FTD-causing mutation in TDP-43 (TDP43[A90 V]-ACM). We report that the diverse human and mouse ALS/FTD-ACMs compromise the MN viability. Remarkably, GRT-X led to consistent protection of MNs. Moreover, ALS/FTD-ACM increases oxidative stress levels, which are prevented with GRT-X treatment. Together, we show that the complementary activation of TSPO and Kv7.2/3 may offer a novel therapeutic strategy for ALS/FTD due to its capacity to protect MNs from noncell-autonomous toxicity induced by diseased astrocytes.}, } @article {pmid40672153, year = {2025}, author = {Sang, X and Jiao, H and Meng, Q and Fang, X and Sundaram, KS and Zhou, J and Xu, Y and Alvarado, AIW and Nuryyev, RL and Ourenik, J and Ourednik, V and Huang, IS and Liu, X and Mei, Y and Qian, T and Ciechanover, A and Pizzo, DP and Lane, MA and Zholudeva, LV and An, J and Snyder, EY and Hu, H and Huang, Z}, title = {The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672153}, issn = {2692-8205}, support = {R01 GM057761/GM/NIGMS NIH HHS/United States ; }, abstract = {G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1α. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1α in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1α that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1[G93A] mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases.}, } @article {pmid40675338, year = {2025}, author = {Shtilbans, A}, title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2025.07.004}, pmid = {40675338}, issn = {1541-6100}, abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10, creatine, and N-acetylcysteine, in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of conditions such as Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.}, } @article {pmid40683276, year = {2025}, author = {Harkness, JR and McDermott, JH and Marsden, S and Jamieson, P and Metcalfe, KA and Khan, N and Macken, WL and Pitceathly, RDS and Record, CJ and Maroofian, R and Kleopa, K and Christodoulou, K and Sabir, A and Islam, L and Santra, S and Durmusalioglu, EA and Atik, T and Isik, E and Cogulu, O and Urquhart, JE and Beaman, GM and Demain, LA and Jackson, A and Blakes, AJM and Byers, HJ and Bennett, H and Lin, WH and Adamson, A and Patel, S and Yue, WW and Taylor, RW and Reunert, J and Marquardt, T and Buchert, R and Haack, T and Losch, H and Ryba, L and Lassuthova, P and Valkovičová, R and Haberlová, J and Lauerová, B and Trúsiková, E and Polavarapu, K and Kilicarslan, OA and Lochmüller, H and Zamani, M and Chamanrou, N and Shariati, G and Sadeghian, S and Azizimalamiri, R and Maddirevula, S and AlMuhaizea, M and Alkuraya, FS and Horvath, R and Gungor, S and Manzur, A and Munot, P and Matthews, R and Banka, S and Reilly, MM and Bennett, D and O'Keefe, RT and Newman, WG}, title = {Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series.}, journal = {The Lancet. Neurology}, volume = {24}, number = {8}, pages = {667-680}, doi = {10.1016/S1474-4422(25)00198-X}, pmid = {40683276}, issn = {1474-4465}, mesh = {Adolescent ; Animals ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; *Cell Cycle Proteins/genetics ; *Infections/complications ; *Peripheral Nervous System Diseases/etiology ; Drosophila ; Nuclear Proteins ; Guanine Nucleotide Exchange Factors ; }, abstract = {BACKGROUND: The reasons why some individuals have severe neuropathy following an infection are not known. Through the agnostic screening of children with acute axonal neuropathy after an infection, we identified several families with biallelic variants in RCC1. We aimed to describe the clinical phenotype of these patients, and the molecular and cellular pathology associated with the genetic variants identified in these families.

METHODS: For this case series, we identified children affected by a severe, acute-onset axonal neuropathy following infection through an international research consortium of paediatric neurologists and clinical geneticists from nine countries (Canada, Cyprus, Czechia, Germany, Iran, Saudi Arabia, Slovakia, Türkiye, and the UK). Clinical assessments included nerve conduction studies and neuroimaging. We did exome or genome sequencing in DNA samples from all patients. We characterised the proteins encoded by the genetic variants by use of thermal stability and enzymatic assays, using recombinantly expressed proteins. We assessed cellular protein transport under heat or oxidative stress by use of immunofluorescence in primary fibroblasts, obtained from patients. We generated a humanised Drosophila knock-in model to assess the effects of stress on the in vivo function of RCC1.

FINDINGS: Between Nov 2, 2011, and July 10, 2024, we identified 24 individuals from 12 families who had severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]). Eight biallelic missense variants in RCC1 were identified in affected individuals with autosomal recessive inheritance. Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients. The RCC1 variants in these patients code for proteins that alter GDP-to-GTP exchange activity and have reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.

INTERPRETATION: We describe an autosomal recessive, acute-onset paediatric axonal neuropathy, seemingly triggered by infection, that affects individuals with biallelic RCC1 variants. In these children, the disease can mimic Guillain-Barré syndrome. The pathological mechanisms underlying this novel axonal neuropathy might overlap with those of amyotrophic lateral sclerosis. Cellular studies indicate that RCC1 variants affect nucleocytoplasmic transport, which is crucial for healthy axonal function. Future studies should be directed at pre-symptomatic treatment by exploring ways to maintain nucleocytoplasmic transport.

FUNDING: National Institute for Health and Care Research, LifeArc, and Wellcome Trust.}, } @article {pmid40685330, year = {2025}, author = {Far, BF and Akbari, M and Habibi, MA and Katavand, M and Nasseri, S}, title = {CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.}, journal = {Cell proliferation}, volume = {58}, number = {11}, pages = {e70099}, pmid = {40685330}, issn = {1365-2184}, mesh = {Humans ; Animals ; *CRISPR-Cas Systems ; *Translational Research, Biomedical ; Gene Editing ; Genetic Engineering/methods ; Genetic Variation ; COVID-19/therapy ; SARS-CoV-2 ; Immunotherapy ; }, abstract = {CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.}, } @article {pmid40687373, year = {2025}, author = {Hollensen, AK and Sørensen, MH and Thomsen, SV and Thomsen, HS and Damgaard, CK}, title = {Using circular RNAs to target toxic RNA-binding proteins in amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {3}, pages = {101525}, pmid = {40687373}, issn = {2329-0501}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration and is in many cases associated with mutations in genes encoding RNA-binding proteins (RBPs), including fused in sarcoma (FUS) and heterogeneous nuclear ribonuclearprotein A1 (hnRNPA1). These mutations often cause cytoplasmic mislocalization and aggregation of these typically nuclear proteins. Current treatment options for ALS are limited, highlighting the need for new therapeutic strategies. Here, we demonstrate an approach using circular RNAs (circRNAs) to target disease-associated RBPs for degradation. We designed circRNAs containing binding sites for both the target RBPs (FUS or hnRNPA1) and ring finger and CCCH-type domains 2 (RC3H2), an RNA-binding E3 ubiquitin ligase. Through RNA immunoprecipitations and protein analyses, we show that these circRNAs can form ternary complexes with their target RBPs and RC3H2. Importantly, we observed significant reductions in steady-state protein levels of ALS-associated FUS-P525L (20%) and hnRNPA1-P288S (30%) mutants when treated with their respective targeting circRNAs. These findings provide proof of concept for using circRNAs as scaffolds to promote the degradation of disease-associated RBPs, establishing a foundation for developing advanced RNA-based therapeutic strategies for ALS and potentially other RBP-related diseases.}, } @article {pmid40688669, year = {2025}, author = {Zhu, RK and Shi, J and Zhou, HJ and Ge, L and Yin, WH and Zeng, H and Wang, XW}, title = {Biological applications of graphene-based nanomaterials in neurodegenerative diseases.}, journal = {Materials today. Bio}, volume = {33}, number = {}, pages = {102064}, pmid = {40688669}, issn = {2590-0064}, abstract = {Neurodegenerative diseases (NDDs) have become a major challenge in global public health due to neurotoxicity caused by progressive neuronal degeneration and abnormal protein aggregation, which has attracted widespread attention. Graphene-based nanomaterials provide innovative solutions for the early diagnosis and precise treatment of NDDs by virtue of their ultra-high conductivity, large specific surface area and multifunctional properties. In this paper, we systematically discuss the key applications of these materials in the diagnosis and treatment of NDDs, and deeply analyze the technological breakthroughs and clinical translation challenges. The core of this paper is to illustrate that graphene-based nanomaterials are expected to reshape the paradigm of NDDs diagnosis and treatment through cross-scale technological innovations, promoting the synergistic development of early diagnosis, personalized treatment and real-time monitoring, and providing a transformative strategy for overcoming NDDs.}, } @article {pmid40689333, year = {2025}, author = {Tian, M and Xin, C and Huo, J and Liu, Q and Dong, H and Bai, L and Wang, Y and Li, R and Liu, Y}, title = {Unlocking amyotrophic lateral sclerosis: the role of adiponectin in inflammation and disease progression.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1605822}, pmid = {40689333}, issn = {1664-2295}, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS), immune cells become activated, resulting in a persistent pro-inflammatory milieu and contributing to the development of ALS. Adiponectin produces anti-inflammatory effects via its adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). Currently, there has been limited research conducted on the correlation between adiponectin and inflammation in ALS.

METHODS: This cross-sectional study recruited a cohort of 82 ALS patients and 25 controls. Adiponectin and inflammatory mediators in plasma were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, flow cytometry, immunocytochemistry, and ELISA were employed to examine the levels of AdipoR1, AdipoR2, and inflammatory markers in monocytes and macrophages obtained from ALS patients. The effects of Adiponectin receptor agonists (AdipoRon) on AdipoR expression, inflammatory responses, and macrophages polarization were investigated.

RESULTS: Plasma adiponectin level in ALS patients was markedly lower than controls. This decrease was found to be positively associated with IL-1β, IL-2, IL-6, IL-8, and TNF-α, while negatively correlated with IL-4 and IL-10. Furthermore, there was a positive correlation between plasma adiponectin level and ALS Functional Rating Scale-Revised (ALSFRS-R), and a negative correlation with the disease progression rate (δFS). Mediation research demonstrated that IL-2, or TNF-α, or IL-10 acted as a mediator between adiponectin and δFS. AdipoR1 and AdipoR2 showed a notable increase in expression in peripheral blood monocytes and activated macrophages obtained from ALS patients, concomitant with elevated level of IL-1β. AdipoRon treatment resulted in a decrease in the expression of AdipoR1. Simultaneously, AdipoRon decreased the levels of IL-1β and MHC-II, while boosting the levels of IL-10 and CD206. This regulation enabled the transformation of macrophages from the M1 to the M2 phenotype, therefore aiding in the protection of neurons.

CONCLUSION: Our findings demonstrated a notable association between adiponectin level and inflammation in the peripheral regions of ALS patients. These results may offer new understanding into the control of inflammation and propose a possible treatment approach for ALS.}, } @article {pmid40696471, year = {2025}, author = {Lin, CF and Chen, YH and Yeh, CC and Hsu, SPC and Fu, YS}, title = {Xenotransplantation of Human Umbilical Mesenchymal Stromal Cells Derived from Wharton's Jelly Mitigates Mouse Amyotrophic Lateral Sclerosis.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {395}, pmid = {40696471}, issn = {1757-6512}, support = {V114C-203//Taipei Veterans General Hospital/ ; 113-2314-B-075-061//National Science and Technology Council in Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology ; Animals ; Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; *Mesenchymal Stem Cell Transplantation ; Mice ; Mice, Transgenic ; Superoxide Dismutase-1 ; *Wharton Jelly/cytology ; Spinal Cord/pathology ; Transplantation, Heterologous ; Superoxide Dismutase/genetics/metabolism ; Umbilical Cord/cytology ; Motor Neurons/pathology ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord, eventually leading to paralysis, respiratory failure, and death. Currently, no effective treatment exists for ALS.

METHODS: This study examined the therapeutic potential of human umbilical cord mesenchymal stromal cells (HUMSCs) by transplanting 2 × 10⁶ HUMSCs into the spinal canal of transgenic mice expressing mutant human superoxide dismutase 1 (SOD1) at 8 weeks of age.

RESULTS: Survival analysis showed that the SOD1 group lived up to 171 days, while the SOD1 + HUMSCs group survived up to 199 days, extending lifespan by 17 days on average. Motor function tests, including rotarod performance, grip strength, open field activity, and balance beam tests, demonstrated that while the SOD1 group experienced progressive decline, the SOD1 + HUMSCs group showed improvement. Electrophysiological assessments at 20 weeks of age revealed weak muscle action potential in the SOD1 group, whereas the SOD1 + HUMSCs group exhibited noticeable improvements. Histological analysis indicated significant spinal cord atrophy in the SOD1 group, while HUMSCs transplantation mitigated this degeneration. Moreover, HUMSCs reduced blood-spinal cord barrier leakage and T lymphocyte infiltration, alleviating inflammation. The number and size of activated microglia and astrocytes increased in the SOD1 group but were reduced with HUMSCs treatment. Additionally, HUMSCs preserved more motor neurons in the anterior horns.

CONCLUSION: Collectively, transplantation of HUMSCs effectively reduced inflammatory reaction in spinal cord, decreased loss of neurons, ameliorated disease deterioration, and extended life span, suggesting that it could serve as a new direction of ALS treatment to improve patients' quality of life or behavioral function.}, } @article {pmid40698100, year = {2025}, author = {Singh, D and Singhal, S and Kanaujiya, V and Ranjan, A and Mani, VE and Paliwal, VK and Jain, V and Aishwarya, A and Agarwal, R}, title = {Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.}, journal = {Romanian journal of ophthalmology}, volume = {69}, number = {2}, pages = {200-207}, pmid = {40698100}, issn = {2501-2533}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Retinal Ganglion Cells/pathology ; *Visual Acuity/physiology ; *Nerve Fibers/pathology ; Adult ; *Optic Disk/pathology ; Aged ; Intraocular Pressure/physiology ; Biomarkers ; }, abstract = {AIM: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS).

METHODS: Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS™ HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan.

RESULTS: RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes.

DISCUSSION: All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters.

CONCLUSION: In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.}, } @article {pmid40701662, year = {2026}, author = {Toomey, J and Lewis, J and Hannikainen, IR and Earp, BD}, title = {A qualitative study of true self judgments, epistemic access, and medical decision-making.}, journal = {Journal of medical ethics}, volume = {52}, number = {7}, pages = {453-458}, doi = {10.1136/jme-2025-110957}, pmid = {40701662}, issn = {1473-4257}, mesh = {Humans ; *Judgment ; Female ; Qualitative Research ; *Decision Making ; Male ; Adult ; *Self Concept ; *Clinical Decision-Making ; Middle Aged ; }, abstract = {BACKGROUND: Toomey et al (2024) found that US participants were more likely to follow a medical treatment preference-expressed after substantial cognitive decline-of a third person rather than their own future self. This correlated with a greater tendency to see the third person as still their true self. We hypothesised that the greater epistemic access one has to one's own true self as opposed to others might drive this difference.

METHODS: A codebook designed to capture different kinds of evidence and reasoning was developed, and participants' explanations for their treatment decisions in Toomey et al's study were coded and qualitatively analysed.

RESULTS: In first-person cases, participants were more likely to explain their treatment decision with reference to perceived direct access to their own true self. In contrast, in third-person cases, participants more often relied on proxies or heuristics, such as the presumption that an expressed preference is an authentic one or that preferences expressed with greater cognition tend to better reflect the true self.

CONCLUSIONS: These findings support the hypothesis that differential epistemic access to the true self in first- and third-person cases may drive different medical treatment decisions. Participants may be trying to follow the patient's 'true' or 'authentic' preference in all cases, but relying on different kinds of evidence in so doing.}, } @article {pmid40704991, year = {2025}, author = {Ganssauge, J and Hawkins, S and Namboori, SC and Leung, SK and Mill, J and Bhinge, A}, title = {Rapid and inducible mislocalization of endogenous TDP43 in a novel human model of amyotrophic lateral sclerosis.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40704991}, issn = {2050-084X}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Cell Nucleus/metabolism ; Protein Transport ; }, abstract = {Transactive response DNA binding protein 43 kDa (TDP43) proteinopathy, characterized by the mislocalization and aggregation of TDP43, is a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). In this study, we describe the development of a new model of TDP43 proteinopathy using human induced pluripotent stem cell (iPSC)-derived neurons. Utilizing a genome engineering approach, we induced the mislocalization of endogenous TDP43 from the nucleus to the cytoplasm without mutating the TDP43 gene or using chemical stressors. Our model successfully recapitulates key early and late pathological features of TDP43 proteinopathy, including neuronal loss, reduced neurite complexity, and cytoplasmic accumulation and aggregation of TDP43. Concurrently, the loss of nuclear TDP43 leads to splicing defects, while its cytoplasmic gain adversely affects microRNA expression. Strikingly, our observations suggest that TDP43 is capable of sustaining its own mislocalization, thereby perpetuating and further aggravating the proteinopathy. This innovative model provides a valuable tool for the in-depth investigation of the consequences of TDP43 proteinopathy. It offers a clinically relevant platform that will accelerate the identification of potential therapeutic targets for the treatment of TDP43-associated neurodegenerative diseases, including sporadic ALS.}, } @article {pmid40705135, year = {2025}, author = {Jung, HJ and Jeong, WS and Kang, HW and Kang, M and Lee, EJ and Lim, YM and Park, JS and Kim, H}, title = {Serum GFAP predicts survival in advanced ALS: a prospective multicenter study.}, journal = {Journal of neurology}, volume = {272}, number = {8}, pages = {532}, pmid = {40705135}, issn = {1432-1459}, support = {RS-2023-00211443//Ministry of Science and ICT, Republic of Korea/ ; 2023IP0108//Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea/ ; 25-BR-04-01//KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT, Republic of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis ; *Glial Fibrillary Acidic Protein/blood ; Male ; Female ; Middle Aged ; *Neurofilament Proteins/blood ; Aged ; *Brain-Derived Neurotrophic Factor/blood ; Biomarkers/blood ; Prospective Studies ; Disease Progression ; Adult ; Prognosis ; ROC Curve ; }, abstract = {BACKGROUND: Neurofilament light chain (NfL) is a well-established biomarker of axonal damage in amyotrophic lateral sclerosis (ALS), but its limited disease specificity warrants the identification of complementary markers. This study aimed to evaluate the prognostic value of serum glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF) as adjunctive biomarkers to NfL in ALS.

METHODS: Serum NfL, GFAP, and BDNF levels were measured using ultrasensitive single-molecule array (SIMOA) assays in two independent ALS cohorts from Asan Medical Center (n = 65) and Kyungpook National University Chilgok Hospital (n = 53), along with 15 healthy controls. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Associations with clinical severity, disease progression rate, and survival were evaluated using correlation analyses, Kaplan-Meier survival estimates, and Cox proportional hazards models.

RESULTS: Serum NfL, GFAP, and BDNF levels were significantly elevated in ALS versus controls, with area under the curve (AUC) values of 0.969, 0.613, and 0.875, for NfL, GFAP, and BDNF, respectively. NfL and GFAP levels increased with advancing King's stage (NfL: τ = 0.226, p = 0.011; GFAP: τ = 0.160, p = 0.023), though only NfL correlated with disease progression rate (r = 0.309, p = 0.001). Notably, elevated GFAP was independently associated with poorer survival in advanced ALS (King's stage 3-4), with a hazard ratio of 6.907 (95% CI: 1.978-24.119, p = 0.002).

CONCLUSIONS: While NfL remains a robust marker of ALS progression, GFAP may serve as an independent prognostic marker in late-stage disease. Combining these markers may enhance prognostic accuracy and support personalized ALS care.

Neurofilament light chain (NfL) is a widely accepted biomarker for axonal damage in ALS and correlates with disease progression. However, its lack of disease specificity limits its standalone prognostic value, necessitating the discovery of complementary biomarkers to improve prognostic accuracy.

WHAT THIS STUDY ADDS: This study demonstrates that while NfL remains a strong indicator of ALS progression, glial fibrillary acidic protein (GFAP) serves as an independent prognostic marker, particularly in advanced stages of the disease. Furthermore, it shows that serum BDNF levels are also elevated in ALS patients.

Combining NfL and GFAP as a biomarker panel could significantly enhance prognostic accuracy and facilitate more personalized treatment strategies for ALS patients, especially in later disease stages. This could guide clinical trial design and improve patient stratification for therapeutic interventions.}, } @article {pmid40708508, year = {2026}, author = {Rana, A and Malviya, R and Rajput, S and Sridhar, SB and Wadhwa, T}, title = {Trends in Nanoparticle-based Strategies for the Management of Neuroinflammation.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {1}, pages = {39-55}, pmid = {40708508}, issn = {1996-3181}, mesh = {Humans ; *Neuroinflammatory Diseases/drug therapy ; Animals ; *Nanoparticles/therapeutic use ; *Drug Delivery Systems/methods ; *Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/drug effects ; Microglia/drug effects ; }, abstract = {Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.}, } @article {pmid40709087, year = {2025}, author = {Wang, G and Zhou, X and Pang, X and Ma, K and Li, L and Song, Y and Hou, D and Wang, X}, title = {Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1625821}, pmid = {40709087}, issn = {1663-9812}, abstract = {With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.}, } @article {pmid40710301, year = {2025}, author = {Pasqualucci, E and Angeletti, D and Rosso, P and Fico, E and Zoccali, F and Tirassa, P and De Virgilio, A and de Vincentiis, M and Severini, C}, title = {Management of Dysarthria in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {14}, pages = {}, pmid = {40710301}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Dysarthria/therapy/diagnosis/etiology/physiopathology/complications ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as the leading neurodegenerative disorder affecting the motor system. One of the hallmarks of ALS, especially its bulbar form, is dysarthria, which significantly impairs the quality of life of ALS patients. This review provides a comprehensive overview of the current knowledge on the clinical manifestations, diagnostic differentiation, underlying mechanisms, diagnostic tools, and therapeutic strategies for the treatment of dysarthria in ALS. We update on the most promising digital speech biomarkers of ALS that are critical for early and differential diagnosis. Advances in artificial intelligence and digital speech processing have transformed the analysis of speech patterns, and offer the opportunity to start therapy early to improve vocal function, as speech rate appears to decline significantly before the diagnosis of ALS is confirmed. In addition, we discuss the impact of interventions that can improve vocal function and quality of life for patients, such as compensatory speech techniques, surgical options, improving lung function and respiratory muscle strength, and percutaneous dilated tracheostomy, possibly with adjunctive therapies to treat respiratory insufficiency, and finally assistive devices for alternative communication.}, } @article {pmid40717814, year = {2025}, author = {Righes, G and Semenzato, L and Koutsikos, K and Zanato, V and Pinton, P and Giorgi, C and Patergnani, S}, title = {The role of autophagy in the pathogenesis and treatment of multiple sclerosis.}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2529196}, pmid = {40717814}, issn = {2769-4127}, abstract = {Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.}, } @article {pmid40717894, year = {2025}, author = {Yu, M and Ma, H and Lai, X and Wu, J and Shen, M and Yan, J}, title = {Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1592578}, pmid = {40717894}, issn = {1663-4365}, abstract = {Mesenchymal stem cell-derived extracellular vesicles, as carriers for intercellular communication, are rich in bioactive substances such as proteins and nucleic acids, and show unique potential in the treatment of neurodegenerative diseases. Their vesicular structure, with a diameter of 30-150 nm, can penetrate the blood-brain barrier and modulate the activity of microglia and astrocytes by delivering functional molecules. This process inhibits the release of pro-inflammatory factors and enhances the expression of anti-inflammatory mediators, thereby alleviating neuroinflammation in the pathological process of neurodegenerative diseases. As natural drug carriers, extracellular vesicles can improve the targeted delivery efficiency of therapeutic molecules. However, their specific anti-inflammatory mechanisms remain not fully understood and require further exploration. This article discusses the anti-inflammatory effects in the context of neurodegenerative diseases and provides a summary and outlook on the anti-inflammatory actions associated with extracellular vesicles from past research.}, } @article {pmid40722288, year = {2025}, author = {Dhakal, D and Chen, C and Zhang, B and Li, G}, title = {Health-Related Quality of Life, Psychological Health, and Patient-Reported Outcomes of Amyotrophic Lateral Sclerosis Patients in China.}, journal = {Brain sciences}, volume = {15}, number = {7}, pages = {}, pmid = {40722288}, issn = {2076-3425}, abstract = {Objectives: This study explored the health-related quality of life (HRQoL), psychological health, and patient-reported outcomes (PROs) of patients with amyotrophic lateral sclerosis (ALS) in China, providing insights for enhancing clinical care. Methods: A cross-sectional study was conducted among Chinese ALS patients between February and May 2024. Demographics, clinical characteristics, and PROs were assessed. HRQoL and psychological health were evaluated via the 5-item amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-5) and the 4-item patient health questionnaire (PHQ-4), respectively. Spearman's rank correlation, multiple linear regression, and the Kruskal-Wallis H test were used to analyze associations between clinical factors, HRQoL, and psychological health. Results: A total of 237 participants aged 46-65 years (63.3%) were included. The mean ALSAQ-5 score was 64.86±19.34, indicating an impaired HRQoL, whereas the mean PHQ-4 score (5.82 ± 4.10,) suggested varied degree of anxiety and depression. Age, disease duration, ALS severity, fatigue, stress, and pain severity, and respiratory support were significantly associated with HRQoL (p < 0.05). Age, stress severity, and pain severity were significant predictors of psychological distress (p < 0.01). Patients reported diagnostic delay, profound lifestyle changes (96.4%), fear of paralysis (84.8%), and death (49.8%). Most patients (80.6%) expressed a strong desire to stop ALS progression, prioritizing treatments that improve breathing, muscle weakness, swallowing, and mobility issues. Conclusions: ALS profoundly impacts patients' HRQoL and psychological health. Integrating PROs into clinical care strategies is crucial for improving patient outcomes and guiding treatment priorities.}, } @article {pmid40724820, year = {2025}, author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T}, title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724820}, issn = {1422-0067}, mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; }, abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.}, } @article {pmid40725270, year = {2025}, author = {Tahri, A and Niccolai, E and Amedei, A}, title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725270}, issn = {1422-0067}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; }, abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.}, } @article {pmid40727259, year = {2025}, author = {Sun, W and Zhu, A and Chang, H and Xia, J and Gao, J and Zhang, Z and Chi, F and Zhu, Y and Bao, X}, title = {Causal associations and shared genetic etiology between neurodegenerative diseases and constipation.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251362469}, pmid = {40727259}, issn = {2542-4823}, abstract = {BACKGROUND: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated.

OBJECTIVE: We aim to investigate the causal link and shared genetic basis between NDDs and constipation.

METHODS: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes.

RESULTS: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades.

CONCLUSIONS: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.}, } @article {pmid40730291, year = {2025}, author = {Magdalena, R and Ferrada, L and Ramírez, E and Smith-Ghigliotto, JF and Salazar, K and Nualart, F}, title = {Dehydroascorbic acid impairs neurite growth through RIPK1-associated caspase activation.}, journal = {Free radical biology & medicine}, volume = {239}, number = {}, pages = {406-416}, doi = {10.1016/j.freeradbiomed.2025.07.036}, pmid = {40730291}, issn = {1873-4596}, mesh = {*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; *Neurites/drug effects/metabolism/pathology ; Animals ; *Dehydroascorbic Acid/pharmacology ; Enzyme Activation/drug effects ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Imidazoles/pharmacology ; Indoles/pharmacology ; *Caspases/metabolism ; Mice ; Amino Acid Chloromethyl Ketones/pharmacology ; Ascorbic Acid ; Antioxidants/pharmacology ; Humans ; }, abstract = {Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.}, } @article {pmid40735390, year = {2025}, author = {Liu, Y and Chen, G and Li, M and Li, M and Xie, D and Luo, Z}, title = {Development of long-acting riluzole transdermal patch against amyotrophic lateral sclerosis: Mechanistic insights into polyglyceryl-3 dioleate-enhanced drug release and skin permeation.}, journal = {International journal of pharmaceutics: X}, volume = {10}, number = {}, pages = {100363}, pmid = {40735390}, issn = {2590-1567}, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often experience difficulty swallowing, making oral administration unsuitable for effective treatment. A transdermal drug delivery system (TDDS) offers a long-acting, non-invasive alternative for ALS therapy. In this study, a riluzole transdermal patch capable of sustained release over 72 h was developed. In vitro skin permeation and pharmacokinetic experiments were conducted to evaluate the impact of various factors-including drug loading, type and concentration of chemical penetration enhancers (CPEs), and type of pressure-sensitive adhesive-on riluzole absorption through the skin. The optimized patch formulation contained 17 % (w/w) riluzole and 10 % (w/w) polyglyceryl-3 dioleate (PGD), with an adhesive layer thickness of 111 μm. The final prescription penetration rate of riluzole was found to be 2.96 μg/(h·cm[2]). Optimized formulation displayed enhanced stability and prolonged pharmacokinetic performance (C max = 74.34 ± 13.62 ng/mL, MRT0-t = 34.91 ± 11.31 h). No significant skin irritation was observed. The role of PGD in the in vitro release and in vivo transdermal absorption of riluzole was thoroughly investigated. The results revealed that PGD not only reduced the interaction between riluzole and the pressure-sensitive adhesive, enhancing drug release but also increased the fluidity of skin lipids, leading to improved transdermal absorption. This study provides a comprehensive molecular-level understanding of PGD's effect on riluzole permeation, offering valuable insights for the rational selection of CPEs in the development of riluzole TDDS.}, } @article {pmid40736059, year = {2026}, author = {Zhao, Q and Zhao, Z and Zhao, G and Xue, L and Chen, L and Zhou, G and Liang, J and Qin, M and Hu, M}, title = {Effect of Defocus Incorporated Multiple Segments (Fog Vision +0.50 D) Combined With 0.01% Atropine on the Preclinical and Early Stages of Myopia in Children.}, journal = {Journal of pediatric ophthalmology and strabismus}, volume = {63}, number = {1}, pages = {11-22}, doi = {10.3928/01913913-20250530-04}, pmid = {40736059}, issn = {1938-2405}, mesh = {Humans ; *Atropine/administration & dosage ; Female ; *Myopia/therapy/physiopathology/diagnosis ; Male ; Child ; *Refraction, Ocular/physiology ; Retrospective Studies ; *Mydriatics/administration & dosage ; Follow-Up Studies ; Axial Length, Eye ; Treatment Outcome ; *Eyeglasses ; Ophthalmic Solutions ; Child, Preschool ; Visual Acuity/physiology ; Disease Progression ; Adolescent ; }, abstract = {PURPOSE: To retrospectively analyze the efficacy of multi-zone positive optical defocus lenses (DIMS) + fog vision + 0.01% atropine for the treatment of children with preclinical and early stages of myopia.

METHODS: The axial length (AL) and refraction were analyzed at baseline and after 12 months of follow-up in 192 eyes treated with combined therapy. The success of treatment was defined as an annual AL growth rate within the physiological growth range and myopia progression of -0.50 diopters (D)/year or greater. Subgroup analysis was performed to investigate the percentage of treatment success in the overall population compared to the subgroups based on baseline AL and age.

RESULTS: Overall, the success rates were 87% and 93% for AL control and myopia control, respectively. Compared to before combined therapy, there was an increase in AL after treatment (boys: P < .001; girls: P < .001). The change in spherical equivalent (SE) was consistent with the change in AL, with both boys and girls showing an increase in SE after treatment, with a statistically significant difference in girls (boys: P = .059; girls: P = .001). There was no statistically significant difference in the percentage of treatment success in either boys or girls based on baseline AL and age subgroups compared to the overall population.

CONCLUSIONS: The treatment regimen of DIMS + fog vision + 0.01% atropine demonstrated significant control effects on myopia in preclinical and early stages of myopia in children across different genders, baseline ALs, and ages. Timely intervention is recommended once a tendency toward myopia is observed in children.}, } @article {pmid40739673, year = {2025}, author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X}, title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {690}, pmid = {40739673}, issn = {2047-783X}, mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; }, abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.}, } @article {pmid40740086, year = {2025}, author = {Ghazali, L and Hamid, SSA and Mohamad, H and Aziz, A}, title = {Clinical review of laryngomalacia in a tertiary hospital.}, journal = {The Medical journal of Malaysia}, volume = {80}, number = {4}, pages = {443-447}, pmid = {40740086}, issn = {0300-5283}, mesh = {Humans ; *Laryngomalacia/diagnosis/epidemiology/therapy/classification ; Male ; Female ; Retrospective Studies ; Tertiary Care Centers ; Infant ; Severity of Illness Index ; Infant, Newborn ; }, abstract = {INTRODUCTION: Laryngomalacia is the most common cause of stridor in infants, with severity ranging from mild to severe forms. Accurate classifications of severity is essential for guiding management and improving outcomes.

MATERIAL AND METHODS: We conducted a retrospective study of paediatric patients under two years of age diagnosed with laryngomalacia at a tertiary referral centre between January 2010 and December 2020. Data collected included demographic details, clinical presentation, comorbidities, endoscopic findings, treatment, and follow-up duration. Severity was classified using a symptoms-based scoring system by Shah et al, while laryngomalacia types were determined according to Olney et al's endoscopic classification. Association between severity, endoscopic findings, comorbidities and treatment choice were analysed using logistic regression.

RESULTS: A total of 148 patients were included (59.49% male). Mild, moderate, and severe laryngomalacia were observed in 45.27%, 35.14%, and 19.59% of patients, respectively. Type 3 laryngomalacia, identified via endoscopy, was significantly associated with severe disease (p<0.001). Comorbidities, particularly gastroesophageal reflux disease, cardiac, pulmonary, syndromic, neurological conditions and synchronous airway lesions, were significantly linked to higher severity (p<0.05). A strong association was found between severity and treatment: moderate cases had 89.6 times, and severe cases 133.3 times, the odds of receiving surgical intervention compared to mild cases (p<0.001).

CONCLUSION: Mild laryngomalacia was most prevalent, but severity increased with specific comorbidities and endoscopic findings. Objective symptom scoring and endoscopic classification are valuable for assessing severity and guiding appropriate management in laryngomalacia.}, } @article {pmid40740433, year = {2025}, author = {Shahim, P and AlQahtani, A and Kokkinis, AD and Kazmi, N and Ezuma-Ngwu, M and Misra, J and Harmison, G and Benoit, N and Jones, M and Howe, E and Schindler, AB and Joe, GO and Grunseich, C}, title = {CSF and blood neuronal injury biomarkers in spinal bulbar muscular atrophy and amyotrophic lateral sclerosis 4.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf275}, pmid = {40740433}, issn = {2632-1297}, abstract = {Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis 4 (ALS4) are two forms of motor neuron disease characterized by clinically slow disease progression. Based on the current limited human studies, the contribution of central nervous neurodegeneration to these diseases and the rate of clinical progression is unclear. Neuronal proteins glial fibrillary acidic protein (GFAP), neurofilament light (NfL) chain, or Total-tau measured in either cerebrospinal fluid or blood could serve as sensitive markers of neurodegeneration. We studied 56 adult participants (32 SBMA, 7 ALS4, and 17 controls) who were enrolled at the National Institutes of Health, of whom 22 (10 SBMA, 7 ALS4, and 5 controls) underwent paired CSF and serum sampling, and of whom 6 participants were assessed longitudinally up to 24 months from initial visit. An additional 7 controls completed CSF sampling only. CSF GFAP, NfL chain, and Total-tau correlated with corresponding levels in serum (r = 0.74, r = 0.47, and r = 0.70, respectively). CSF GFAP was increased in patients with SBMA (median, 8840 pg/mL, interquartile range (IQR) 5780-10489) as compared to controls (median, 5315 pg/mL, IQR 1822-6657; P = 0.029) but not compared with ALS4 (median, 5015 pg/mL, IQR 3172-9803; P = 0.31). Patients with SBMA had increased concentrations of CSF NfL chain (median, 719 pg/mL, IQR 483-773) as compared to ALS4 (median, 307 pg/mL, IQR 187-629; P = 0.034) or controls (median, 395 pg/mL, IQR 307-497; P = 0.024). In contrast, serum concentrations of either biomarker did not differ significantly between SBMA, ALS4, or controls. Higher CSF GFAP and NfL chain levels were associated with lower SBMA Functional Rating Scale scores (r = -0.49 and r = -0.42, respectively). Over the course of 24 months, the average change in SBMA Functional Rating Scale was -0.83 points, while the changes in CSF GFAP and NfL chain were progressive (increased 1.4-fold and 1.3-fold, respectively). Our data suggest that SBMA patients have increased concentrations of CSF GFAP and NfL chain as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity. Importantly, these results indicate that SBMA is associated with progressive neurodegeneration and that either CSF GFAP or NfL chain may be useful for patient stratification and monitoring treatment effects in clinical trials.}, } @article {pmid40744389, year = {2025}, author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK}, title = {Natural bioactive compounds as modulators of autophagy: A herbal approach to the management of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178003}, doi = {10.1016/j.ejphar.2025.178003}, pmid = {40744389}, issn = {1879-0712}, mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Animals ; *Biological Products/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.}, } @article {pmid40744561, year = {2025}, author = {Mora, G and Gil-Monreal, M and Osuna, MD and Vijayarajan, VBA and Montull, JM and Llenes, JM and Recasens, J and Cirujeda, A and Marí, AI and Torra, J}, title = {First case of triple resistance to EPSPS, ALS, and synthetic auxin herbicides in Bassia scoparia (L.) Voss in Europe.}, journal = {Pesticide biochemistry and physiology}, volume = {213}, number = {}, pages = {106529}, doi = {10.1016/j.pestbp.2025.106529}, pmid = {40744561}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicide Resistance/genetics ; *3-Phosphoshikimate 1-Carboxyvinyltransferase/antagonists & inhibitors/genetics/metabolism ; *Bassia scoparia/drug effects/genetics/enzymology ; *Indoleacetic Acids/pharmacology ; Plant Proteins/genetics/metabolism ; }, abstract = {Bassia scoparia (L.) Voss has evolved resistance to five herbicide modes of action (MoAs) worldwide, including multiple resistance to up to four MoAs. Seeds were collected from a putatively resistant B. scoparia population (GUI-R) that survived successive herbicide applications of synthetic auxins, acetolactate synthase (ALS), and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors in a no-till winter cereal field in Catalonia, Spain, in 2022, to assess resistance levels and mechanisms. Dose-response assays confirmed that GUI-R was 2-, 340-, 42.7-, and 60-fold more resistant to glyphosate, thifensulfuron, MCPA, and 2,4-D, respectively, based on plant weight, and 3.2-, 123-, 57.9-, and 32-fold more resistant based on plant survival. GUI-R showed cross-resistance to imazamox (46 % survival), but not to dicamba or fluroxypyr (100 % mortality), at the label rate. Preliminary studies using malathion pre-treatment, a cytochrome P450 inhibitor, reversed 2,4-D resistance in GUI-R at the label rate, resulting in a 97 % reduction in biomass. Molecular studies revealed that GUI-R has 4.9 additional copies of the EPSPS:ALS gene, with no known mutations and less shikimate accumulation than the susceptible population. ALS gene sequencing identified the Pro197Ser, Pro197Leu, and Trp574Leu mutations, along with a combined Pro197Ser + Trp574Leu mutation. In conclusion, EPSPS gene amplification and ALS mutations confer target-site resistance to glyphosate, thifensulfuron and imazamox in GUI-R. Resistance to 2,4-D and MCPA is probably driven by P450-mediated non-target-site resistance and further research is necessary to confirm mechanisms. This biotype represents the first case of glyphosate resistance in Europe for the species, as well as the first triple resistance.}, } @article {pmid40744595, year = {2025}, author = {Li, J and Zhang, Y and Li, L and Wei, S and Huang, Z and Chen, L and Huang, H}, title = {Expression of Echinochloa oryzoides CYP71A1 and GSTU23 catalyzes the metabolism of thiobencarb, thereby conferring resistance.}, journal = {Pesticide biochemistry and physiology}, volume = {213}, number = {}, pages = {106555}, doi = {10.1016/j.pestbp.2025.106555}, pmid = {40744595}, issn = {1095-9939}, mesh = {*Echinochloa/drug effects/genetics/metabolism/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology/metabolism ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Thiocarbamates/metabolism/pharmacology ; *Plant Proteins/genetics/metabolism ; *Glutathione Transferase/metabolism/genetics ; }, abstract = {Echinochloa oryzoides (Ard.) Fritsch. is a notorious and prevalent weed in paddy fields. Thiobencarb (TB), a thiocarbamate herbicide, is widely applied in paddy fields for the control of pre-emergence weeds. However, owing to the prolonged and large-scale usage of TB, certain Echinochloa oryzoides populations have evolved resistance to it. In this study, a population of Echinochloa oryzoides from a paddy field was suspected of being resistant to the TB herbicide. Notably, this population also displayed multiple resistance and cross-resistance to Acetolactate synthase (ALS), Acetyl-CoA carboxylase (ACCase), and hormone-based herbicides. The resistance to TB was partially reversed by 50.8 % and 44.7 % upon treatment with a glutathione S-transferase (GST) inhibitor (NBD-Cl) and a cytochrome P450 inhibitor (malathion), respectively. This confirmed that metabolic resistance was the predominant mechanism underlying the observed resistance. RNA-seq analysis uncovered the overexpression of CYP71A1 and GSTU23 in the resistant (R) population. This study is the first to screen and validate metabolic enzymes capable of effectively metabolizing TB in an Echinochloa oryzoides. Functional verification was conducted using a yeast in vitro expression system, which confirmed the metabolic capabilities of both CYP71A1 and GSTU23 genes towards TB. Collectively, these findings demonstrate that the overexpression of CYP71A1 and GSTU23 in the R population endows Echinochloa oryzoides with the evolutionary capacity to develop resistance to thiobencarb. This study has shed light on the resistance mechanisms of Echinochloa oryzoides to TB, thereby enhancing our understanding of its herbicide tolerance. Moreover, these results highlight the necessity for targeted strategies to control resistant populations, ultimately contributing to more effective and sustainable herbicide resistance management in agriculture.}, } @article {pmid40744617, year = {2025}, author = {Kaspary, TE and Cutti, L and Turra, GM and Angonese, PS and Dos Santos, OD and Merotto, A}, title = {Conyza bonariensis resistance to glyphosate and ALS inhibitors involves target and non-target site resistance.}, journal = {Pesticide biochemistry and physiology}, volume = {213}, number = {}, pages = {106501}, doi = {10.1016/j.pestbp.2025.106501}, pmid = {40744617}, issn = {1095-9939}, mesh = {Glyphosate ; *Herbicide Resistance/genetics ; *Glycine/analogs & derivatives/pharmacology ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics/metabolism ; *Conyza/drug effects/genetics ; Mutation ; Plant Proteins/genetics/antagonists & inhibitors/metabolism ; }, abstract = {Herbicide resistance in Conyza bonariensis (hairy fleabane) poses a significant challenge to agricultural systems worldwide. The genetic variability and prolific seed production of this species contribute significantly to its adaptative potential and fast spread in the agricultural fields. This study aimed to investigate the mechanisms underlying multiple herbicide resistance to glyphosate and ALS inhibitors in C. bonariensis biotypes from Southern Brazil. Resistance factors exceeded 100 times for chlorimuron-ethyl and 49 times for glyphosate. DNA Sequencing revealed the target-site mutations Pro106Thr in the EPSPS gene conferring glyphosate resistance, and Pro197Arg and Trp574Leu in the ALS gene contributing to chlorimuron-ethyl resistance. Additionally, the resistance factor decreased at least 80 % for resistant biotypes after application of chlorimuron-ethyl following treatment with the P450 inhibitor malathion, which might indicate enhanced metabolism mediated by cytochrome P450 enzymes. Copy number variation and overexpression of ALS and EPSPS genes were not related to resistance. Biotype II carries the Pro197Arg mutation and exhibited cross-resistance to imazethapyr, diclosulam, bispyribac‑sodium, and flucarbazone‑sodium. Biotypes carrying the Trp574Leu mutation were resistant to imazethapyr, diclosulam and flucarbazone‑sodium but demonstrated varying resistance patterns to bispyribac‑sodium, highlighting the complexity of resistance mechanisms. These findings underscore the importance of understanding both target and non-target-site resistance mechanisms to develop effective management strategies, including herbicide rotation and molecular diagnostics, to mitigate the spread of herbicide-resistant C. bonariensis in agricultural systems.}, } @article {pmid40745959, year = {2026}, author = {Dogra, S and Kouznetsova, VL and Tsigelny, IF}, title = {Repurposing FDA-approved drugs for treatment of amyotrophic lateral sclerosis using machine learning.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {198-206}, doi = {10.1080/21678421.2025.2536027}, pmid = {40745959}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Machine Learning ; *Drug Repositioning/methods ; United States Food and Drug Administration ; United States ; Drug Approval ; Molecular Docking Simulation ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons. Current medications are largely ineffective, associated with side effects, and hindered by a lack of agreement over treatment pathways. The time-intensive process and high costs further limit the development of therapeutics. Therefore, this research aimed to identify FDA-approved drugs that inhibit three proteins (Casein kinase 1, Protein tyrosine kinase 2, Ephrin type-A receptor 4) associated with ALS.

METHODS: A machine learning (ML) model was trained for each protein to identify an inputted compound as an active inhibitor of that protein. The FDA-approved drugs were then screened through these models, and 18 drugs were identified as likely inhibitors for all three proteins. The results were validated through protein-ligand docking of each drug to its respective protein(s).

RESULTS: Risperidone was the most active drug, with an average ML score of 1 and binding affinity of -8.9. The ML scores and binding affinities had a strong correlation, indicating reliability.

CONCLUSION: This research predicted multiple drugs that can simultaneously target many proteins involved in ALS, creating more effective treatment options at a lower cost. This procedure can be applied to efficiently discover drugs for other diseases in the future.}, } @article {pmid40746518, year = {2025}, author = {Liu, QZ and Zeng, L and Sun, NZ}, title = {Radiomics for preoperative pancreatic ductal adenocarcinoma risk stratification: Cross-population validation, multidimensional integration, challenges, and future directions.}, journal = {World journal of radiology}, volume = {17}, number = {7}, pages = {110048}, pmid = {40746518}, issn = {1949-8470}, abstract = {This editorial critically evaluated Liu et al's recent retrospective analysis of 283 Chinese patients with resectable pancreatic ductal adenocarcinoma (PDAC) that validated a preoperative computed tomography-based risk scoring system originally developed in South Korea. The scoring system incorporated five parameters: (1) Tumor size; (2) Portal venous phase density; (3) Necrosis; (4) Peripancreatic infiltration; and (5) Suspected metastatic lymph nodes. While demonstrating satisfactory recurrence prediction capability without requiring complex technologies, thereby supporting clinical utility in Chinese populations, the study exhibited notable limitations. Most analyzed patients lacked neoadjuvant chemotherapy exposure, resulting in underrepresentation of low-risk subgroups. Additionally, the short follow-up duration potentially compromised long-term prognostic assessment. Contemporary advances in radiomics coupled with machine learning have enhanced multimodal data integration for PDAC management. However, clinical implementation continues to confront challenges including variability in imaging parameters, incomplete understanding of molecular underpinnings, and confounding treatment effects. Future investigations should prioritize developing multidimensional predictive frameworks that synergize radiographic, molecular, and clinical data. Prospective multicenter validation and artificial intelligence-powered real-time risk stratification systems represent essential steps to overcome current barriers in precision medicine translation, ultimately advancing personalized therapeutic strategies for PDAC.}, } @article {pmid40746624, year = {2025}, author = {Kashyap, PV and Singh, D and Nair, A and Jaiswal, A and Pandey, V}, title = {Effect of Edaravone Therapy on Amyotrophic Lateral Sclerosis Functional Rating Score (ALS-FRS) in Patients of Amyotrophic Lateral Sclerosis (ALS) in Central India: A Retrospective Open Label Study.}, journal = {Annals of neurosciences}, volume = {}, number = {}, pages = {09727531251357377}, pmid = {40746624}, issn = {0972-7531}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons and is characterised by a diverse range of clinical manifestations. With the understanding of its pathophysiology, many treatments have emerged in last two decades. This study aims to evaluate the impact of intravenous Edaravone on Amyotrophy Lateral Sclerosis Functional Rating Scale (ALS-FRS) scores and patient survival outcomes of Amyotrophic Lateral Sclerosis patients in Central India.

METHODS: This retrospective study was conducted over a span of 2.5 years and included patients diagnosed with definitive or probable ALS, as per the revised El Escorial criteria. The effects of intravenous (IV) Edaravone on ALS-FRS-R scores were compared between two groups: the intervention group (patients who received IV Edaravone) and the non-intervention group (patients who did not receive IV Edaravone). Data collected included demographic details and ALS-FRS-R scores that were recorded at baseline after each treatment cycle, for a total six cycles. These scores were compared with those of the control group at the corresponding time points. Survival outcomes were also evaluated between the two groups and side effect profile of the drug was also noted.

RESULTS: Data of ALS patients (definitive and probable) were screened, and 62 patients were enrolled, of which 12 were excluded, thus there were 25 ALS patients in the intervention group and 25 patients in the non-intervention group. The two groups were matched for demographic parameters and the ALS-FRS scores were noted at the baseline at each cycle till 6 cycles and compared. It was inferred that the scores were not significant statistically (p > .001) among the two groups, nor did the survival rates vary significantly.

CONCLUSION: Intravenous Edaravone therapy had no beneficial effect on the ALS-FRS score in the intervention group when compared to the non-intervention group, nor did the survival rates improve. Keywords: Amyotrophic lateral sclerosis, Edaravone Therapy, ALS FRS Score.}, } @article {pmid40747225, year = {2025}, author = {Li, J and Wang, W}, title = {Challenges of Klebsiella pneumoniae infections post-liver transplantation: Insights and future directions.}, journal = {World journal of hepatology}, volume = {17}, number = {7}, pages = {107213}, pmid = {40747225}, issn = {1948-5182}, abstract = {Klebsiella pneumoniae infections (KPIs), particularly carbapenem-resistant Klebsiella pneumoniae (CRKP), pose significant challenges in liver transplantation (LT) recipients, with high morbidity and mortality. Guo et al's study highlights risk factors, such as elevated day-one alanine aminotransferase levels and prolonged catheterization, and identifies polymyxin B and ceftazidime/avibactam as effective treatments. However, limitations like the absence of pre-transplant colonization data and host-pathogen interaction insights highlight the need for enhanced strategies. Future directions should include routine CRKP colonization surveillance, immune and genomic profiling, and the development of novel therapeutics. By integrating these approaches, we can improve the prevention, diagnosis, and treatment of KPIs in LT patients.}, } @article {pmid40747386, year = {2025}, author = {Arnold, WD and Castoro, R and Saxena, S}, title = {Innovations In Physical Medicine and Rehabilitation: Advances in the Diagnosis, Treatment, and Care of Amyotrophic Lateral Sclerosis.}, journal = {Missouri medicine}, volume = {122}, number = {3}, pages = {199-205}, pmid = {40747386}, issn = {0026-6620}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/rehabilitation ; *Physical and Rehabilitation Medicine/trends/methods ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that causes loss of upper and lower motor neurons, leading to muscle weakness and ultimately death. This review highlights recent advancements in Neuromuscular Medicine and Physical Medicine and Rehabilitation (PM&R), emphasizing innovations in the diagnosis, treatment, and care delivery for ALS. The field of PM&R emphasizes a multidisciplinary, patient-centered approach, incorporating advanced diagnostic tools, therapeutic strategies, adaptive equipment, and telerehabilitation to optimize function. Neuromuscular PM&R physicians play a key role in managing symptoms and maximizing functional independence. Current disease-modifying therapies include riluzole and edaravone which provide only modest benefits, but emerging gene therapies like tofersen for SOD1-related ALS offer promise for targeted treatment for genetic forms of ALS. Future advancements in regenerative therapies, biotechnologies, and digital health integration hold the potential to improve care and enhance the quality of life and functional independence of individuals living with ALS.}, } @article {pmid40750607, year = {2025}, author = {Nógrádi, B and Molnár, K and Kristóf, R and Horváth, O and Huang, YT and Ridgway, Z and Elicegui, A and Fuertes-Alvarez, S and Alonso-Martin, S and Szebeni, GJ and Gémes, N and Ramadan, A and Smith, HL and Krizbai, IA and Patai, R and Siklós, L and Klivényi, P and Chaytow, H and Gillingwater, TH}, title = {The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7053}, pmid = {40750607}, issn = {2041-1723}, support = {2021/MNDS/RP/8430GILL//MND Scotland (Motor Neuron Disease Scotland)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism/genetics ; *Receptors, CCR2/metabolism/genetics/immunology ; Animals ; *Chemokine CCL2/metabolism/immunology/genetics ; Humans ; Male ; *Neuromuscular Junction/pathology/metabolism/immunology ; Mice ; Muscle, Skeletal/pathology/metabolism/innervation/immunology ; Disease Models, Animal ; Macrophages/immunology/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Female ; Mice, Transgenic ; Leukocytes/immunology/metabolism ; }, abstract = {Systemic immune changes have been implicated in amyotrophic lateral sclerosis (ALS), but precise mechanisms and cellular targets remain unknown. Neuromuscular junction (NMJ) denervation is another major pathophysiological event in ALS, but it remains unclear whether immune system dysregulation contributes to this process. Here, we report leukocyte and macrophage infiltration in ALS patient-derived skeletal muscle biopsies. Immune cell infiltration was replicated across the hTDP-43, TDP-43[A315T] (male only) and TDP-43[M337V] mouse models, occurring from pre-symptomatic stages and targeted to NMJ-enriched muscle regions. Proteomic analysis implicated the CCL2-CCR2 axis as a driving factor. CCL2[+] cells were enriched around NMJs in hTDP-43 mice, and in ALS patient skeletal muscle. Local treatment with CCL2-neutralising antibodies or normal IgG antibodies in hTDP-43 mice reduced leukocyte infiltration and ameliorated NMJ denervation. These results demonstrate that the CCL2-CCR2 axis drives immune cell infiltration targeting NMJs in ALS, identifying a potential avenue for therapeutic intervention to prevent NMJ denervation.}, } @article {pmid40754996, year = {2025}, author = {Stam, R}, title = {Low frequency magnetic field exposure and neurodegenerative disease: systematic review of animal studies.}, journal = {Electromagnetic biology and medicine}, volume = {44}, number = {4}, pages = {566-580}, doi = {10.1080/15368378.2025.2540435}, pmid = {40754996}, issn = {1536-8386}, mesh = {Animals ; *Magnetic Fields/adverse effects ; *Neurodegenerative Diseases/etiology/pathology/therapy ; Humans ; Disease Models, Animal ; }, abstract = {Epidemiological studies have found an association between occupational exposure to low frequency magnetic fields and the occurrence of motor neuron disease and Alzheimer's disease. No association has been found for Parkinson's disease and the evidence for multiple sclerosis is insufficient. Animal models studying the effects of low frequency magnetic fields on neurodegenerative disease induction or progression could provide more evidence on causation and the underlying mechanisms. A systematic search and review was conducted of peer-reviewed research articles involving animal experiments on the effects of low frequency magnetic field exposure on behavioural and neuroanatomical outcomes relevant for neurodegenerative diseases in humans. Firstly, experimental studies in naive animals do not support a causal relationship between exposure to low frequency magnetic fields and the induction of neuropathology relevant for Alzheimer's disease, but the number of studies relevant for motor neuron disease, multiple sclerosis and Parkinson's disease is too limited to draw conclusions. Secondly, experimental studies in existing animal models for neurodegenerative disease support a therapeutic (beneficial) effect of low frequency magnetic field treatment on behavioural and neuroanatomical abnormalities relevant for dementia (including Alzheimer's disease), multiple sclerosis and Parkinson's disease and no effect on disease progression in models relevant for motor neuron disease.}, } @article {pmid40760594, year = {2025}, author = {Zhang, Q and Zhou, X and Yang, G and Zhang, L}, title = {Atopic dermatitis in amyotrophic lateral sclerosis successfully treated by dupilumab: A case report.}, journal = {Medicine}, volume = {104}, number = {31}, pages = {e43737}, pmid = {40760594}, issn = {1536-5964}, mesh = {Humans ; Male ; Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/complications ; *Dermatitis, Atopic/drug therapy/complications ; Pruritus/drug therapy/etiology ; }, abstract = {RATIONALE: Atopic dermatitis (AD) is a common skin disorder characterized by symmetric erythematous papules in flexural areas, with pruritus of varying intensity persisting throughout its course. Amyotrophic lateral sclerosis (ALS) is a neurological disease with progressive loss of muscle function, and its treatment remains a challenge worldwide. When patients suffer from both conditions, the skin issues are often overlooked by both physicians and family members. However, the pruritus becomes unbearable for the patients, particularly as they experience a progressive loss of the ability to scratch autonomously.

PATIENT CONCERNS: An elderly 75-year-old male patient with comorbid ALS and AD, suffering from prolonged pruritus, had lost faith in all topical and oral medications.

DIAGNOSIS: AD and ALS.

INTERVENTIONS: The patient received subcutaneous dupilumab with an initial 600 mg dose followed by 300 mg every 2 weeks, and was monitored for 12 weeks during follow-up.

OUTCOMES: The patient exhibited gradual reduction in pruritus severity and skin lesions throughout the treatment course. No adverse reactions other than mild conjunctivitis were reported.

LESSONS: This case demonstrates the successful application of dupilumab in an AD patient with comorbid ALS. It not only provides a clinically instructive case reference for dupilumab therapy in AD, but also underscores that pruritus in ALS patients warrants greater clinical attention.}, } @article {pmid40760788, year = {2025}, author = {Ke, S and Yan, J and Li, B and Feng, X}, title = {Causal Association Between Immune Cell Traits and Risk of Multiple Malignant and Nonmalignant CNS Diseases: A Mendelian Randomization and Single-Cell Transcriptomic Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70632}, pmid = {40760788}, issn = {2162-3279}, mesh = {Humans ; Mendelian Randomization Analysis ; Single-Cell Analysis ; Quantitative Trait Loci/genetics ; Glioblastoma/genetics/immunology ; *Central Nervous System Diseases/genetics/immunology ; Transcriptome ; Gene Expression Profiling ; Brain Neoplasms/genetics/immunology ; }, abstract = {BACKGROUND: The influence of immune cell traits (ICTs) on the onset of multiple brain diseases has been previously investigated; however, it is limited by the sample size or colocalization evidence. Besides, the impact remains inconclusive.

METHODS: We performed a Mendelian randomization (MR) study to elucidate the causal correlation between significant ICTs and diverse brain disorders and explored the biomarkers linked to glioblastoma (GBM), a form of solid tumor, by integrating expression quantitative trait locus (eQTL) and single-cell RNA sequencing (scRNA-seq) analyses. The nonnegative matrix factorization (NMF) method was utilized to reclassify malignant cells into distinct cell states. Related functional analyses at the scRNA-seq level were also performed.

RESULTS: We examined 731 ICTs across 13 brain disorders; impacts from these ICTs varied a lot across different brain diseases. Such ICTs mainly involved T/natural killer (NK) cell activation, B cell differentiation, and myeloid cell suppression or activation. Pleiotropy or heterogeneity in current results has been checked and excluded via sensitivity analyses. Specifically, colocalization analyses demonstrated protective roles of distinct ICTs in T/B/NK cell panels for amyotrophic lateral sclerosis (ALS) and GBM, while myeloid and human leukocyte antigen (HLA)-associated traits were associated with increased risk of Alzheimer's disease (AD), and then two memory cell traits were linked to the increased risk of major depressive disease (MDD). By NMF, we identified six distinct cell states within GBM cells. Furthermore, we established an eight-marker glioblastoma risk signature (GBRS) using scRNA-seq and eQTL data, with higher GBRS scores observed in the NFkB cluster and EGFR cluster, indicating their highlighted aggression among malignant cells. Epigallocatechin gallate could be an effective treatment candidate targeting the EGFR cluster via markers of SQLE and VCP.

CONCLUSION: Our findings identified causal effects of distinct ICTs on both malignant and nonmalignant brain diseases and underscored the pivotal role of neuroinflammation in their etiology. With combined evidence from eQTL and scRNA-seq, GBM could be better characterized and managed.}, } @article {pmid40771035, year = {2026}, author = {Hattori, N and Mukai, Y and Nishikawa, N and Hasegawa, K and Tomiyama, M and Kimura, Y and Tsuboi, Y and Takahashi, R and Nakamura, R and Izumi, Y and Watanabe, H and Seki, M and Sekiguchi, K and Tateishi, S and Matsushita, Y and Nakamura, Y}, title = {Efficacy and Safety of IncobotulinumtoxinA for Treatment of Sialorrhea: A Multicenter, Phase 3 Study in Japan.}, journal = {Movement disorders clinical practice}, volume = {13}, number = {1}, pages = {120-130}, pmid = {40771035}, issn = {2330-1619}, support = {//Teijin Pharma/ ; }, mesh = {Humans ; *Sialorrhea/drug therapy/etiology ; *Botulinum Toxins, Type A/adverse effects/therapeutic use/pharmacology/administration & dosage ; Male ; Female ; Middle Aged ; Japan ; Aged ; *Neuromuscular Agents/adverse effects/therapeutic use ; Adult ; Treatment Outcome ; }, abstract = {BACKGROUND: Sialorrhea, caused by various neurological diseases, impairs patient health and quality of life. After the results of a randomized controlled trial, incobotulinumtoxinA was approved for the treatment of chronic sialorrhea in the United States and Europe; however, no pharmacotherapy has been approved in Japan.

OBJECTIVE: The aim was to evaluate the efficacy and safety of incobotulinumtoxinA treatment for chronic sialorrhea in a single-arm phase 3 study in Japan.

METHODS: Patients with chronic sialorrhea caused by neurological diseases (Parkinson's disease, atypical parkinsonism, and stroke, group A) and broader diseases (eg, muscular dystrophy and amyotrophic lateral sclerosis, group B) were enrolled. IncobotulinumtoxinA 100 U was injected into the salivary glands once every 16 weeks for 48 weeks. A primary endpoint was assessed in group A, whereas secondary endpoints and safety were assessed in both groups.

RESULTS: From November 2021 to August 2023, 92 patients (58 and 34 in groups A and B, respectively) received incobotulinumtoxinA at 28 institutions. The primary endpoint, the least square mean (standard error) of change in unstimulated salivary flow rate from baseline to 4 weeks, was -0.08 (0.009, 95% confidence interval [CI]: -0.10, -0.06) g/min, achieving the prespecified efficacy criteria (upper limit of the 95% CI <-0.04). The secondary endpoints were consistent across efficacy measures, indicating that reduced salivary secretion and improved drooling symptoms persisted for 48 weeks. The most common adverse events were dry mouth and dysphagia.

CONCLUSIONS: The first study in Japan confirmed the efficacy of incobotulinumtoxinA treatment for chronic sialorrhea with good patient tolerability and no new safety concerns.}, } @article {pmid40771731, year = {2025}, author = {Shi, DD and Tian, J and Ding, J}, title = {Adenosine deaminase in pleural effusion: Bridging diagnosis and the pathophysiology of inflammation.}, journal = {World journal of clinical cases}, volume = {13}, number = {22}, pages = {106925}, pmid = {40771731}, issn = {2307-8960}, abstract = {This editorial underscores the importance of Maranhão et al's study, which investigates pleural adenosine deaminase (P-ADA) as a biomarker for inflammatory pleural effusions. Despite advances in imaging, distinguishing between inflammatory and non-inflammatory causes of pleural effusion remains a diagnostic challenge. The authors conducted a rigorous retrospective cohort analysis of 157 patients (124 with inflammatory exudates and 33 with non-inflammatory transudates), establishing a robust cutoff value of P-ADA ≥ 9.00 U/L for diagnosing inflammatory diseases using receiver operating characteristic curve analysis and internal statistical calibration. This is the first study to define a standardized P-ADA threshold in a Brazilian cohort, addressing previous inconsistencies in cutoff values. Furthermore, the authors delved into the pathophysiological mechanisms underlying elevated P-ADA, linking it to purinergic signaling pathways and immune cell activation, particularly emphasizing the role of ADA2 isoforms in macrophages and lymphocytes. Their findings support P-ADA as a non-invasive, cost-effective biomarker for early diagnosis, treatment stratification, and minimizing the need for invasive procedures such as thoracentesis. This has particular relevance in resource-limited settings, where streamlined diagnostics can reduce healthcare costs and improve patient outcomes. Future studies must prioritize global validation, explore the integration of adenosine deaminase with additional biomarkers (e.g., interleukin 6, C-reactive protein), and support the development of point-of-care technologies.}, } @article {pmid40781905, year = {2025}, author = {Steffke, C and Baskar, K and Bachhuber, F and Wiesenfarth, M and Dorst, J and Schuster, J and Schöberl, F and Reilich, P and Regensburger, M and German, A and Günther, R and Vidovic, M and Petri, S and Meyer, T and Hagenacker, T and Grosskreutz, J and Weyen, U and Weydt, P and Haarmeier, T and Lingor, P and Wolf, J and Hermann, A and Prudlo, J and Günther, K and Knehr, A and Elmas, Z and Uzelac, Z and Witzel, S and Ruf, WP and Freischmidt, A and Ho, R and Ludolph, AC and Weishaupt, JH and Tumani, H and Oeckl, P and Brenner, D and Catanese, A}, title = {Targeted Proteomics upon Treatment with Tofersen Identifies Novel Response Markers for Superoxide Dismutase 1-Linked Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {98}, number = {6}, pages = {1318-1334}, pmid = {40781905}, issn = {1531-8249}, support = {SFB 1506//Deutsche Forschungsgemeinschaft/ ; Ca2/1//Deutsche Gesellschaft für Muskelkranke/ ; AlamarNeurologyGrant//Alamar Biosciences/ ; Exzellenzstipendium2022_EKES.18//Else Kröner-Fresenius-Stiftung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics/blood ; Male ; Female ; Middle Aged ; *Proteomics/methods ; *Superoxide Dismutase-1/genetics ; Biomarkers/cerebrospinal fluid/blood ; Aged ; Adult ; Neurofilament Proteins/cerebrospinal fluid ; Longitudinal Studies ; }, abstract = {OBJECTIVE: Tofersen is the first effective and approved therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS [SOD1-ALS]). Following treatment with tofersen, neurofilament levels in patients' cerebrospinal fluid (CSF) and serum seem to respond earlier than clinical parameters. This evidence prompted us to hypothesize that this novel treatment could provide an opportunity to identify additional biomarkers responsive to therapy in SOD1-ALS.

METHODS: We investigated a panel of 120 neural, glial, and inflammatory markers in CSF and serum samples longitudinally collected from a total of 28 SOD1-ALS patients at baseline, and after 3, 6 and 12 months of treatment with tofersen, followed by validation with conventional methodology.

RESULTS: We identified a set of proteins, including neurofilament light chain, neurofilament heavy chain, amyloid-beta 1-40 and amyloid-beta 1-42, neuropeptide Y (NPY), and ubiquitin C-terminal hydrolase L1 (UCHL1), whose CSF levels both differed between SOD1-ALS and the control group, and were responsive to tofersen at 3 and 6 months after treatment initiation. Another group of markers, including the neuropentraxin (NPTX) family members NPTX1, NPTX2 and NPTXR, did not separate untreated SOD1-ALS from controls, but was responsive to tofersen. At 12 months on tofersen the levels of neurofilament light chain, neurofilament heavy chain, NPTX1, NPTX2, and NPTXR remained reduced compared with baseline, and correlated with the clinical response to tofersen. Consistent with increasing CSF pleocytosis and intrathecal immunoglobulin production, inflammatory markers were significantly increased after 12 months of treatment.

INTERPRETATION: Our results highlight a complex, time-dependent differential response of CSF biomarkers to tofersen treatment, and may pave the way for developing a panel of responsive proteins to make biomarker endpoints more robust in clinical trials for SOD1-ALS and beyond. ANN NEUROL 2025;98:1318-1334.}, } @article {pmid40787733, year = {2025}, author = {Raaphorst, J and Gullick, NJ and Shokraneh, F and Brassington, R and Min, M and Ali, SS and Gordon, PA}, title = {Non-targeted immunosuppressive and immunomodulatory therapies for idiopathic inflammatory myopathies.}, journal = {The Cochrane database of systematic reviews}, volume = {8}, number = {8}, pages = {CD015855}, pmid = {40787733}, issn = {1469-493X}, mesh = {Humans ; *Myositis/drug therapy ; *Immunosuppressive Agents/therapeutic use/adverse effects ; Randomized Controlled Trials as Topic ; Dermatomyositis/drug therapy ; *Immunomodulating Agents/therapeutic use/adverse effects ; Bias ; Child ; Adult ; Polymyositis/drug therapy ; }, abstract = {BACKGROUND: Idiopathic inflammatory myopathies (IIM) are autoimmune-mediated inflammatory disorders of skeletal muscles with non-muscle involvement in some people, which carry significant morbidity and mortality. Treatment of IIM represents an area of unmet need. This review is an update of a review previously published in 2012, as new and promising data on non-targeted treatments have emerged.

OBJECTIVES: To assess the effects (benefits and harms) of non-targeted immunosuppressant and immunomodulatory treatments for IIM: dermatomyositis (DM, including juvenile dermatomyositis, jDM), immune-mediated necrotising myopathy (IMNM), anti-synthetase syndrome (ASS), overlap-myositis (OM) and polymyositis (PM). We also included cancer-related myositis and amyopathic dermatomyositis.

SEARCH METHODS: On 3 February 2023, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, Embase, MEDLINE, ClinicalTrials.gov and WHO ICTRP. We intended to check references and citations, and contact experts to identify additional studies, but lacked the resources.

SELECTION CRITERIA: We included all randomised controlled trials (RCTs) or quasi-RCTs involving participants (adults and children) with IIM according to defined criteria. We included non-targeted immunosuppressants and immunomodulatory treatments alone or in combination, compared with a placebo, no treatment or another non-targeted immunosuppressant or immunomodulatory treatment. Our two primary outcomes were improvement of function or disability and improvement of muscle strength compared with baseline. By preference, we used the Health Assessment Questionnaire Disability Index (HAQ-DI) for disability and the Manual Muscle Test-8 (MMT8) score (adults or children) for muscle strength. Other outcomes were achievement of definitions of improvement (DOI) (the International Myositis Assessment and Clinical Studies (IMACS) Group or the more recent total improvement scores (TIS); for children, we reported achievement of improvement defined by the Paediatric Rheumatology International Trials Organisation (PRINTO)), cumulative corticosteroid dose, change in skin disease activity, serious adverse event and withdrawals for lack of benefit or adverse events.

DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess the risk of bias, we used the domain-based Cochrane risk of bias tool (RoB 1). We used fixed-effect models and, when needed, random-effects models for meta-analysis. We created summary of findings tables for any comparison for which data were available but prioritised comparisons of the following with placebo, no treatment or standard care: immunoglobulin, azathioprine and methotrexate. We included other comparisons as additional tables. We assessed the certainty of evidence using the GRADE approach.

MAIN RESULTS: We identified 16 studies (789 participants). The risk of bias in all but one study was high or unclear. Intravenous immunoglobulin (IVIg), compared to placebo, probably improves disability and muscle strength in participants with refractory IIM (standardised mean difference (SMD) 0.86, 95% confidence interval (CI) 0.51 to 1.21 (disability) and 0.78, 95% CI 0.43 to 1.13 (muscle strength); 3 RCTs, 136 participants; both moderate-certainty evidence). IVIg has a higher response rate based on American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria than placebo (risk ratio (RR) 1.80, 95% CI 1.26 to 2.56; 1 RCT, 95 participants; moderate-certainty evidence). IVIg, compared to placebo, improves skin symptoms (Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) total activity score 0 to 100; higher worse) in people with refractory DM (mean difference (MD) -8.20, 95% CI -11.91 to -4.49; 1 RCT, 95 participants; moderate-certainty evidence). There may be more serious adverse events with IVIg than with placebo (RR 1.91, 95% CI 0.50 to 7.30; 2 RCTs, 144 participants; very low-certainty evidence), but little or no difference between IVIg and placebo in withdrawals for either lack of benefit or adverse events (RR 1.02, 95% CI 0.24 to 4.33; 3 RCTs, 154 participants; very low-certainty evidence). For azathioprine versus placebo, one study showed little or no effect of azathioprine on improvement in muscle strength, but the evidence was very uncertain (RR 1.33, 95% CI 0.43 to 4.13; 1 RCT; 16 participants; very low-certainty evidence). The evidence was also very uncertain for cumulative steroid dose (MD 12.06 mg/kg, 95% CI -6.09 to 30.21; 1 RCT, 16 participants; very low-certainty evidence). This early study did not assess IMACS DOI or CDASI or measure function or disability. Serious adverse events and withdrawals for either lack of benefit or adverse events were not systematically reported. For methotrexate, there may be little or no improvement in adults with DM or PM in function (Amyotrophic Lateral Sclerosis Functional Rating Scale 0 to 40, higher better) (MD 1.24, 95% CI -1.60 to 4.08; 1 RCT, 27 participants; very low-certainty evidence), muscle strength (MMT scale 0 to 80, higher better) (MD -5.68, 95% CI -12.94 to 1.58; 1 RCT, 27 participants; very low-certainty evidence), achievement of IMACS DOI (RR 1.01, 95% CI 0.74 to 1.39; 1 RCT, 27 participants; very low-certainty evidence). Cumulative steroid dose was measured, but the data could not be analysed, and change in CDASI was not measured. In children with new-onset jDM on a background therapy of prednisone, a higher proportion may achieve minimal improvement according to the PRINTO criteria with methotrexate than with placebo (RR 1.40, 95% CI 1.01 to 1.96; 1 RCT, 93 participants; low-certainty evidence). Serious adverse events may occur slightly more frequently with methotrexate (RR 1.48, 95% CI 0.54 to 4.07; 2 RCTs, 124 participants; low-certainty evidence). There may be fewer withdrawals for lack of benefit or adverse events with methotrexate (RR 0.62, 95% CI 0.37 to 1.05; 3 RCTs, 151 participants; low-certainty evidence).

AUTHORS' CONCLUSIONS: Our review shows improvement in disability, muscle strength and skin symptoms following IVIg in people with refractory DM (for PM, these data are not reliable; other subtypes have not been investigated in RCTs). The improvements related to IVIg in DM may be clinically meaningful, but the absence of established minimal clinically important differences (MCIDs) for both disability and muscle strength in IIM does not facilitate interpretation. For the other agents, the small number of trials of immunosuppressive and immunomodulatory therapies is inadequate to decide whether these agents are beneficial in IIM (excluding IBM). Our review shows room for improvement in the conduct and reporting of clinical trials in IIM, as well as the need to further investigate MCIDs for important outcome measures in IIM.}, } @article {pmid40788112, year = {2025}, author = {Guha, A and Si, Y and Smith, R and Singh, BK and Zogu, B and Yadav, A and Smith, KA and Kazamel, M and Jiang, N and Ho, R and Thalacker-Mercer, A and Andrabi, SA and Da Silva Pereira, JDT and Salgado, JS and Agrawal, M and Velic, EH and King, PH}, title = {The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.}, journal = {Aging}, volume = {17}, number = {8}, pages = {2033-2062}, pmid = {40788112}, issn = {1945-4589}, support = {R21 NS111275/NS/NINDS NIH HHS/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; I01 BX006231/BX/BLRD VA/United States ; T32 NS095775/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Fibroblast Growth Factors/metabolism/genetics/blood ; Animals ; Mice ; *Oxidative Stress ; Male ; Female ; *Muscle, Skeletal/metabolism/pathology ; Middle Aged ; Spinal Cord/metabolism/pathology ; Mice, Transgenic ; Aged ; Klotho Proteins ; Superoxide Dismutase-1/genetics/metabolism ; Myokines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1[G93A] mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho, with higher levels detected in ALS muscle biopsies and lower levels in post-mortem muscle compared to controls. Plasma FGF21 levels were increased in ALS patients and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In cellulo, FGF21 was induced in differentiating muscle cells and ectopic treatment with FGF21 enhanced muscle differentiation. Ectopic FGF21 mitigated oxidative stress-induced loss of viability in iPSC-derived ALS motor neurons and muscle cells expressing SOD1[G93A]. In summary, FGF21 is a novel biomarker in ALS which exerts trophic effects in the neuromuscular system.}, } @article {pmid40794238, year = {2026}, author = {Jellinger, KA}, title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {133}, number = {5}, pages = {831-841}, pmid = {40794238}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Supranuclear Palsy, Progressive/epidemiology/pathology ; Comorbidity ; }, abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.}, } @article {pmid40795306, year = {2026}, author = {Guo, J and Zou, Q and Xu, J and Lei, J and Yin, X and Li, B and Fu, J and Mi, J and Wang, Y and Huang, H and Zhang, CY and Chen, X}, title = {In vivo self-assembled SOD1-siRNAs mitigate muscle atrophy and denervation in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {785-800}, pmid = {40795306}, issn = {1460-2156}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/complications ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Mice ; *RNA, Small Interfering/administration & dosage/genetics ; *Muscular Atrophy/genetics/therapy/etiology/pathology ; Humans ; Disease Models, Animal ; Extracellular Vesicles/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the death of both upper and lower motor neurons. Approximately 20% of familial ALS cases are associated with mutations in the superoxide dismutase type 1 (SOD1) gene. Developing a specific strategy to characteristically silence the pathogenic SOD1 gene remains a crucial goal amidst significant challenges. In this study, we developed a synthetic biology strategy to reprogramme the liver as a tissue chassis for the in vivo self-assembly of small extracellular vesicles (sEVs)-encapsulated SOD1-siRNA, aiming to target spinal neurons and silence mutant SOD1 specifically in Tg(SOD1G93A) transgenic mice. We designed a cytomegalovirus (CMV) promoter-directed synthetic construct to encode a SOD1-siRNA along with a neuron-targeting rabies virus glycoprotein (RVG) tagged on the sEV surface. Theoretically, upon liver uptake, this construct reprogrammes liver cells to generate and self-assemble SOD1-siRNAs into RVG-tagged sEVs. Subsequently, the sEV-encapsulated SOD1-siRNAs are transported via the endogenous sEV circulation and guided by the RVG tag to the spinal neurons. Experimental results illustrated that intravenous administration of this synthetic construct effectively facilitated in vivo self-assembly of SOD1-siRNAs into circulating sEVs. The functional delivery of SOD1-siRNAs to the spinal cord and cerebral cortex was confirmed through in vivo tracking of sEVs and sEV-encapsulated siRNAs. Treatment of Tg(SOD1G93A) transgenic mice with this construct significantly reduced mutant SOD1 protein levels in the spinal cord and cerebral cortex. Consequently, the characteristic symptoms of ALS, including decreased body weight, shortened lifespan, compromised motor function, muscle atrophy, neuroinflammation, motor neuron loss and neuromuscular junction degeneration, were substantially ameliorated by the synthetic construct. Furthermore, an AAV-based strategy was devised for the enduring self-assembly of sEV-encapsulated SOD1-siRNA, whereby a single injection led to substantial and sustained inhibition of mutant SOD1 and significant symptom amelioration in transgenic mice. Overall, this study established an effective and convenient therapeutic approach for mitigating muscle atrophy and denervation in animal model, presenting a promising solution for future ALS treatment.}, } @article {pmid40806469, year = {2025}, author = {Wang, J and Shen, Y and Liao, P and Yang, B and Jiang, R}, title = {Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806469}, issn = {1422-0067}, support = {82401445//National Natural Science Foundation of China/ ; 82271249//National Natural Science Foundation of China/ ; 2024M752251//China Postdoctoral Science Foundation/ ; 2024NSFSC1636//Sichuan Science and Technology Program/ ; 2024HXBH013//Post doctor Research Fund of West China Hospital of Sichuan University/ ; ZYYC23002//1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University/ ; GZC20241141//Postdoctoral Fellowship Program of CPSF/ ; }, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Oligodendrocyte Precursor Cells/metabolism/pathology ; Oligodendroglia/metabolism ; Cell Differentiation ; }, abstract = {Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.}, } @article {pmid40806624, year = {2025}, author = {Șerban, M and Toader, C and Covache-Busuioc, RA}, title = {The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806624}, issn = {1422-0067}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/therapy/drug therapy ; *Artificial Intelligence ; Oxidation-Reduction ; Antioxidants/therapeutic use/pharmacology ; Biomarkers/metabolism ; *Precision Medicine/methods ; Animals ; Reactive Oxygen Species/metabolism ; Brain/metabolism ; Multiomics ; }, abstract = {Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.}, } @article {pmid40807333, year = {2025}, author = {Godela, A and Rogacz, D and Pawłowska, B and Biczak, R}, title = {Natural Neuroinflammatory Modulators: Therapeutic Potential of Fungi-Derived Compounds in Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {15}, pages = {}, pmid = {40807333}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Fungi/chemistry ; *Biological Products/therapeutic use/pharmacology/chemistry ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients' quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds-such as phenolic compounds, carbohydrates, peptides and proteins, and lipids-that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms.}, } @article {pmid40808471, year = {2025}, author = {Zhang, L and Cai, L and Lin, H and Wu, W and Zhu, Y and Cai, J and Hu, C and Lin, X and Sun, H and Wei, X}, title = {Two Birds With One Stone: The Protective Role of the Antidiabetic Drug Sodium-Glucose Cotransporter-2 Inhibitor in Neurodegenerative Diseases.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70221}, doi = {10.1111/ejn.70221}, pmid = {40808471}, issn = {1460-9568}, support = {2021J01397//Natural Science Foundation of Fujian, China/ ; 2022GGA010//Fujian Provincial Health Technology Project/ ; 2023Y9347//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9298//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9343//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; }, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/genetics/drug therapy ; Polymorphism, Single Nucleotide ; Sodium-Glucose Transporter 2/genetics ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; Mendelian Randomization Analysis ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; Genome-Wide Association Study ; Protein Interaction Maps ; }, abstract = {The neuroprotective role of sodium-glucose cotransporter-2 inhibitor (SGLT2i) has attracted considerable interest. The purpose of this study was to investigate the role of SGLT2i in several common neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Utilizing drug-target Mendelian randomization (MR) and colocalization, we used single nucleotide polymorphisms (SNPs) proximal to the SLC5A2 gene to analyze the influence of SGLT2i on AD, PD, ALS, and MS. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Phenome-wide association study (PheWAS) was used to probe the relationship of SGLT2i with other characteristics. Protein-protein interaction (PPI) networks were used to explore how SLC5A2 affects other proteins, and enrichment analysis was used to explore possible biological processes. The MR analysis showed that SGLT2i was negatively associated with AD (OR = 0.77, p = 0.01), PD (OR = 0.52, p = 0.04), ALS (OR = 0.60, p = 0.01), and MS (OR = 0.33, p = 0.027), indicating that SGLT2i could reduce the risk of AD by 23%, PD by 48%, ALS by 40%, and MS by 67%. The colocalization supported this conclusion. The PheWAS showed that SGLT2i was associated with body mass index and systolic blood pressure. SGLT2i is biologically closely related to the development of NDs. This study suggested that SGLT2i was able to reduce the risk of NDs. SGLT2i may perform this process through many mechanisms. This study provides a new perspective on the treatment of NDs; clinical trials and relevant experiments are necessary to further validate the neuroprotective effects of SGLT2i.}, } @article {pmid40810164, year = {2025}, author = {Alo, B and Lamers, C}, title = {Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2353-2383}, pmid = {40810164}, issn = {2575-9108}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood-brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood-brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood-brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood-brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such in vitro and in vivo testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.}, } @article {pmid40812017, year = {2025}, author = {Chahal, S and Debnath, A and Kumari, R and Ridhal, P and Sahoo, RK and Biswal, BK and Mishra, A and Siwach, P}, title = {Antihypertensive potential of diosgenin: A comparative pharmacoinformatics study.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt C}, pages = {110911}, doi = {10.1016/j.compbiomed.2025.110911}, pmid = {40812017}, issn = {1879-0534}, mesh = {Humans ; *Diosgenin/chemistry/pharmacology ; *Molecular Docking Simulation ; *Antihypertensive Agents/chemistry/pharmacology ; Molecular Dynamics Simulation ; *Receptor, Angiotensin, Type 1/chemistry/metabolism ; }, abstract = {The angiotensin II type 1 receptor (AT1R) is an important target protein involved in the regulation of hypertension, a major public health concern affecting 1.28 billion individuals globally. The existing drugs have serious side-effects on medium to long term use, and therefore, search for safer and more effective drug molecules is highly needed. This study explores the antihypertensive potential of thirty-six natural terpenoids targeting the AT1R, with Allisartan isoproxil (active form, LCA) used as a positive control. After initial screening based on the Lipinski rule of five and in silico ADMET profiling, twenty-five terpenoids were selected for molecular docking studies. Diosgenin and Neoandrographolide emerged as lead compounds with superior binding affinities compared to std. drug, LCA. Diosgenin's favorable non-toxic profile (class 6) and significant molecular interactions with critical amino acids in AT1R make it a strong candidate for further validation through MD studies. Molecular dynamics simulations at a microsecond revealed protein stability by reducing fluctuations, a compact and more stable contact exhibited by Diosgenin. Furthermore, MM-PBSA analysis showed a stronger binding affinity and thermodynamic stability of Diosgenin compared to LCA. Diosgenin exhibited no cytotoxicity in HaCaT normal keratinocyte cells at concentrations up to 22 μM (24 h) and 20 μM (48 h), as determined by in vitro validation, indicating its safety for further therapeutic evaluation. Additionally, PPI network and hub genes analysis identified potential molecular targets for Diosgenin, including SRC, ABL1, IGF1R, and JAK2, suggesting possible mechanistic role. Diosgenin is a promising natural therapeutic candidate for hypertension treatment, which could regulate vascular function, smooth muscle cell activity, and endothelial function via various mechanisms by influencing IGF1R, JAK2, KIT, MDM2, MET, and IL2 demonstrated through KEGG pathway analysis.}, } @article {pmid40821619, year = {2023}, author = {Kao, TH and Perry, BJ}, title = {The Current State and Future Directions of Swallowing Care in Amyotrophic Lateral Sclerosis.}, journal = {Current physical medicine and rehabilitation reports}, volume = {11}, number = {2}, pages = {199-211}, pmid = {40821619}, issn = {2167-4833}, support = {K23 NS123369/NS/NINDS NIH HHS/United States ; L30 NS123988/NS/NINDS NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: Difficulty swallowing (dysphagia) is of great concern to patients with ALS as its complications can increase mortality and reduce the quality of life. This review aims to provide an overview of the recent developments and the current state of assessment, treatment, and management of dysphagia in ALS.

RECENT FINDINGS: The optimal timing of assessment, treatment, and management of dysphagia may be early in the ALS disease process, even before the dysphagia occurs. There is wide heterogeneity in SLP practice patterns for the management of dysphagia.

SUMMARY: Dysphagia is common and debilitating; however, for various reasons, there is no clear consensus on how best to manage dysphagia in this population. Future work centered around predicting swallowing decline and improving interventions aimed at prolonging swallowing function in the early stages of the disease process may promote improved dysphagia care.}, } @article {pmid40821656, year = {2025}, author = {Sanghai, N and Tranmer, GK}, title = {Use of Proteomics to Explore Biomarkers of Amyotrophic Lateral Sclerosis (ALS): Proof of Principle from Humanized SOD1 Mouse to Human ALS.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2415-2430}, pmid = {40821656}, issn = {2575-9108}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disease affecting multiple cellular proteins during the progression of the disease. ALS was first discovered by Charcot in 1869, and since then, scientists have been unable to identify a singular cause of the disease. Further, there are no effective treatments available to cure ALS. The benchmark discovery of humanized preclinical SOD1 mouse models, which recapitulates the clinical and pathological phenotypes of human ALS, gives hope to medicinal chemists and neuroscientists around the globe that a suitable drug-like molecule can be discovered and translated into human beings as a means to slow down the progression of the disease. However, little success has been achieved until now in terms of finding an effective treatment for heterogenic and incurable ALS. One area marked for improvement is the use of semiquantitative, antibody-based targeted Western blotting (WB) experiments, which lack the power to analyze multiple cellular events within the entire dysregulated proteomic system. With the inconsistency of WB experiments, unexpected cellular pathways go undiscovered, and hence, loss of translation with no target engagement is seen from preclinical to human clinical ALS. Recent advancements in discovery-based quantitative proteomics have many advantages over WB. These innovative techniques could help solve the inherent problem in WB and their inability to discover multiple altered proteins with the added capability of longitudinal analysis in preclinical SOD1 models, further validating the findings in human ALS. Herein, we applied a holistic approach to summarize various reports on the use of proteomics in ALS from the published literature, and importantly, we found that using a discovery-based proteomics approach in SOD1 preclinical ALS models has revealed a more diverse and global picture of pathological proteins that affect multiple pathways during different stages of disease progression. Furthermore, we found that the proteomic profiling of the humanized SOD1 mouse model provided a proof of principle for translating the diverse pathological biomarker proteins identified in clinical human ALS cases. Moreover, we believe that advancements in the proteomics approach toward ALS biomarkers could bridge the gap between preclinical and clinical studies, enabling scientists worldwide to discover novel biomarkers and treatments that modify the progression of ALS.}, } @article {pmid40822158, year = {2025}, author = {Cao, G and Shi, X and Wang, X and Yang, L and Wang, P and Yuan, Y and Tan, H}, title = {Combined Single-Bundle Anterior Cruciate Ligament and Anterolateral Structure Reconstruction Through a Modified Single Femoral Tunnel.}, journal = {Arthroscopy techniques}, volume = {14}, number = {7}, pages = {103614}, pmid = {40822158}, issn = {2212-6287}, abstract = {Anterior cruciate ligament (ACL) injuries are among the most common sports injuries, and ACL reconstruction is an important treatment method. Residual rotational stability following isolated ACL reconstruction is the main reason for graft rupture and unsatisfactory results. Many researchers have shown that combined ACL and anterolateral structure (ALS) reconstruction could decrease rotational instability and graft rupture rate, as well as improve satisfaction. Various methods have been described to reconstruct the ACL and ALS jointly. However, previous methods still have disadvantages, such as undesirable tunnel convergence, complex maneuver, and insufficient graft filling in the tibial tunnel. Therefore, we present our technique for reconstruction of the ACL and ALS through a modified single femoral tunnel. We have obtained promising clinical outcomes with this technique.}, } @article {pmid40822241, year = {2025}, author = {Tan, X and Gao, N}, title = {The emerging role of cellular senescence in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1599492}, pmid = {40822241}, issn = {1662-4548}, abstract = {Cellular senescence is a state of permanent cell cycle arrest and is considered a key contributor to aging and age-related diseases, including amyotrophic lateral sclerosis (ALS). The physiological processes of aging lead to a variety of molecular and cellular phenotypes, and evidence of overlap between ALS and aging-related biomarkers suggests that cell type-specific senescence may be a critical factor in ALS. Senescent microglial cells, astrocytes, and neurons have been detected in ALS patients and animal models. However, while accumulating evidence suggests a potential link between cellular senescence and ALS, this connection remains not yet conclusively established. Importantly, how senescent cells may contribute to the neuropathophysiology of ALS remains largely unknown. Additionally, the growing popularity of anti-aging therapies has highlighted the potential of senescent cell clearance as a promising strategy for treating age-related diseases, including ALS. This review provides an overview of cellular senescence, discusses recent advances in understanding how senescence in different cell types influences ALS pathogenesis, and explores the potential role of anti-senescence therapies in ALS treatment.}, } @article {pmid40826812, year = {2025}, author = {Asano, H and Kawaguchi, T and Kato, C and Morimoto, S and Yano, M and Minaguchi, M and Yasuda, D and Fukushima, K and Okano, H}, title = {Ropinirole Functions Through a Dopamine Receptor D2-Independent Mechanism to Ameliorate Amyotrophic Lateral Sclerosis Phenotypes in TARDBP-Mutant iPSC-Derived Motor Neurons.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70183}, pmid = {40826812}, issn = {1471-4159}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Receptors, Dopamine D2/genetics/agonists/metabolism ; Humans ; *Indoles/pharmacology/therapeutic use ; Animals ; *Dopamine Agonists/pharmacology ; *DNA-Binding Proteins/genetics ; Phenotype ; Mice ; Mutation ; Reactive Oxygen Species/metabolism ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron (MN) degeneration. Ropinirole hydrochloride (ROPI), a dopamine receptor D2 (DRD2) agonist, was identified through phenotypic screening of MNs derived from patient-derived induced pluripotent stem cells (iPSCs) as a disease model and has emerged as a promising candidate drug for ALS treatment. The ROPALS trial, a phase I/IIa trial in patients with ALS, suggested the safety and efficacy of ROPI, albeit in a small sample size. Interestingly, a DRD2 antagonist and modulator only partially mitigated the suppressive effect of ROPI on the ALS phenotype, and the detailed mechanism of ROPI activity remains unclear. Therefore, in this study, we investigated whether the therapeutic effects of ROPI in ALS are dependent on DRD2. For this purpose, we generated DRD2-deficient iPSCs and showed that ROPI effectively reduced neuronal cell death, reactive oxygen species (ROS) production, and neuronal hyperexcitation, independently of DRD2. Further analyses revealed that ROPI corrected aberrant RNA splicing and restored the mRNA expression of mitochondrial proteins in a DRD2-independent manner. Our findings suggest that ROPI not only functions as a canonical DRD2 agonist but also has pleiotropic DRD2-independent effects, offering a novel avenue for treatment strategies that target multiple pathways involved in ALS pathology.}, } @article {pmid40832743, year = {2025}, author = {Verde, F}, title = {Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {614-619}, doi = {10.1097/WCO.0000000000001411}, pmid = {40832743}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid/metabolism ; *Neurofilament Proteins/cerebrospinal fluid/blood/metabolism ; DNA-Binding Proteins/blood ; tau Proteins/blood ; }, abstract = {REVIEW PURPOSE: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology.

SUMMARY: NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.}, } @article {pmid40832750, year = {2025}, author = {Erdi-Krausz, G and Shaw, PJ}, title = {Antisense oligonucleotide therapy in amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {38}, number = {5}, pages = {574-580}, doi = {10.1097/WCO.0000000000001413}, pmid = {40832750}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy ; Humans ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; C9orf72 Protein ; Superoxide Dismutase-1 ; *Genetic Therapy/methods ; Superoxide Dismutase/genetics ; DNA-Binding Proteins/genetics ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few treatment options available. The approval of tofersen, an antisense oligonucleotide, for SOD1 -ALS by the FDA and EMA may herald a new era of treatment in these patients.

RECENT FINDINGS: So far, trials against the most common genetic form of ALS, C9orf72 , have been unsuccessful, but new preclinical data may show a promising new direction to take. Clinical trials targeting other, more rare genetic mutations associated with familial ALS are currently underway. Other research assessing the use of ASOs to target aberrant splicing associated with sporadic forms of ALS has also produced promising results in preclinical models, using patient-derived induced cellular models and animal models. These therapies are focussed largely on alleviating and reversing TDP-43 pathology, opening up the possibility of not only arresting disease progression, but reversing neurodegeneration.

SUMMARY: ASO therapies have made some promising steps towards treating familial ALS, particularly SOD1 . Ongoing early clinical/preclinical phase research is underway to utilise this technology in other genetic mutations linked with ALS, as well as in sporadic cases.}, } @article {pmid40837865, year = {2025}, author = {Khan, H and Riaz, H and Ahmed, A and Kiyani, MM and Jawad, SM and Ud Din Shah, SS and Abualait, T and Al-Hussain, F and Li, HT and Bashir, S}, title = {CRISPR/Cas9 a genomic engineering technology for treatment in ALS mouse models.}, journal = {Regenerative therapy}, volume = {30}, number = {}, pages = {575-583}, pmid = {40837865}, issn = {2352-3204}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by the death of motor neurons in the spinal cord and brain regions, leading to a reduced survival rate in patients. Nearly 20 gene mutations are associated with ALS, with SOD1, FUS, TARDBP, and C9orf72 mutations being more common. Ninety percent of ALS cases are related to sporadic ALS, while the remaining 10 % are associated with familial ALS. CRISPR/Cas9, a genome engineering technology known as clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9, has the potential for gene editing and for studying the underlying mechanisms of ALS in mouse models. This technique enables neuroscientists to reverse mutations found in ALS mouse models, providing new hope for understanding the complexities of ALS. Additionally, this tool can create mutations to probe the functional changes of genetic diseases. Using CRISPR/Cas9 with an in vivo delivery method involving adeno-associated vectors, it is possible to silence mutations in the SOD1-linked ALS mouse model. Some limitations related to CRISPR/Cas9 have been discussed in previous studies and need to be addressed before clinical trials can proceed. In this review-based study, we summarise the latest research on CRISPR/Cas9 genome editing for ALS in mouse models and discuss its limitations and future prospects as well.}, } @article {pmid40848625, year = {2025}, author = {Gauden, AJ and Gu, B and Han, S and Telischak, NJ and Dodd, R and Do, HM and Marks, MP and Steinberg, GK}, title = {Multimodality treatment maximizing outcome in spinal dural arteriovenous fistulae.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {141}, number = {}, pages = {111571}, doi = {10.1016/j.jocn.2025.111571}, pmid = {40848625}, issn = {1532-2653}, mesh = {Humans ; *Central Nervous System Vascular Malformations/therapy/diagnostic imaging/surgery ; Male ; Female ; Middle Aged ; Retrospective Studies ; *Embolization, Therapeutic/methods ; Treatment Outcome ; Adult ; Aged ; Combined Modality Therapy/methods ; Microsurgery/methods ; Endovascular Procedures/methods ; Spinal Cord ; Young Adult ; *Neurosurgical Procedures/methods ; Adolescent ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistula (sDAVF) is a rare cause of myelopathy and progressive paraplegia. sDAVFs are the most frequent type of spinal vascular malformation and comprise 70 % of all vascular spinal malformations. Despite the availability and published efficacy of both microsurgical resection and endovascular embolization, the optimal treatment for sDAVFs remains to be determined. We aimed to assess the efficacy of a multimodal treatment approach to sDAVFs at our institution.

METHODS: A retrospective review of all sDAVFs treated between 1998 and 2021 at Stanford Hospital and Clinics was conducted. The medical records were inspected and data, including presenting symptoms, duration, angiographic features, and treatment modality, were extracted. Cure was defined as the absence of an arteriovenous fistulous connection on digital subtraction angiography and radiologic improvement on follow-up MRI. Functional outcomes were assessed at presentation and at last follow-up using the Aminoff-Logue Scale (ALS).

RESULTS: 47 patients underwent treatment of sDAVFs between August 1998 to May 2021. As an initial treatment, 32 patients underwent microsurgical excision, and 15 had endovascular embolization. Radiological cure was achieved in 84.4 % of patients during the first treatment and in 97.9 % of patients at the final treatment time point. At initial treatment, surgery cured the sDAVF in 84.4 % of patients, with endovascular embolization curing in 86.7 % of patients. When assessed as an additional treatment for failed prior treatment, surgery achieved cure in 80 % of patients and endovascular embolization in 100 % of patients. At all time points, high cure rates were observed, with success rates achieving 96.9 % and 100 % for surgery and endovascular embolization, respectively. A significant improvement in ALS Gait score was noted after treatment, with a mean reduction of 0.6 from baseline (p = 0.0003). A similar improvement trend was observed in the ALS Micturition score with a mean decrease of 0.3 points (p = 0.057).

CONCLUSIONS: Our study demonstrates high efficacy for cure and improved functional outcomes in both surgical and endovascular treatments, assuming good patient selection. This series also highlights the importance of a multimodality treatment approach in managing spinal dural arteriovenous fistulae. Further delineation is required to determine the radiological and patient factors that might recommend specific initial treatment modalities.}, } @article {pmid40848858, year = {2025}, author = {Chen, X and Ma, Y and Liu, H and Wang, Y}, title = {Multifunctional regulation and treatment of ubiquitin specific protease 10.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 1}, pages = {117251}, doi = {10.1016/j.bcp.2025.117251}, pmid = {40848858}, issn = {1873-2968}, mesh = {Humans ; *Ubiquitin Thiolesterase/metabolism/antagonists & inhibitors/chemistry/genetics ; Animals ; Neoplasms/drug therapy/metabolism/enzymology ; Neurodegenerative Diseases/drug therapy/enzymology/metabolism ; }, abstract = {USP10 is a critical deubiquitinating enzyme within the ubiquitin-specific protease family, playing multifaceted roles in cellular physiology and disease pathogenesis. Structurally composed of a G3BP1-interacting motif, a N-terminal domain (mediating most protein interactions), and a catalytic USP domain (residues 415-795, catalytic triad C424-H736-D751), USP10 regulates diverse cellular pathways by stabilizing key proteins through deubiquitination. It exhibits context-dependent functional duality, particularly in cancer: USP10 promotes tumorigenesis in various cancers (e.g., glioblastoma, esophageal, pancreatic, breast cancers) by stabilizing oncoproteins like CCND1, YAP1, HDAC7, and RUNX1, enhancing proliferation, metastasis, and immune evasion. Conversely, it suppresses tumors (e.g., NSCLC, CRC, thyroid cancer) by stabilizing tumor suppressors like p53, PTEN, and Axin1, inhibiting pathways such as Wnt/β-catenin. Beyond oncology, USP10 contributes to neurodegenerative diseases (neuroprotective in PD/ALS, neurotoxic in AD via Tau stabilization), viral immunity (inhibits SARS-CoV-2 infection), inflammatory responses, male reproduction, and metabolic/cardiovascular disorders. Its regulatory mechanisms include phosphorylation (e.g., by AMPK, AKT, ATM) controlling subcellular localization and activity, and ubiquitination via USP13. USP10's therapeutic significance drives inhibitor development (Spautin-1, D1, Wu-5, P22077, Parthenolide), though cross-reactivity within the USP family due to conserved catalytic domains remains a challenge. Novel strategies like PROTACs and engineered ubiquitin variants (UbVs) offer promise for future selective targeting of USP10 dysregulation in diverse diseases. A comprehensive understanding of its structure and context-specific functions is essential for exploiting its full therapeutic potential.}, } @article {pmid40849231, year = {2026}, author = {Fu, X and Gable, K and Gupta, SD and Zhang, K and Jia, B and Wang, W and Yang, X and Wang, L and Ge, L and Bönnemann, CG and Dunn, TM and Xiong, H}, title = {Characterization of novel and recurrent SPTLC2 variants in childhood-onset amyotrophic lateral sclerosis: Insights into sphingolipid dysregulation.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {4}, pages = {655-664}, pmid = {40849231}, issn = {2214-3602}, mesh = {Child ; Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; Exome Sequencing ; Mutation ; *Serine C-Palmitoyltransferase/genetics ; *Sphingolipids/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder that progressively affects motor neurons. Gain-of-function mutations in serine palmitoyltransferase (SPT) genes, notably SPTLC1 and SPTLC2, have been linked to juvenile ALS. Here, we describe two childhood-onset ALS cases with distinct SPTLC2 mutations, providing new insights into sphingolipid dysregulation and its role in ALS pathogenesis.

MATERIAL AND METHODS: Two Chinese patients with early-onset ALS, both carrying SPTLC2 mutations, were recruited from Beijing Children's Hospital. We conducted whole-exome sequencing (WES) to identify genetic variants, followed by Sanger sequencing for validation. Sphingolipid profiles were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Clinical evaluations included neurological assessments, brain MRI and electromyography. Additionally, mutant cell lines were established to assess the functional effects of the specific mutations.

RESULTS: Patient 1, a 6-year-old male, exhibited a novel heterozygous de-novo SPTLC2 variant (c.197T > G, p.T66R). Patient 2, a 7-year-old female, had a recurrent heterozygous de-novo SPTLC2 variant (c.778G > A, p.E260K). Both patients showed elevated levels of specific sphingolipids compared to controls, with distinct profiles between the SPTLC2-ALS and SPTLC1-hereditary sensory and autonomic neuropathy type 1 (HSAN1) cases. The novel p.T66R mutation was predicted to alter protein interactions within the SPT complex, potentially impairing sphingolipid homeostasis. Functional studies further revealed that the p.T66R variant reduces the inhibitory regulation of SPT by ORMDL proteins, leading to unrestrained SPT activity and excess sphingolipid production.

CONCLUSIONS: Our findings identify a novel SPTLC2 variant linked to childhood-onset ALS and reveal altered sphingolipid profiles associated with different genetic mutations. These results underscore the importance of sphingolipid metabolism in ALS and suggest potential avenues for targeted therapeutic interventions. Further research is needed to explore treatment options aimed at modulating sphingolipid levels and correcting genetic defects, as well as investigating potential biomarkers for early diagnosis.}, } @article {pmid40849485, year = {2025}, author = {Helal, MM and AbouShawareb, H and Abbas, OH and Haddad, R and Zain, Y and Osman, ASA and Hassan, AK}, title = {GLP-1 receptor agonists in Parkinson's disease: an updated comprehensive systematic review with meta-analysis.}, journal = {Diabetology & metabolic syndrome}, volume = {17}, number = {1}, pages = {352}, pmid = {40849485}, issn = {1758-5996}, abstract = {Previous studies have demonstrated an increased risk of developing Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM), as well as more severe and rapid motor and non-motor deterioration in diabetic PD patients compared to their non-diabetic counterparts. Additional research has suggested that diabetic subjects treated with glucagon-like peptide-1 (GLP-1) receptor agonists exhibit a reduced incidence of PD compared to those receiving other anti-diabetic medications. GLP-1 receptor agonists are FDA-approved therapies for T2DM, and recent studies have explored their potential as repurposed treatments for neurodegenerative diseases, including PD, AD, and ALS, as well as cerebrovascular disorders. This systematic review aims to assess the available literature on the efficacy and safety profiles of GLP-1 receptor agonists in PD management. A comprehensive search of PubMed, Scopus, CENTRAL, Web of Science, Embase, and ClinicalTrials.gov was conducted to identify relevant studies. The primary outcomes of this review include motor impairment in PD, as assessed by MDS-UPDRS Part III, as well as motor complications (Part IV) and motor experiences of daily living (Part II), and the incidence of gastrointestinal and systemic side effects. Meta-analysis showed that GLP-1 receptor agonists significantly improved motor function, as reflected by MDS-UPDRS Part III scores in the ON state (mean difference = - 2.88; p = 0.01; I[2] = 30%), although they were associated with a higher incidence of adverse events across all safety outcomes. Findings and conclusions of this review will contribute to a clearer understanding of the therapeutic potential of GLP-1 receptor agonists in PD, guiding future clinical research and treatment strategies.}, } @article {pmid40849781, year = {2025}, author = {Kurochkina, N and Rudrabhatla, P}, title = {Role of Calmodulin in Neurodegeneration and Neuroprotection.}, journal = {Mini reviews in medicinal chemistry}, volume = {25}, number = {13}, pages = {965-974}, pmid = {40849781}, issn = {1875-5607}, support = {1142025//School of Theoretical Modeling, Washington, DC, USA/ ; }, mesh = {*Calmodulin/metabolism/chemistry/antagonists & inhibitors ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Neuroprotection ; *Neuroprotective Agents/pharmacology/chemistry ; Calcium/metabolism ; }, abstract = {Intracellular calcium (Ca[2+]) levels are critical in maintaining cellular activities and are tightly regulated. Neuronal degeneration and regeneration rely on calcium-binding proteins. Calmodulin (CaM) is a calcium sensor and the primary regulator of receptors and ion channels that maintain calcium homeostasis. The calmodulin binding domains are present in proteins that serve as risk factors and biomarkers associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases, suggesting calmodulin ligands as emerging therapeutic targets for treatment. Inhibiting CaM to develop new therapies has drawbacks, as CaM is a ubiquitous molecule involved in many regulatory pathways. Recently, new strategies for disrupting CaM interactions with its targets have shown promising approaches to treatment. The structures of human CaM, its binding proteins, and inhibitors are well studied, with particular emphasis on the conservation of CaM amino acid sequences and the ability to bind protein fragments of high sequence variability, which exhibit common characteristics of amphipathic helices carrying basic amino acids. In this review, we discuss structural characteristics of CaM and its ligands in the context of transcriptional regulation. Specific binding of CaM to (1) basic region/helix-loop-helix/leucine zipper and (2) helix-turn-helix high mobility group box containing Sox families of transcription factors highlights common features of CaM binding sequences, which suggest their regulatory functions. We describe key proteins involved in neurodegeneration and transcription factors subject to calmodulin regulation that are candidates for the development of new approaches to treating neuronal diseases.}, } @article {pmid40851280, year = {2026}, author = {Tröger, J and Rouvalis, A and Dörr, F and Schwed, L and Linz, N and König, A and Machts, J and Vielhaber, S and Thies, T and Prudlo, J and Hermann, A and Kasper, E}, title = {Automatically measured speech intelligibility models bulbar-specific disease severity and progression in Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {101-109}, doi = {10.1080/21678421.2025.2549317}, pmid = {40851280}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Male ; Female ; Disease Progression ; Middle Aged ; *Speech Intelligibility/physiology ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Severity of Illness Index ; Adult ; *Speech Disorders/etiology/diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to widespread motor deterioration, including significant motor speech impairments. Speech intelligibility is a crucial component of communication affected in ALS, requiring objective, scalable assessment methods as an indicator of disease progression and treatment efficacy. Objective: This study investigates whether speech and bulbar function in ALS could be evaluated and monitored utilizing an automated digital measure of speech intelligibility derived from naturalistic picture descriptions. Methods: Speech recordings from 44 patients living with ALS (plwALS) and 49 matched healthy controls (HC) were analyzed and processed utilizing an automated speech analysis pipeline to extract an intelligibility score. These were part of a cross-sectional and longitudinal study involving two assessments. Results: The findings confirmed that speech intelligibility is significantly reduced in plwALS compared to HC. Those with bulbar-onset ALS have lower intelligibility than those with spinal-onset ALS, and the intelligibility of individuals with bulbar symptoms-regardless of the onset type-is lower than in plwALS without bulbar symptoms. Declining ALS-related speech scores correspond with worsening intelligibility in longitudinal assessments. Intelligibility correlates strongly with bulbar-specific clinical measures but not with global scores, highlighting its role in tracking bulbar progression. In some plwALS, we were able to demonstrate that automated speech analyses are more effective in detecting worsening in intelligibility earlier than standard clinical scoring. Conclusion: Our findings highlight that automated speech intelligibility assessments can be a valuable marker to improve clinical monitoring and facilitate earlier intervention in ALS as a supplement to standard assessments.}, } @article {pmid40854024, year = {2025}, author = {Stiles, K and LaBarbera, V}, title = {Recognition and Treatment of Concurrent Amyotrophic Lateral Sclerosis and Myasthenia Gravis.}, journal = {Rhode Island medical journal (2013)}, volume = {108}, number = {9}, pages = {16-18}, pmid = {40854024}, issn = {2327-2228}, } @article {pmid40857020, year = {2025}, author = {Krivickas, B and Scirocco, E and Giacomelli, E and Sharma, S and Benson, M and Keegan, M and Kulesa-Kelley, J and Chibnik, LB and Casagrande, G and Heyd, L and Chase, M and Drake, K and Mohapatra, S and Hagar, JL and Hasenoehrl, MG and Dagostino, D and Sherman, AV and Leite, A and Yu, H and Rosenthal, J and Miller, T and McCaffrey, A and Gwathmey, K and Locatelli, E and Bayat, E and Heitzman, D and Young, E and Goyal, NA and Whitesell, J and Felice, K and Ilieva, H and Swenson, A and Walk, D and Alameda, G and Foster, L and McIlduff, CE and Walsh, A and Zilliox, L and Ajroud-Driss, S and Bodkin, C and Katz, J and Ladha, S and Rivner, M and Rosow, L and Twydell, P and Wasiewski, W and Babu, S and Berry, JD and Paganoni, S}, title = {Multicenter Expanded Access Protocol for Research Through Access to Trehalose in People With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1108-1116}, pmid = {40857020}, issn = {1097-4598}, support = {UF1 NS131791/NS/NINDS NIH HHS/United States ; UF1NS131791//Office of the Director of the National Institutes of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Trehalose/therapeutic use ; Middle Aged ; Male ; Female ; Aged ; Disease Progression ; Adult ; Neurofilament Proteins/blood ; }, abstract = {INTRODUCTION/AIMS: Expanded access protocols (EAPs) allow individuals ineligible for clinical trials to receive investigational products. EAP data can be collected in parallel to randomized clinical trials (RCTs) and serve as a source of evidence in clinical practice. Here, we present the results of a National Institutes of Health (NIH)-funded EAP for amyotrophic lateral sclerosis (ALS).

METHODS: Participants received trehalose, a drug studied in a parallel RCT, for up to 24 weeks; clinical and biomarker data were collected throughout the study.

RESULTS: Seventy participants were enrolled at 20 study centers across the United States. Treatment with trehalose did not affect the levels of neurofilament light chain [estimated flat slope per month was -0.005, SE = 0.0078; 95% CI (-0.021, 0.011)] or disease progression [estimated least square mean change of the ALS Functional Rating Scale-Revised total score and slow vital capacity (percent predicted) from baseline to Week 24 were -5.6 (0.67); 95% CI (-7.0, -4.3) and -4.53 (4.308); 95% CI (-13.55, 4.48)], respectively. No unexpected treatment-related risks were identified. Serious adverse events were deemed not related to trehalose (20 occurrences in 13 [18.6%] participants with eight deaths).

DISCUSSION: This EAP establishes a framework for implementing multi-center EAPs that complement data collected from RCTs. Additional NIH-funded EAPs are currently underway. Data and additional serum samples collected in this study are available to the research community for further study.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT05597436.}, } @article {pmid40859959, year = {2025}, author = {Mao, S and Qiao, R and Wang, Q and Shen, L and Li, D and Huo, X and Wang, J and Liu, K and Chen, W and Zhu, T and Zhang, B and Leng, S and Bai, Y}, title = {Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70329}, pmid = {40859959}, issn = {2688-2663}, abstract = {Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.}, } @article {pmid40860154, year = {2025}, author = {Li, D and Wei, Y and Yang, R and Luo, X and Liu, Y and Zhao, W and Yang, H and Wu, Y and Wang, Y and Huang, Z}, title = {An unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling in C9orf72-poly-GA mice.}, journal = {Theranostics}, volume = {15}, number = {16}, pages = {8176-8201}, pmid = {40860154}, issn = {1838-7640}, mesh = {Animals ; *Astrocytes/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; YAP-Signaling Proteins ; Mice ; Disease Models, Animal ; *C9orf72 Protein/genetics/metabolism ; Mice, Knockout ; *Excitatory Amino Acid Transporter 2/metabolism ; *Cell Cycle Proteins/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; beta Catenin/metabolism ; Motor Neurons/metabolism/pathology ; *Wnt Signaling Pathway ; Neurons/metabolism ; Humans ; Signal Transduction ; }, abstract = {Rationale: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the central nervous system (CNS). Non-neuronal cells, particularly astrocytes, have been recognized as pivotal contributors to ALS onset and progression. However, the underlying mechanisms of interactions between astrocytes and motor neurons during ALS remain unclear. Recent studies have identified the neuronal Hippo kinase mammalian sterile 20-like kinase 1 (MST1) as a key regulator of neurodegeneration in ALS. Yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is predominantly expressed in astrocytes. However, the role of astrocytic YAP in ALS and its underlying mechanisms remain unexplored. Methods: To evaluate the function of YAP in ALS, we established a C9orf72-poly-GA mouse model (ALS mice) via intracerebroventricular injection of AAV viruses. Furthermore, mice with conditional knockout (CKO) of YAP in astrocytes (YAP[GFAP]-CKO mice) were generated and then YAP[GFAP]-CKO ALS mice and their littermate controls (YAP[f/f] ALS mice) were used as experimental subjects. Behavioral tests, immunostaining, Nissl staining, quantitative real-time PCR (qPCR), and Western blotting were used to assess the effects of astrocytic YAP deletion in ALS progression. In addition, we investigated the role and mechanism of astrocytic YAP in the pathogenesis of ALS by integrating RNA sequencing (RNA-seq) from primary cultured astrocytes with single-nucleus transcriptomic (snRNA-seq) from C9orf72-ALS/FTD patients. Then, in vitro experiments including primary cultured astrocytes and neurons were used to further elucidate the potential molecular mechanism of astrocytic YAP in ALS. Finally, we evaluated the therapeutic effects of the excitatory amino acid transporter-2 (EAAT2) activator LDN-212320 and the Hippo kinase MST1/2 inhibitor XMU-MP-1 as candidate treatments for ALS. Results: We found that YAP was upregulated and activated specifically in astrocytes, but not in neurons or microglia, within the motor cortex of ALS mice. Conditional knockout of YAP in astrocytes exacerbated motor deficits, neuronal loss, pathological translocation of TDP-43, inflammatory infiltration, and reduced astrocytic proliferation in ALS mice. Mechanistically, Wnts secreted by degenerating neurons and astrocytes activated YAP/β-catenin signaling and further promoted the expression of EAAT2 in astrocytes, which prevented neuronal glutamate excitotoxicity, neuronal loss, and motor dysfunction in ALS mice. Interestingly, treatment with LDN-212320 promoted EAAT2 expression and partially restored motor deficits and neuronal loss in YAP[GFAP]-CKO ALS mice. Finally, activation of YAP by XMU-MP-1 upregulated β-catenin and EAAT2 expression, and partially alleviated motor deficits and neurodegeneration in ALS mice. Conclusions: These results identify an unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling to prevent glutamate excitotoxicity of neurons in ALS mice, and provide a novel drug target for ALS.}, } @article {pmid40865525, year = {2025}, author = {McEachin, ZT and Chung, M and Stratton, SA and Han, C and Kim, WJ and Sheth, U and Thomas, EV and Issenberg, E and Kamra, T and Merino, P and Levites, Y and Raj, N and Dammer, EB and Duong, DM and Ping, L and Shantaraman, A and Trautwig, AN and Gadhavi, J and Assefa, E and Gearing, M and Kelly, KM and Roemer, SF and DeTure, M and Asress, S and Kukar, T and Fournier, C and Dickson, DW and Petrucelli, L and Golde, TE and Oskarsson, B and Gendron, TF and Seyfried, NT and Glass, JD}, title = {Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS.}, journal = {Cell}, volume = {188}, number = {23}, pages = {6424-6435.e17}, pmid = {40865525}, issn = {1097-4172}, support = {RF1 AG079318/AG/NIA NIH HHS/United States ; R01 NS105971/NS/NINDS NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS137434/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy/pathology/cerebrospinal fluid/metabolism ; Humans ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/therapeutic use ; Male ; Female ; Spinal Cord/metabolism/pathology ; Middle Aged ; Aged ; Biomarkers/cerebrospinal fluid ; DNA-Binding Proteins/metabolism ; Central Nervous System/metabolism ; }, abstract = {C9orf72-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic G4C2 repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system (CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSF from BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers, including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNS tissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures in c9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundance that correlated with BIIB078 concentration was observed. Thus, despite widespread distribution, BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASO therapies.}, } @article {pmid40865585, year = {2025}, author = {Xu, C and Naudet, F and Kim, TT and Hengartner, MP and Horowitz, MA and Kirsch, I and Moncrieff, J and Pigott, E and Plöderl, M}, title = {Large responses to antidepressants or methodological artifacts? A secondary analysis of STAR∗D, a single-arm, open-label, nonindustry antidepressant trial.}, journal = {Journal of clinical epidemiology}, volume = {187}, number = {}, pages = {111943}, doi = {10.1016/j.jclinepi.2025.111943}, pmid = {40865585}, issn = {1878-5921}, mesh = {Humans ; *Antidepressive Agents/therapeutic use ; Male ; Female ; Middle Aged ; Adult ; Psychiatric Status Rating Scales ; Treatment Outcome ; *Depression/drug therapy ; Aged ; Artifacts ; *Major Depressive Disorder/drug therapy ; }, abstract = {OBJECTIVES: To replicate Stone et al's (2022) finding that the distribution of response in clinical antidepressant trials is trimodal with large, medium-effect, and small subgroups.

METHODS: To apply finite mixture modeling to pre-post Hamilton Depression Rating Scale (HDRS) differences (n = 2184) of STAR∗D study's level 1, a single-arm, open-label study. For a successful replication, the best fitting model had to be trimodal, with comparable components as in Stone et al. Secondary/sensitivity analyses repeated the analysis for different baseline levels of depression severity, imputed values, and patient-reported depression symptoms.

RESULTS: The best fitting models were either bimodal or trimodal but the trimodal solution did not meet criteria for replication. The bimodal model had 1 component with HDRS mean change of M = -13.0, SD = 6.7 and included 65.3% of patients, and another component with M = -1.8, SD = 5.1, 34.7%, respectively. For the trimodal model, the component with the largest change (M = -14.3, SD = 6.4) applied to 52% of patients, which differed substantially from the large effect component in Stone et al (M = -18.8, SD = 5.1), which applied to 7.2%. Secondary/sensitivity analyses arrived at similar conclusions, and for patient-reported depression symptoms the best fitting models were unimodal or bimodal.

CONCLUSION: This analysis failed to identify the trimodal distribution of response reported in Stone et al. In addition to being difficult to operationalize for regulatory purposes, results from mixture modeling are not sufficiently reliable to replace the more robust approach of comparing mean differences in depression rating scale scores between treatment arms.}, } @article {pmid40876427, year = {2025}, author = {Ibrahim, SI and Zaher, DM and Hersi, FA and Hamouda, AO and Al Hindawi, MA and Omar, HA}, title = {Repurposing edaravone in oncology: Bridging antioxidant defense and immune modulation.}, journal = {International immunopharmacology}, volume = {164}, number = {}, pages = {115413}, doi = {10.1016/j.intimp.2025.115413}, pmid = {40876427}, issn = {1878-1705}, mesh = {Humans ; *Edaravone/therapeutic use/pharmacology ; *Neoplasms/drug therapy/immunology ; Animals ; Drug Repositioning ; *Antioxidants/therapeutic use/pharmacology ; Tumor Microenvironment/drug effects ; *Antineoplastic Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; *Immunomodulating Agents/therapeutic use/pharmacology ; Immunomodulation/drug effects ; }, abstract = {Edaravone, a synthetic free radical scavenger originally approved for neurological disorders such as stroke and amyotrophic lateral sclerosis (ALS), is gaining attention for its emerging potential role in cancer. Beyond its well-established antioxidant properties, edaravone demonstrates significant anti-inflammatory and immunomodulatory activities, including the inhibition of key pathways such as NF-κB, JAK2/STAT3, and TLR4/IL-6, suggesting potential to modulate immune responses within the tumor microenvironment. This review discusses how edaravone disrupts oncogenic signaling, induces cell cycle arrest, and enhances apoptosis, particularly in cancer stem cells and therapy-resistant models. It also examines edaravone's dual role in combination therapies, where it may improve the cytotoxicity of chemotherapeutic and radiotherapeutic agents while simultaneously protecting normal tissues from treatment-induced toxicities. By linking mechanistic insights with therapeutic outcomes, this review highlights the rationale for repurposing edaravone as a potential adjuvant in cancer therapy. Although clinical data are currently limited, preliminary findings are encouraging and warrant further investigation into edaravone's potential use in cancer treatment regimens.}, } @article {pmid40878249, year = {2025}, author = {Silva, MM and Cunha, EM and Briois, V and Rochet, A}, title = {Unraveling hydride dynamics on cubic palladium nanoparticles.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {36}, pages = {19358-19364}, doi = {10.1039/d5cp02672e}, pmid = {40878249}, issn = {1463-9084}, abstract = {Palladium-based materials exhibit a high affinity for hydrogen molecules, enabling the effortless formation of a hydride phase. This property is widely exploited in several catalytic reactions and hydrogen storage materials. However, the effects of morphological parameters, support interactions, and formation kinetics remain incompletely understood. In this work, we applied in situ time-resolved X-ray absorption spectroscopy (XAS) to investigate the impact of nanoparticle sizes and support materials on the dynamic formation of palladium hydrides during thermal treatment under H2. A detailed analysis using multivariate curve resolution with alternating least squares (MCR-ALS) enabled the extraction of concentration profiles and the identification of pure species involved in the process, thereby revealing distinct kinetic behaviours across the samples. This study provides valuable insights into how particle size and support influence the kinetics of hydrogen absorption in palladium systems, which can significantly impact catalytic performance.}, } @article {pmid40878665, year = {2025}, author = {Abrahao, A and Da Silva, P and Ciepielewska, M and Zinman, L}, title = {Real-world safety and tolerability of intravenous edaravone in patients with amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {6}, pages = {305-312}, pmid = {40878665}, issn = {1758-2032}, mesh = {Humans ; *Edaravone/administration & dosage/adverse effects/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Free Radical Scavengers/administration & dosage/adverse effects ; }, abstract = {AIMS: This retrospective cohort study describes real-world safety and tolerability outcomes in United States-based edaravone-treated patients with ALS.

PATIENTS & METHODS: Amerita Specialty Infusion Services provided IV edaravone to patients with ALS treated with their first dose between 25 September 2017-30 September 2022. Mean ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) %-predicted measures were recorded within ± 100 days from care initiation to approximate baseline values.

RESULTS: Included patients (n = 243) received/were still receiving IV edaravone/edaravone oral suspension as of 30 September 2022. At initiation, 66.7% were male, mean age ± SD was 61.2 ± 11.2 years, and 61.3% were covered by government insurance. In patients with provider-recorded ALSFRS-R (n = 115) and FVC (n = 84) %-predicted measures within ± 100 days from care initiation, mean ± SD values were 35.1 ± 8.9 and 72.3% ± 21.7%, respectively. Mean ± SD therapy duration was 13.5 ± 11.4 months. Discontinuation reasons included death/hospice (n = 82), patient's choice (n = 38), doctor's choice (n = 31), insurance (n = 18), and other (n = 12). Reasons for IV edaravone discontinuation and IV edaravone administration access device were not associated.

CONCLUSIONS: Treatment discontinuation was primarily related to ALS disease progression/death, rather than safety or tolerability. This study representative of real-world patients with ALS suggests that edaravone showed consistent safety and tolerability profiles with previous studies.}, } @article {pmid40879603, year = {2026}, author = {Karimi, S and Ghaheri, A and Madani, H and Beheshti Maal, A and Sadri, B and Khodadoust, E and Sharafi, F and Vosough, M and Nabavi, SM}, title = {Intravenous vs intrathecal transplantation of allogeneic GMP/GCP compliant Wharton's jelly mesenchymal stromal cells in ALS patients: a phase I study.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {1}, pages = {33-41}, pmid = {40879603}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Mesenchymal Stem Cell Transplantation/methods ; Middle Aged ; Female ; Male ; Aged ; Adult ; Injections, Spinal ; Mesenchymal Stem Cells ; *Wharton Jelly/cytology ; Treatment Outcome ; Transplantation, Homologous/methods ; }, abstract = {INTRODUCTION: There are a few therapeutic approaches for Amyotrophic Lateral Sclerosis (ALS) which can only slow down or stop the disease progression for a limited period of time. Since it has been proven that Mesenchymal Stromal Cells (MSCs) produce neurotrophic factors and have some neuroprotective effects, stem cell therapy has been proposed as an alternative or add-on treatment for ALS patients.

METHOD & MATERIAL: In this open-label clinical trial, two-repeated dose of 60 million GMP compliant Wharton's Jelly-derived Mesenchymal Stromal Cells (WJ-MSCs) were transplanted intrathecally (#6 patients) or intravenously (#6 patients) twice with a 3-month interval.

RESULTS: No adverse events related to the intervention or injected cells were reported. While no significant improvement in the total revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score or overall clinical efficacy was achieved, patients reported improvements in specific sub-items such as salivation, swallowing, and their speech. Additionally, reductions in muscle tremors and fasciculations, as well as increased muscle strength were observed.

CONCLUSION: In conclusion, using WJ-MSCs is safe and feasible in ALS patients, but the efficacy of these cells should be assessed in future studies with more patients, different routes of cell administration, and maybe with higher doses of the injected cells.}, } @article {pmid40881744, year = {2025}, author = {Zeppieri, M}, title = {Advantages and future outlooks in the use of telemedicine in liver transplantation.}, journal = {World journal of transplantation}, volume = {15}, number = {3}, pages = {104825}, pmid = {40881744}, issn = {2220-3230}, abstract = {To maintain care during the coronavirus disease 2019 outbreak, telemedicine was implemented quickly. Jowell et al's pandemic study on telehealth integration and liver transplant evaluation is examined in this editorial. The study showed that telehealth did not affect clinical outcomes including time to evaluation, listing rates, or pre-transplant death. The study found that telehealth did not increase sociodemographic inequalities, suggesting a fair care framework. The editorial discusses how telemedicine in hepatology might help patients receive expert treatment while reducing logistical and financial burdens. Telehealth can democratize liver transplantation by delivering equivalent clinical results as in-person examinations. However, the editorial highlights technological barriers, difficulties in remotely assessing mental and physical health, and the need for specialized outreach to underserved communities. After the pandemic, telemedicine is essential to a more flexible, patient-centered healthcare system. The editorial encourages creativity and research to overcome challenges, improve hybrid care models, and ensure telehealth's egalitarian and successful potential. Pandemic insights can improve liver transplantation treatment and outcomes for diverse patient populations.}, } @article {pmid40883656, year = {2026}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {Geographic distribution of amyotrophic lateral sclerosis-related genes: a systematic review.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {4}, pages = {511-517}, pmid = {40883656}, issn = {1758-2032}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Genetic Predisposition to Disease ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease. There is no effective treatment, but disease-modifying therapies do exist. Objective. To identify the geographical distribution of ALS-related genes.

METHODS: A systematic review was conducted according to the PRISMA 2020 guidelines in PubMed and Web of Science. Inclusion criteria: patients with ALS, no age or gender restriction, English and Spanish languages, studies published until 31 July 2025.

RESULTS: Thirty-eight results were obtained, 32 were selected, 19 articles were assessed for eligibility, and 8 articles were included from databases. Three articles recommended by clinical experts were added, so 11 results were reviewed. This research showed that published articles on the geographic distribution of ALS-related genes are limited, particularly for underrepresented regions such as Africa.

CONCLUSION: The findings demonstrate the need for intensified international research to improve knowledge of the genetic epidemiology of ALS.}, } @article {pmid40884436, year = {2025}, author = {Berry, JD and Bowser, R}, title = {Cardiac Troponin T in Tofersen-Treated SOD1 ALS Patients: Beginning to Resolve the Catch-22 of Identifying Treatment Responsive Biomarkers in ALS Drug Development.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1039-1041}, doi = {10.1002/mus.70017}, pmid = {40884436}, issn = {1097-4598}, } @article {pmid40885478, year = {2025}, author = {Hafiz, B and Aldahlawi, A and Ashqar, A and Hamzah, A and Alotaibi, Y and Bajunaid, K and Baeesa, S}, title = {Outcomes of Surgical versus Endovascular Treatment of Spinal Dural Arteriovenous Fistula: A Systematic Review and Meta-Analysis.}, journal = {World neurosurgery}, volume = {202}, number = {}, pages = {124420}, doi = {10.1016/j.wneu.2025.124420}, pmid = {40885478}, issn = {1878-8769}, mesh = {Humans ; *Central Nervous System Vascular Malformations/surgery ; *Endovascular Procedures/methods ; Treatment Outcome ; Embolization, Therapeutic/methods ; *Neurosurgical Procedures/methods ; *Microsurgery/methods ; }, abstract = {BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are the most prevalent type of spinal vascular malformation and can lead to progressive neurological impairments if left untreated. Endovascular embolization and microsurgical resection are treatment options, although the optimal treatment method remains a subject of debate. Our objective is to conduct a comprehensive systematic review and meta-analysis to compare the outcomes of endovascular and microsurgical treatments for SDAVFs.

METHODS: An exhaustive literature search was conducted in the PubMed, Embase, Scopus, and Web of Science databases, encompassing publications from 2014 to 2024. A total of 522 patients from 7 studies (417 surgical and 105 endovascular) met the inclusion criteria. Information on post-treatment complications, recurrence/failure rates, and functional improvement as assessed by the Aminoff-Logue Scale (ALS) or modified ALS was extracted. I[2] statistics were used to evaluate heterogeneity, and random-effects models were used to compute risk ratios and odds ratios.

RESULTS: Compared to endovascular intervention, surgical treatment was linked to significantly lower rates of recurrence or treatment failure (risk ratio: 0.19; 95% confidence interval: 0.09-0.39; P < 0.001), especially in long-term follow-up and thoracic-level studies. With greater ALS/modified ALS gains and a higher percentage of patients achieving full or partial recovery, functional improvement favored surgery. Although complication types varied, complication rates were similar across modalities (odds ratio: 0.84; 95% confidence interval: 0.48-1.49). Asymmetry in funnel plots indicated possible publication bias in favor of successful surgical outcomes.

CONCLUSIONS: For SDAVFs, surgical ligation provides better long-term results than endovascular embolization in terms of neurological recovery and recurrence prevention. Even though both procedures are usually safe, surgery is the recommended first-line course of action due to the higher failure and recurrence rates linked to embolization, especially in patients with operable anatomy and progressive symptoms.}, } @article {pmid40894255, year = {2025}, author = {Hu, N and Chen, L and Hu, G and Ma, R}, title = {Advancements in extracellular vesicle therapy for neurodegenerative diseases.}, journal = {Exploration of neuroprotective therapy}, volume = {5}, number = {}, pages = {}, pmid = {40894255}, issn = {2769-6510}, support = {R01 DA043138/DA/NIDA NIH HHS/United States ; R01 MH112848/MH/NIMH NIH HHS/United States ; R21 DA042704/DA/NIDA NIH HHS/United States ; R21 DA046831/DA/NIDA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.}, } @article {pmid40897843, year = {2025}, author = {Lai, Q and Zhang, X and Jiang, S and Krzyaniak, MD and Alayoglu, S and Agarwal, A and Liu, Y and Edenfield, WC and Kobayashi, T and Wang, Y and Dravid, V and Wasielewski, MR and Miller, JT and Kratish, Y and Marks, TJ}, title = {Stable single-site organonickel catalyst preferentially hydrogenolyses branched polyolefin C-C bonds.}, journal = {Nature chemistry}, volume = {17}, number = {10}, pages = {1488-1496}, pmid = {40897843}, issn = {1755-4349}, support = {DOE DE-SC0024448//U.S. Department of Energy (DOE)/ ; DE-FG02-99ER14999//U.S. Department of Energy (DOE)/ ; DE-SC0001329//U.S. Department of Energy (DOE)/ ; DE-SC0012704//U.S. Department of Energy (DOE)/ ; NSF ECCS-2025633//National Science Foundation (NSF)/ ; NNA04CC36G//NASA | Ames Research Center/ ; }, abstract = {Current methods of processing accumulated polyolefin waste typically require harsh conditions, precious metals or high metal loadings to achieve appreciable activities. Here we examined supported, single-site organonickel catalysts for polyolefin upcycling. Chemisorption of Ni(COD)2 (COD, 1,5-cyclooctadiene) onto Brønsted acidic sulfated alumina (AlS) yields a highly electrophilic Ni(I) precatalyst, AlS/Ni(COD)2, which is converted under H2 to the active AlS/Ni[II]H catalyst. This single-site system exhibits unique hydrogenolysis selectivity that favours cleaving branched polyolefin C-C linkages, enabling the hydrogenolytic separation of polyethylene and isotactic polypropylene (iPP) mixtures. Moreover, AlS/Ni[II]H remains highly selective and active for hydrogenolysis of iPP admixed with polyvinyl chloride, and the spent catalyst can be repeatedly regenerated by AlEt3 treatment. Experimental mechanistic analysis and density functional theory modelling reveal a turnover-limiting C-C scission pathway featuring β-alkyl transfer and strong olefin binding. These results highlight the potential of nickel-based systems for the selective upcycling of complex plastic waste streams.}, } @article {pmid40897992, year = {2025}, author = {Quigley, SE and Quigg, KH and Goutman, SA}, title = {Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.}, journal = {CNS drugs}, volume = {39}, number = {10}, pages = {949-993}, pmid = {40897992}, issn = {1179-1934}, support = {R01NS127188/NH/NIH HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; R01TS000344/ACL/ACL HHS/United States ; R01NS120926/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/physiopathology/drug therapy ; Animals ; Clinical Trials as Topic/methods ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.}, } @article {pmid40898684, year = {2026}, author = {Zhu, Y and Bai, J and Wang, H and Li, M and Yang, F and Pang, X and Du, R and Zhao, J and Huang, X and Cui, F}, title = {The difference between cystatin C- and creatinine-based estimated glomerular filtration rate and survival in amyotrophic lateral sclerosis: a population-based cohort study.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {2}, pages = {153-161}, pmid = {40898684}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/blood ; *Cystatin C/blood ; *Glomerular Filtration Rate/physiology ; Female ; Male ; Middle Aged ; *Creatinine/blood ; Aged ; Prognosis ; Cohort Studies ; Adult ; Biomarkers/blood ; }, abstract = {OBJECTIVES: We investigated the relationship between cystatin C- and creatinine-based estimated glomerular filtration rate (eGFRdiff) and amyotrophic lateral sclerosis (ALS) outcomes.

METHODS: We enrolled ALS patients diagnosed between January 2014 and December 2019. Experienced neurologists followed up the participants until January 2022. Absolute difference between eGFR (eGFRabdiff) and relative difference between eGFR (eGFRrediff) were obtained. Cox proportional hazard models were used to evaluate the relationship between eGFRdiff and ALS survival.

RESULTS: Negative eGFRabdiff were common in the patients (74.7%). For each SD increase of eGFRabdiff, the risk of poor prognosis for ALS patients decreased by 1.9% (HR, 0.981; 95% CI, 0.973-0.989). For each 10% increment in eGFRrediff, the risk of poor prognosis for ALS patients decreased by 17.7% (HR, 0.823; 95% CI, 754-0.898).

CONCLUSIONS: We found that large eGFRdiff was associated with poor prognosis in ALS. Monitoring eGFRdiff in ALS population facilitates prognostic stratification assessment and precise management.}, } @article {pmid40901171, year = {2025}, author = {Budha, B and Chapagain, A and Adhikari, D and Bajracharya, S and Poudel, D and Budha, R and Adhikari, S and Gurmaita, RK}, title = {Acquired hemophilia a in a female with minimal change disease and hypothyroidism: a rare case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {9}, pages = {6168-6172}, pmid = {40901171}, issn = {2049-0801}, abstract = {INTRODUCTION: Juvenile amyotrophic lateral sclerosis (J-ALS) is extremely rare neurodegenerative motor neuron disorder that begins in early childhood or adolescence, before the age of 25 years old. It is characterized by gradual disease progression with comparison to adult-onset ALS and is often linked to genetic mutations.

CASE PRESENTATION: A 16-years-old female presented with long history of generalized weakness since age of 10 years, followed by bilateral sensorineural hearing loss, bulbar symptoms, and limb spasticity. Neurological examination revealed upper motor neuron signs in upper limbs, lower motor neuron signs in lower limbs, and bulbar involvement. Nerve conduction test was normal however, MRI showed early degenerative changes, and diagnosed with J-ALS after careful evaluation. She was started on Riluzole. Despite ICU care and supportive interventions including PEG and tracheostomy, she succumbed to respiratory failure.

DISCUSSION: Rarity, atypical presentation, and finical constraints can delay diagnosis of J-ALS. However, early diagnosis after careful evaluation of clinical symptoms, medical history, electrophysiological and imaging studies followed by prompt treatment with Riluzole and supportive interventions can help prolong survival and improve quality of life.

CONCLUSION: J-ALS is a rare motor neuron disease which possess immense diagnostic challenges, can exhibit relentless progression over short period of time with time.}, } @article {pmid40901333, year = {2025}, author = {Agrawal, H and Gupta, N}, title = {Deep learning models for pathological classification and staging of oesophageal cancer.}, journal = {World journal of clinical oncology}, volume = {16}, number = {8}, pages = {109893}, pmid = {40901333}, issn = {2218-4333}, abstract = {This letter comments on Wei et al's study applying the Wave-Vision Transformer for oesophageal cancer classification. Highlighting its superior accuracy and efficiency, we discuss its potential clinical impact, limitations in dataset diversity, and the need for explainable artificial intelligence to enhance adoption in pathology and personalized treatment.}, } @article {pmid40903950, year = {2026}, author = {Liu, Y and Tang, T and Cai, H and Liu, Z}, title = {Bidirectional communication between the gut microbiota and the central nervous system.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3411-3425}, pmid = {40903950}, issn = {1673-5374}, abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiota-based treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.}, } @article {pmid40903956, year = {2026}, author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L}, title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3387-3410}, pmid = {40903956}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domain-like receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.}, } @article {pmid40903965, year = {2026}, author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M}, title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4148-4156}, pmid = {40903965}, issn = {1673-5374}, abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.}, } @article {pmid40904199, year = {2025}, author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME}, title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70577}, pmid = {40904199}, issn = {1755-5949}, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; }, abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.

RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.

CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.}, } @article {pmid40904817, year = {2025}, author = {Kuo, T and Reynolds, T and Chen, L and Park, C and Rascati, K and Godley, P}, title = {Racial and ethnic disparities in ALS: a longitudinal electronic health records study.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251365001}, pmid = {40904817}, issn = {1756-2856}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options and significant variability in care. Racial and ethnic disparities in ALS management and outcomes have been reported, but findings remain inconsistent.

OBJECTIVES: This study aimed to evaluate racial and ethnic disparities in ALS care, specifically differences in healthcare utilization, treatment patterns, and survival, within a large healthcare system.

DESIGN: This retrospective cohort study analyzed electronic health records from a large healthcare system in Texas for patients diagnosed with ALS between 2013 and 2023, examining racial and ethnic differences in treatment and outcomes.

METHODS: Patients were identified using International Classification of Diseases (ICD) codes. Baseline characteristics, including race/ethnicity and socioeconomic factors, were collected. Primary outcomes included the use of noninvasive ventilation (NIV), tracheostomy, gastrostomy, mobility aids, and ALS medications; secondary outcomes included time to diagnosis and survival. Racial and ethnic disparities were assessed using generalized linear regression and Cox proportional hazards models, adjusting for demographic and socioeconomic factors.

RESULTS: A total of 636 patients were included (74.5% Non-Hispanic White, 5.3% Non-Hispanic Black, 7.4% Hispanic, and 12.7% Other). Non-Hispanic Black patients had significantly higher tracheostomy rates than Non-Hispanic White patients (35.3% vs 8.7%; adjusted odds ratio (OR), 6.20; 95% confidence interval (CI), 2.43-15.84). Hispanic patients had lower odds of receiving riluzole (42.6% vs 61.8%; adjusted OR, 0.36; 95% CI, 0.18-0.71) and higher rates of emergency department visits (adjusted OR, 2.00; 95% CI, 1.09-3.65) and hospitalizations (adjusted OR, 2.57; 95% CI, 1.37-4.81). No significant racial or ethnic differences were observed in time to diagnosis or survival after adjustment.

CONCLUSION: Significant racial and ethnic disparities exist in ALS care, particularly in tracheostomy utilization, medication prescribing, and healthcare access. These findings underscore the need for targeted interventions to promote equitable ALS management, including provider education and improved healthcare accessibility.}, } @article {pmid40905501, year = {2026}, author = {Huang, Y and Wan, Y and Chen, J and Qin, M and Wang, J and Liang, H}, title = {Knowledge mapping of biomarkers in amyotrophic lateral sclerosis: a comprehensive bibliometric and visual analysis.}, journal = {Neurodegenerative disease management}, volume = {16}, number = {2}, pages = {191-207}, pmid = {40905501}, issn = {1758-2032}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid ; Humans ; *Biomarkers/cerebrospinal fluid ; *Bibliometrics ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, and there is currently an urgent need to identify valuable biomarkers to accelerate diagnosis, optimize treatment and prognosis.

METHODS: To conduct a bibliometric analysis of publications related to "ALS biomarker" over the past 20 years, utilizing the subject search feature of the Web of Science Core Collection along with CiteSpace, VOSviewer, and Bibliometrix.

RESULTS: This review presents a 20-year bibliometric analysis of ALS biomarker research (2004-2024), analyzing 2535 publications showing rising trends. The United States led contributions, with Turner, Martin R as the most productive/cited author. Key research hotspots included cerebrospinal fluid, tdp-43, clinical trial, and neuroinflammation. Topics such as neurofilament light chain, machine learning, and exosomes could potentially represent the cutting edge of future research.

CONCLUSION: In summary, this study uses bibliometric analysis of ALS biomarker research to provide a forward-looking perspective on its future limitations and potential.}, } @article {pmid40906916, year = {2025}, author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT}, title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3425-3437}, doi = {10.1021/acschemneuro.5c00376}, pmid = {40906916}, issn = {1948-7193}, mesh = {Animals ; Administration, Intranasal/methods ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Delivery Systems/methods ; Humans ; Mice ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.}, } @article {pmid40908696, year = {2025}, author = {Paul, S and Tiwari, P and Dubey, S}, title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.}, journal = {Protein and peptide letters}, volume = {32}, number = {8}, pages = {539-556}, pmid = {40908696}, issn = {1875-5305}, mesh = {Humans ; *Drug Discovery/methods ; *Neurodegenerative Diseases/drug therapy/enzymology ; Molecular Docking Simulation ; *Enzyme Inhibitors/chemistry/therapeutic use/pharmacology ; Animals ; }, abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management.

METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes.

RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects.

DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity.

CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.}, } @article {pmid40908710, year = {2025}, author = {Giove, E and Ferraro, PM and Lungu, M and Pasquinelli, L and Truffelli, R and Trinchero, C and Rebagliati, B and Caponnetto, C and Vignolo, M and Rao, F}, title = {Effects of Dog-Assisted Occupational Therapy on Upper Limb Functions in ALS and Other Neuromuscular Disorders: A Randomized Controlled Pilot Study.}, journal = {Muscle & nerve}, volume = {72}, number = {5}, pages = {1122-1129}, doi = {10.1002/mus.70012}, pmid = {40908710}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/psychology ; Male ; Female ; Pilot Projects ; Middle Aged ; *Animal Assisted Therapy/methods ; *Upper Extremity/physiopathology ; Aged ; *Occupational Therapy/methods ; Animals ; Dogs ; Hand Strength/physiology ; *Neuromuscular Diseases/rehabilitation/physiopathology ; Treatment Outcome ; Adult ; }, abstract = {INTRODUCTION/AIMS: The beneficial effects of animal-assisted therapy (AAT) on balance, walking endurance, and mood symptoms in amyotrophic lateral sclerosis (ALS) have been previously demonstrated. In this study, we aimed at expanding upon these findings by further evaluating its effects on upper limb (UL) functions and mood symptoms both in ALS and other neuromuscular disorders (NMDs).

METHODS: Sixty-eight patients participated in a regular 2-week occupational therapy program once a day. For three days a week, in place of the traditional treatment, the AAT group (N = 34) performed a session in interaction with the therapy dog. Outcome measures included hand grip strength, manual dexterity, and mood symptoms. Differences between baseline and post-treatment values were assessed using the Wilcoxon Signed-Rank Test, and one-way analysis of covariance was used to examine between-group differences in post-treatment values, adjusting for baseline measurements.

RESULTS: Both groups improved in hand grip strength (p = 0.004-0.03), whereas mood symptoms improved exclusively in the AAT group (p = 0.0003-0.03). Post-treatment values were significantly better in the AAT group (p = 0.01-0.03). When ALS patients were analyzed separately, the improvement of hand grip strength and mood symptoms was observed only in the AAT group (p = 0.001-0.04), which accordingly showed better post-treatment values (p = 0.0007-0.05).

DISCUSSION: Our findings indicate that AAT has greater beneficial effects than traditional treatments on UL strength and mood symptoms. These findings have the potential to facilitate more effective rehabilitation strategies both in ALS and other NMDs.}, } @article {pmid40908789, year = {2026}, author = {Carletta, O and Perfetto, C and Rifai, OM and Manganelli, F and Waldron, FM and Maniatis, T and Gregory, JM and Gerbino, V}, title = {Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {2}, pages = {489-501}, doi = {10.1093/brain/awaf324}, pmid = {40908789}, issn = {1460-2156}, support = {883-791//Motor Neuron Disease Association Biomedical/ ; //V.G. and T.M./ ; GR-2021-12375436//Italian Ministry of Health/ ; //AriSLA (motorTBK1)/ ; 2021/MNDS/RP/8440GREG//MND Scotland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/immunology ; Humans ; Animals ; Female ; Male ; Mice ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Genotype ; *Interferon Type I/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Severity of Illness Index ; Cohort Studies ; *Interferons/genetics ; Mice, Transgenic ; Adult ; Mutation ; }, abstract = {Innate immune signalling pathways are hyperactivated in the CNS of patients with amyotrophic lateral sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1 and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial. Here, we systematically profile type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n = 18), genetic ALS caused by: (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n = 11); and (ii) a SOD1 mutation (SOD1-ALS; n = 5), alongside age- and sex-matched individuals who died of a non-neurological cause (n = 12). Using this deeply phenotyped cohort we have implemented targeted transcriptomic analysis and immunohistochemistry to interrogate the nature and extent of the activation of the type-I IFN response in patients. We determined disease- and genotype-specific IFN signatures that correlate with clinical phenotype. Correlation analysis linked six ISGs with aggressive disease progression, as indicated by negative correlation with age at death in ALS patients. Notably, significant upregulation of ISGs was observed in C9-ALS patients, with higher ISG expression correlating with shorter disease duration. Noting that our genotype- and disease-specific signatures correlated with metrics of disease progression, we explored the therapeutic potential of targeting this pathway in a mouse model of ALS. Treatment with an IFN pathway inhibitor reduced IFN response markers, delayed disease progression, including motor decline, and extended survival in ALS mice. We conclude that upregulation of gene expression in the type-I IFN pathway represents a key pathological feature of ALS and that inhibiting this pathway may provide a promising therapeutic approach for treating ALS.}, } @article {pmid40909873, year = {2025}, author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J}, title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.}, journal = {FASEB bioAdvances}, volume = {7}, number = {8}, pages = {e70041}, pmid = {40909873}, issn = {2573-9832}, abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.}, } @article {pmid40913874, year = {2025}, author = {Peethambaran, ST and Ashokan, A and Subhose, V}, title = {A case report on Ayurvedic management of progressive bulbar palsy-A rare amyotrophic lateral sclerosis phenotype.}, journal = {Journal of Ayurveda and integrative medicine}, volume = {16}, number = {5}, pages = {101176}, pmid = {40913874}, issn = {0975-9476}, abstract = {This case report is the description of a devastating illness, Progressive Bulbar Palsy (PBP) of a sixty-seven years old male patient. He presented with complaints of slurred speech, hearing impairment, generalised weakness of limbs, weakened grip to hold objects in hand, difficulty to walk with normal speed, frequent dizzy feeling while walking, severe fatigue, increased anger, heaviness of head, depression, anxiety, decreased memory and headache for 1 year. When he consulted conventional medicine, in Magnetic Resonance Imaging (MRI) of brain, only 'Partial empty sella' and age related mild cerebral atrophy was detected and the patient was diagnosed PBP clinically. They prescribed Riluzole 50 mg tablet twice a day and Fluoxetine 10mg capsules at night time for 3 months, but obtained no relief for symptoms and consulted this Out Patient Department (OPD). In Ayurvedic parlance, PBP resembles conditions like Kaphavruta vata. In this patient, Pittavritavata symptoms like bhrama (∼dizziness) was also present in increased severity. Diagnosis was done with the aid of Gold Coast diagnostic criteria. Internal and external medications with properties alleviating avarana (∼occlusion) of vata by kapha and pitta, shodhana (∼expelling the aggravated doshas and cleanses the body internally), rejuvenating (Rasayana) properties, for overall strengthening of nervous system and musculoskeletal system, enhancing balance and coordination, improving speech and memory were used. The assessment was done before and after the treatment by 'Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The score before and after the treatment was 35 and 45 respectively out of 48. The treatment helped to increase the quality of life exceptionally as symptomatic relief was obtained. As it is a devastating disorder with poor prognosis and most probably will lead to death, it is advisable to repeat the treatments in regular intervals, depending on the recurrence of symptoms, if any.}, } @article {pmid40916343, year = {2026}, author = {Wu, J and Guo, J and Wu, J and Song, J and Xu, J and Lin, Y and Huang, C and Shi, C and Li, J and Li, C and Chen, Y and Wang, W and Gao, J and Zhou, Q and Zhang, Y and Li, S and Li, XJ and Zhang, CY and Chen, X and Yan, S}, title = {In vivo self-assembled siRNAs ameliorate neurological pathology in TDP-43-associated neurodegenerative disease.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {3}, pages = {828-839}, doi = {10.1093/brain/awaf330}, pmid = {40916343}, issn = {1460-2156}, support = {2021YFA0805300//National Key Research and Development Program of China/ ; 82171244//National Natural Science Foundation of China/ ; 32470564//National Natural Science Foundation of China/ ; 81922026//National Natural Science Foundation of China/ ; 32170981//National Natural Science Foundation of China/ ; 82271902//National Natural Science Foundation of China/ ; 82394422//National Natural Science Foundation of China/ ; 82371874//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; *RNA, Small Interfering/administration & dosage/genetics/therapeutic use ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Genetic Therapy/methods ; Disease Models, Animal ; *Neurodegenerative Diseases/pathology/genetics/therapy ; }, abstract = {Abnormal accumulation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Small interfering RNAs (siRNAs) targeting TDP-43 offer potential therapeutic strategies for these diseases. However, efficient and safe delivery of siRNAs to the CNS remains a challenge. Here, we present a synthetic biology-based approach that leverages endogenous small RNA processing machinery to self-assemble siRNA-encapsulating small extracellular vesicles and uses the natural circulatory system of the host to transport siRNAs. Specifically, we engineered liver cells to express and package TDP-43-targeting siRNAs into rabies virus glycoprotein-tagged small extracellular vesicles, which are released into the circulation and cross the blood-brain barrier to deliver siRNAs to the CNS. In a mouse model of TDP-43 pathology induced by stereotactic injection of mutant TDP-43 (M337V) virus, treatment with in vivo self-assembled TDP-43 siRNAs (IVSA-siR-TDP43) effectively reduced TDP-43 accumulation, leading to significant improvements in motor function and neuropathology. Additionally, an adeno-associated virus-based delivery system was used to produce IVSA-siR-TDP43, demonstrating sustained therapeutic effects in TDP-43-associated neurodegeneration. These findings highlight a novel, effective and minimally invasive gene therapy platform for addressing TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, offering a promising avenue for future clinical applications.}, } @article {pmid40919318, year = {2025}, author = {Harrison, D and Billinton, A and Bock, MG and Clarke, NP and Digby, Z and Gabel, CA and Lindsay, N and Reader, V and Scanlon, J and Smolak, P and Thornton, P and Wescott, H and Watt, AP}, title = {Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.}, journal = {RSC medicinal chemistry}, volume = {16}, number = {11}, pages = {5318-5332}, pmid = {40919318}, issn = {2632-8682}, abstract = {Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.}, } @article {pmid40920272, year = {2025}, author = {Ku, JB and Pak, RJ and Ku, SS and Holland, RD and Kim, HS}, title = {Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review.}, journal = {Tissue engineering and regenerative medicine}, volume = {22}, number = {8}, pages = {1051-1066}, pmid = {40920272}, issn = {2212-5469}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation ; *Spinal Cord Injuries/therapy ; Animals ; Amyotrophic Lateral Sclerosis/therapy ; *Cell- and Tissue-Based Therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Neurotraumatic conditions, such as spinal cord injury, brain injury, and neurodegenerative conditions, such as amyotrophic lateral sclerosis, pose a challenge to the field of rehabilitation for its complexity and nuances in management. For decades, the use of cell therapy in treatment of neurorehabilitation conditions have been explored to complement the current, mainstay treatment options; however, a consensus for standardization of the cell therapy and its efficacy has not been reached in the medical community. This study aims to provide a comparative review on the very topic of cell therapy use in neurorehabilitation conditions in an attempt to bridge the gap in knowledge.

METHODS: Studies were searched from the PubMed database published from 2014 to 2024 employing the terms including but not exclusive to "spinal cord injury," "brain injury," "amyotrophic lateral sclerosis," "regenerative medicine," "cell therapy," and "stem cell." Following the PRISMA 2020 statement, the studies were screened, included, and excluded. Thirty three studies were identified and selected for this review.

RESULTS: Countless researchers investigated the efficacy of various stem cell products for the treatment of numerous neurotraumatic conditions, such as spinal cord injury, traumatic brain injury, and neurodegenerative conditions such as amyotrophic lateral sclerosis. The recent decade of studies suggest that in neurotraumatic conditions, bone-marrow-derived and neural stem cells can be effective, and in neurodegenerative conditions, such as ALS, mesenchymal and neural stem cells can be efficacious.

CONCLUSION: Emerging data from the latest research is encouraging to the patients suffering from neurotraumatic and neurodegenerative conditions, which present themselves as a need for further studies with improved standardization in study design, including cell source specification, differentiation and culture method, and outcome measures to ensure a wide applicability.}, } @article {pmid40922888, year = {2025}, author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF}, title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e89629}, pmid = {40922888}, issn = {2168-8184}, abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.}, } @article {pmid40923926, year = {2025}, author = {Arnold, L and Tomsitz, D and Buchillon, R and Leding, J and Senner, S and Frey, S and Janjic, N and French, LE and Heinzerling, L}, title = {Successful treatment of localized Merkel cell carcinoma with avelumab in a patient with amyotrophic lateral sclerosis.}, journal = {Immunotherapy}, volume = {17}, number = {12}, pages = {867-870}, pmid = {40923926}, issn = {1750-7448}, mesh = {Aged ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Antineoplastic Agents, Immunological/therapeutic use ; *Carcinoma, Merkel Cell/drug therapy/complications ; Immune Checkpoint Inhibitors/therapeutic use ; *Skin Neoplasms/drug therapy/complications ; Treatment Outcome ; }, abstract = {Currently, the first-line treatment of non-metastatic Merkel cell carcinoma (MCC) is complete resection. In case of unresectable or metastatic MCC, immune checkpoint inhibitor (ICI) therapy with avelumab (or in the US also pembrolizumab or retifanlimab) is indicated. We report on a patient with a primary, non-metastatic MCC on the left eyelid and amyotrophic lateral sclerosis (ALS). Due to ALS, the patient's communication was limited to eye movement and blinking. Complete resection or definitive radiotherapy of the tumor while preserving the function of the eye muscles was not possible. No prior data was available for patients with ALS under ICI therapy. In agreement with the patient and his family, a monotherapy with avelumab, a programmed death ligand 1 (PD-L1) inhibitor, was initiated. This led to a complete remission of the tumor with a progression-free survival of over 24 months and importantly no deterioration of the ALS.}, } @article {pmid40925732, year = {2025}, author = {, }, title = {[Expert consensus on the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {48}, number = {9}, pages = {815-830}, doi = {10.3760/cma.j.cn112147-20250614-00332}, pmid = {40925732}, issn = {1001-0939}, support = {82270107//National Natural Science Fundation of China/ ; }, mesh = {Humans ; *Neuromuscular Diseases/complications ; *Sleep Apnea Syndromes/diagnosis/therapy/etiology ; Noninvasive Ventilation ; Sleep Apnea, Obstructive/diagnosis/therapy ; China ; }, abstract = {Neuromuscular diseases are often accompanied by various types of sleep-related breathing disorders, which can exacerbate the underlying condition and are associated with a poor prognosis. Early identification is essential, and interventions such as non-invasive ventilation, oxygen therapy, and respiratory rehabilitation should be initiated promptly to mitigate disease progression and improve outcomes. Nevertheless, the rates of missed and misdiagnosed cases remain common in clinical practice. Currently, there are no standardized guidelines for the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases in China. Therefore, based on the latest domestic and international research progress, and combined with domestic clinical diagnosis and treatment experience, the Sleep Disorder Group of Chinese Thoracic Society has brought together multidisciplinary experts to develop this expert consensus. This consensus provides a comprehensive overview of the epidemiology, clinical manifestations, diagnostic approaches, assessment strategies, and treatment of sleep-disordered breathing related to neuromuscular diseases. It formulates evidence-based recommendations to guide clinical practice, with the aim of providing standardized recommendations for their diagnosis and management.Statement 1: The neuromuscular disorders that are most frequently associated with sleep-disordered breathing include: myasthenia gravis (1A), amyotrophic lateral sclerosis (2B), post-polio syndrome (2B), myotonic dystrophy (2B), peripheral neuropathies (2C), and metabolic myopathies, among other neuromuscular conditions.Statement 2: Patients with neuromuscular disorders frequently develop multiple types of sleep-disordered breathing concurrently or sequentially, with obstructive sleep apnea (OSA) being the most prevalent manifestation. Distinct clinical manifestations of OSA are observed across different neuromuscular disease subtypes (1A).Statement 3: Neuromuscular disorders predispose to central sleep apnea (CSA), with clinical manifestations varying significantly across disease subtypes, stages of progression, and severity levels (1A).Recommendation 1: In patients with neuromuscular disorders exhibiting progressive hypercapnia or worsening hypoxemia, clinicians should investigate potential comorbid nocturnal alveolar hypoventilation and/or sleep-associated hypoxemia (1A).Recommendation 2: When sleep-disordered breathing is suspected, patients with neuromuscular disorders should be evaluated for symptoms of sleep-disordered breathing. Meanwhile, sleep monitoring, non-invasive CO2 monitoring, and related examinations should be actively performed according to the actual situation (1A). A polysomnography should be performed when there is a high clinical suspicion of sleep-disordered breathing but a negative result on a portable sleep monitor (1A).Recommendation 3: (1) Noninvasive positive pressure ventilation (NPPV) titration under polysomnography is the standard method to determine the effective treatment parameters for neuromuscular diseases with sleep-disordered breathing (1A). (2) Positive airway pressure titration in OSA patients with neuromuscular diseases should follow American Academy of Sleep Medicine (AASM) guidelines (1A). (3) For neuromuscular disorders with CSA or Cheyne-Stokes respiration, bi-level positive airway pressure (BPAP) with ST pattern is recommended (1A); When BPAP is not tolerated or accompanied by severe Cheyne-Stokes respiratory and heart failure in patients, adaptive support ventilation (ASV) should be used (2B). (4) Patients with neuromuscular disease and sleep-related alveolar hypoventilation should be treated with BPAP or variable assurance pressure support (VAPS) (1A). (5) BPAP with alternate frequency is preferred for neuromuscular disorders with "pseudo-central events" (1A).Recommendation 4: Oxygen therapy alone is not recommended for neuromuscular disease patients combined with sleep-disordered breathing (2D). Oxygen therapy with monitoring of CO2 level is recommended when non-invasive ventilation therapy cannot effectively correct hypoxemia (2C). Diaphragmatic pacing should not be routinely used in amyotrophic lateral sclerosis patients with respiratory failure (2B). Transvenous phrenic nerve stimulation is not currently applied to CSA caused by neuromuscular disorders (2D). Respiratory rehabilitation may improve respiratory muscle strength in a subset of patients with neuromuscular disorders (2B). Protiline can be used for REM-associated alveolar hypoventilation, and daytime sleepiness could be addressed with methylphenidate and modafinil (2C).Recommendation 5: Neuromuscular disease combined with sleep-disordered breathing is a chronic disease requiring patient-centered, individualized education and long-term follow-up management (1A).}, } @article {pmid40926822, year = {2025}, author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q}, title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.}, journal = {Alpha psychiatry}, volume = {26}, number = {4}, pages = {46108}, pmid = {40926822}, issn = {2757-8038}, abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders.

METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model.

RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029).

CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.}, } @article {pmid40930472, year = {2025}, author = {Roger, AL and Huston, ML and Spaulding, M and Metz, CM and Froeb, R and Wu, R and Kehoe, S and Mitchell, GS and ElMallah, MK}, title = {Therapeutic acute intermittent hypoxia modestly improves breathing in Pompe disease.}, journal = {Respiratory physiology & neurobiology}, volume = {338}, number = {}, pages = {104489}, doi = {10.1016/j.resp.2025.104489}, pmid = {40930472}, issn = {1878-1519}, support = {K99 HL161420/HL/NHLBI NIH HHS/United States ; }, mesh = {*Glycogen Storage Disease Type II/therapy/complications/physiopathology ; Animals ; Mice ; Disease Models, Animal ; *Hypoxia ; alpha-Glucosidases/genetics/deficiency ; Male ; Diaphragm/physiopathology ; Motor Neurons/physiology ; Mice, Knockout ; *Respiration ; Mice, Inbred C57BL ; }, abstract = {Pompe disease is an autosomal recessive neuromuscular disorder characterized by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for lysosomal glycogen degradation in all cells. Respiratory distress is a common symptom among patients with Pompe disease resulting from weakness of primary respiratory neuromuscular units of the diaphragm and genioglossus and the motor neurons which innervate them. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA) which slows the decline of motor function and extends life expectancy. However, ERT does not cross the blood-brain barrier and thus, is unable to treat the critical pathology present in motor neurons hindering long-term efficacy. In the present study, we sought to explore an alternative treatment for Pompe patients to improve breathing by improving the function of motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a non-invasive therapeutic modality which has had success in improving respiratory and non-respiratory motor function in patients with spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Here, we treated adult Gaa[-/-] mice with a single, week-long tAIH protocol, followed by bi-weekly tAIH for 4 months. We report three critical findings: (1) both short and long-term tAIH therapy modestly improve breathing in Gaa[-/-] mice; (2) long-term tAIH-therapy in WT mice moderately elevates breathing responses; and (3) these trending improvements to respiration in Gaa[-/-] may be related to changes in chemoreflex activation, reduced kyphosis, and improved overlap of acetylcholine receptors and phrenic motor neuron axon terminals in the diaphragm muscle.}, } @article {pmid40931339, year = {2025}, author = {Epplen, ASC and Rothöft, M and Stahlke, S and Theiss, C and Matschke, V}, title = {Caffeine mitigates ROS accumulation and attenuates motor neuron degeneration in the wobbler mouse model of amyotrophic lateral sclerosis.}, journal = {Cell communication and signaling : CCS}, volume = {23}, number = {1}, pages = {394}, pmid = {40931339}, issn = {1478-811X}, mesh = {Animals ; *Caffeine/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Disease Models, Animal ; *Reactive Oxygen Species/metabolism ; Mice ; Oxidative Stress/drug effects ; Male ; *Neuroprotective Agents/pharmacology ; *Nerve Degeneration/pathology/drug therapy ; NAD/metabolism ; Humans ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by oxidative stress and progressive motor neuron degeneration. This study evaluates the potential neuroprotective effects of caffeine in the Wobbler mouse, an established model of ALS.

METHODS: Wobbler mice received caffeine supplementation (60 mg/kg/day) via drinking water, and key parameters, including muscle strength, NAD metabolism, oxidative stress, and motor neuron morphology, were assessed at critical disease stages.

RESULTS: Caffeine delayed motor performance decline, as observed in grip strength tests during the early symptomatic phase. Histological analyses revealed that significantly fewer motor neurons were lost in caffeine-treated mice at p41, despite no changes in soma morphology. Biochemical assays demonstrated that caffeine significantly reduced ROS levels and restored NAD levels to wildtype-like values, although NMNAT2 protein expression remained unaffected. The data suggest that caffeine mitigates oxidative stress through alternative pathways, potentially involving enhanced mitochondrial function and antioxidative defenses.

CONCLUSIONS: These findings highlight the potential of caffeine as a protective agent for delaying motor neuron degeneration in ALS. Future studies should explore optimal dosing strategies, combinatorial treatment approaches, and the underlying molecular mechanisms, to enable translation of these findings to human ALS patients.}, } @article {pmid40932199, year = {2026}, author = {Spittel, S and Grehl, T and Weydt, P and Kettemann, D and Fabian, R and Rödiger, A and Smesny, U and Steinbach, R and Ilse, B and Weyen, U and Petri, S and Lumi, R and Bjelica, B and Lingor, P and Grosskreutz, J and Göricke, BM and Pfeilschifter, W and Schmeja, W and Dorst, J and Mensch, A and Siebert, J and Norden, J and Bernsen, S and Subramanian, SK and Hildebrandt, B and Walter, B and Münch, C and Maier, A and Meyer, T}, title = {Dextromethorphan/quinidine (DMQ) for reducing bulbar symptoms in amyotrophic lateral sclerosis - assessment of treatment experience in a multicenter study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {1-2}, pages = {185-197}, doi = {10.1080/21678421.2025.2557932}, pmid = {40932199}, issn = {2167-9223}, mesh = {Humans ; *Dextromethorphan/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Male ; Female ; Middle Aged ; *Quinidine/therapeutic use ; Aged ; Patient Reported Outcome Measures ; Drug Combinations ; Treatment Outcome ; Patient Satisfaction ; Adult ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), dextromethorphan/quinidine (DMQ) has been reported to reduce bulbar symptoms, including dysarthria and dysphagia. However, data on patients' perceptions of DMQ treatment are limited.

METHODS: Data on DMQ treatment were collected from 1065 ALS patients treated at 13 ALS centers between 10-2015 and 06-2025. Patient-reported outcome measures (PROM) of 179 participants were remotely assessed via the "ALS App". PROM included the self-explanatory version of the ALS Functional Rating Scale (ALSFRS-R-SE), the Net Promoter Score (NPS); and Treatment Satisfaction Questionnaire for Medication (TSQM-9).

RESULTS: Mean disease duration was 29.3 months (SD 38.1). ALS progression before treatment was 0.82 points/month (ALSFRS-R). Mean DMQ treatment duration was 8.4 months (SD 10.8), including 35.2% (n = 374) of shorter (<3 months), 35.3% (n = 375) of longer (3-9 months), and 29.5% (n = 313) of very long DMQ treatment (>9 months). Patients' recommendation (n = 178) was positive (NPS: +23) with higher scores after very long DMQ treatment (NPS +37) compared to longer (NPS +15) and shorter treatment (NPS +7.5), respectively. TSQM-9 scores (n = 163) demonstrated high satisfaction for effectiveness 60.0 (SD 25.9), convenience 73.8 (SD 18.2), and global satisfaction 63.4 (SD 29.8).

INTERPRETATION: The positive perception in PROM underscores the value of DMQ as an individualized treatment option for bulbar symptoms in ALS. However, shortage of clinical data, online assessment, and selection biases are among the limitations of this study that need to be addressed in further investigations.}, } @article {pmid40940798, year = {2025}, author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X}, title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940798}, issn = {2073-4409}, mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Microglia/metabolism ; Phagocytosis ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.}, } @article {pmid40943341, year = {2025}, author = {Yang, EJ}, title = {The Emerging Role of the Brain-Gut Axis in Amyotrophic Lateral Sclerosis: Pathogenesis, Mechanisms, and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943341}, issn = {1422-0067}, support = {(KIOM) KSN2224011//KIOM/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology/etiology/metabolism/pathology ; *Gastrointestinal Microbiome ; *Brain/metabolism ; Dysbiosis/microbiology/complications ; Animals ; *Brain-Gut Axis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Although genetic and environmental factors are established contributors, recent research has highlighted the critical role of the gut-brain axis (GBA) in ALS pathogenesis. The GBA is a bidirectional communication network involving neural, immune, and endocrine pathways that connect the gut microbiota with the central nervous system. Dysbiosis in ALS disrupts this axis, leading to increased intestinal permeability, neuroinflammation, and excitotoxicity. Notably, reductions in butyrate-producing bacteria, alterations in microbial metabolites, and enhanced NLRP3 inflammasome activation have been observed in patients with ALS. These changes may precede motor symptoms, suggesting a potential causative role. Interventions targeting the microbiome, such as dietary modulation, have shown promise in delaying disease onset and reducing inflammation. However, the clinical evidence remains limited. Given that gut dysbiosis may precede neurological symptoms, microbiota-targeted therapies offer a novel and potentially modifiable approach to ALS treatment. Understanding the role of GBA in ALS will open new avenues for early diagnosis and intervention. Further clinical trials are required to clarify the causal links and evaluate the efficacy of microbiome-based interventions. Understanding the brain-gut-microbiota axis in ALS could lead to new diagnostic biomarkers and therapeutic strategies.}, } @article {pmid40943950, year = {2025}, author = {Pochhammer, J and Kiani, S and Hobbensiefken, H and Hobbensiefken, H and Reichert, B and Taivankhuu, T and Becker, T and Gundlach, JP}, title = {Lactate in Drainage Fluid to Predict Complications in Robotic Esophagectomies-A Pilot Study in a Matched Cohort.}, journal = {Journal of clinical medicine}, volume = {14}, number = {17}, pages = {}, pmid = {40943950}, issn = {2077-0383}, abstract = {Background/Objectives: Despite advances in minimally invasive procedures, anastomotic leakages (ALs) after esophageal resections mark the most feared complication. Its early detection can lead to quick interventional treatment with improved survival. Nonetheless, early detection remains challenging, and scores are imprecise and complex. Methods: In our study we analyzed mediastinal drainage fluid to find parameters suggesting AL even before it became clinically evident and correlated them to routine biomarkers. All patients with AL after robotically assisted esophageal resections were included and matched 1:1 with uneventful controls. Additionally, transhiatal distal esophageal resections operated during this period were included. Drainage fluid was collected on postoperative days (PODs) 1-4 with consecutive blood gas analysis. Test quality was determined by the area under the curve (AUC) of the receiver operating characteristic curve (ROC). Results: In total, 40 patients were included, with 17 developing AL. There were no significant differences in gender, age, BMI or oncological treatment. The 30-day morbidity rate was 65.0%. The study was restricted to events in the first 12 days. While lactate value in drainage fluid differed significantly from POD 3 onwards in the two groups, serum CRP remained without significant differences. We developed the LacCRP score (CRP/30 + lactate/2). The AUC on POD 3 was 0.96, with a sensitivity and specificity of 100% and 75%, respectively. An estimator of 1.08 was found in multivariate analysis: one-point increase in the LacCRP score increases AL probability by 8%. Conclusions: This study demonstrates that postoperative lactate determinations in drainage fluid can predict AL after esophageal resection, and its combination with serum CRP results in a reliable LacCRP score.}, } @article {pmid40947692, year = {2025}, author = {Manubolu, K and Peeriga, R}, title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098375978250820220024}, pmid = {40947692}, issn = {1874-6128}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.}, } @article {pmid40949365, year = {2025}, author = {Dai, JW and Xing, YX and Sun, NZ}, title = {Adjuvant chemotherapy for gallbladder cancer: Current evidence, controversies, and future directions.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {8}, pages = {108160}, pmid = {40949365}, issn = {1948-9366}, abstract = {Gallbladder cancer is an aggressive malignancy notorious for its poor prognosis and treatment challenges, even at early stages. In their recent work, Kim et al utilized data from the National Cancer Database to explore whether adding chemotherapy to surgical intervention could improve survival outcomes for patients diagnosed with stage II gallbladder cancer. The use of adjuvant chemotherapy following curative surgery in this patient population has been a long-standing source of debate. Historically, the lack of clear guidelines for managing stage II gallbladder cancer has resulted in inconsistent, sometimes contradictory findings from various studies regarding the effectiveness of postoperative chemotherapy. Consequently, many clinicians have relied on studies involving other biliary tract cancers to justify the routine use of prophylactic chemotherapy after surgery, aiming to minimize recurrence risk. Given the rarity, high mortality rate, and the small sample sizes typical in gallbladder cancer studies, Kim et al's contribution represents a significant and commendable effort to address these challenges. Kim et al designed a retrospective cohort study with well-defined inclusion criteria and clear treatment classifications. Notably, their findings suggested that in stage II gallbladder cancer, adjuvant chemotherapy did not yield a meaningful survival benefit over surgery alone. These results therefore casted doubt on the routine practice of administering chemotherapy to all patients postoperatively, prompted clinicians to reconsider their approach. Furthermore, this controversy directly influences clinical decisionmaking and guideline recommendations, as uncertainty regarding the benefit of adjuvant chemotherapy may lead to heterogeneous practices across different institutions and regions. This article critically assessed the research design, methodology, and clinical implications of the study by Kim et al. It also provided an in-depth exploration of the broader question regarding the appropriateness of adjuvant chemotherapy following surgery for stage II gallbladder cancer, highlighting the necessity of rigorous study designs to produce reliable evidence.}, } @article {pmid40949612, year = {2025}, author = {Gao, L and Wang, J and Bi, Y}, title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {11015-11044}, pmid = {40949612}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism/drug effects ; *Drug Delivery Systems/methods ; Nanomedicine/methods ; Nanoparticles/chemistry ; Organelles/drug effects/metabolism ; Liposomes/chemistry ; *Nanoparticle Drug Delivery System/chemistry ; Drug Carriers/chemistry ; }, abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.}, } @article {pmid40949727, year = {2025}, author = {Gu, Q and Shen, J and Chu, S and Huang, Q and Chen, A and Li, L and Li, R}, title = {Analysis of the resistance level and target site resistance mechanisms of Echinochloa crus-galli to penoxsulam from Hubei Province, China.}, journal = {PeerJ}, volume = {13}, number = {}, pages = {e19973}, pmid = {40949727}, issn = {2167-8359}, mesh = {*Echinochloa/drug effects/genetics/enzymology ; Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; China ; *Herbicide Resistance/genetics ; *Sulfonamides/pharmacology ; *Herbicides/pharmacology ; Mutation ; *Plant Weeds/drug effects/genetics ; Oryza/parasitology ; Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa crus-galli is a grass weed that infests rice fields and causes significant crop yield losses. In this study, we surveyed 15 resistant E. crus-galli populations collected from rice fields in Hubei Province, China, and investigated the resistance levels and target site resistance mechanisms to the acetolactate synthase (ALS) inhibitor penoxsulam. The results of whole-plant bioassay experiments revealed that 15 populations presented different levels of resistance to penoxsulam. The Trp-574-Leu mutation was detected in ten resistant populations, and the Pro-197-Leu mutation was detected in one resistant population. Additionally, the in vitro ALS activity in resistant populations (18-ETF, 18-WJJ, and 18-WMJ) was 51.28-, 5.51-, and 8.46-fold greater than that in the susceptible population. The ALS from these resistant populations requires a much higher penoxsulam concentration for activity inhibition. ALS gene expression in three resistant populations (18-ETF, 18-WJJ, and 18-WMJ) was 1.53-, 1.58-, and 1.41-fold greater than that in the susceptible population 18-NJ before penoxsulam treatment. Our results indicated that target-site mutation in ALS is at least partially responsible for barnyardgrass resistance to penoxsulam in Hubei Province.}, } @article {pmid40955309, year = {2025}, author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M}, title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {8135-8159}, pmid = {40955309}, issn = {1177-8881}, mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; }, abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.}, } @article {pmid40958367, year = {2025}, author = {Gao, M and Han, J and Zhu, Y and Wen, X and Feng, L and Zhou, T}, title = {Obesity Impacts Post-Myocardial Infarction Neovascularization by Downregulating AQP1 Expression via the TRPC5-NFATc3 Signaling Pathway.}, journal = {Comprehensive physiology}, volume = {15}, number = {5}, pages = {e70048}, doi = {10.1002/cph4.70048}, pmid = {40958367}, issn = {2040-4603}, support = {82470455//National Natural Science Foundation of China/ ; 82200463//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Myocardial Infarction/metabolism ; *TRPC Cation Channels/metabolism/genetics ; Mice ; *Obesity/metabolism/complications ; *Aquaporin 1/metabolism/genetics ; *NFATC Transcription Factors/metabolism/genetics ; Signal Transduction/physiology ; Down-Regulation ; Male ; Mice, Inbred C57BL ; Humans ; Neovascularization, Physiologic ; Endothelial Cells/metabolism ; }, abstract = {Obesity is associated with impaired angiogenesis and poor recovery following myocardial infarction (MI), yet the underlying molecular mechanisms remain poorly defined. The transient receptor potential cation channel subfamily C member 5 (TRPC5) is known to regulate angiogenesis, but its role in the context of obesity-related MI is unclear. Here, we show that TRPC5 expression is downregulated in obese mice hearts following MI, resulting in compromised angiogenic function. Riluzole, an FDA-approved drug for amyotrophic lateral sclerosis, activates TRPC5 and restores the migration, sprouting, and tube formation function of coronary artery endothelial cells isolated from diet-induced obese (DIO) MI mice. In obese mice, riluzole enhances post-MI neovascularization, reduces infarct size, and improves cardiac function. Notably, TRPC5-mediated angiogenesis requires aquaporin-1 (AQP1), whose expression is regulated by TRPC5 via the nuclear factor of activated T cells 3 (NFATc3) transcription factor. Silencing AQP1 abolishes the pro-angiogenic effects of TRPC5 activation, establishing AQP1 as a critical downstream effector. In conclusion, our data provide evidence that the TRPC5-NFATc3-AQP1 pathway is essential for post-MI angiogenesis in obesity and support riluzole as a promising therapeutic approach to enhance angiogenesis in obese individuals following MI.}, } @article {pmid40958782, year = {2025}, author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z}, title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.}, journal = {Journal of multidisciplinary healthcare}, volume = {18}, number = {}, pages = {5743-5758}, pmid = {40958782}, issn = {1178-2390}, abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking.

METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research.

RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease.

CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.}, } @article {pmid40964461, year = {2025}, author = {Chen, HW}, title = {Sustained Bulbar and Respiratory Function in a Case Most Consistent With Bulbar-Onset Amyotrophic Lateral Sclerosis Following Axial Spinal Traction: A 21-Month Report.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e92341}, pmid = {40964461}, issn = {2168-8184}, abstract = {Bulbar-onset amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by early decline in speech, swallowing, and respiratory function, and is associated with a poor prognosis. We report the case of a woman whose treating neurologist determined, eight months after symptom onset, that her presentation was most consistent with bulbar-onset ALS. At 16 months, she began receiving intermittent pelvis-stabilized axial spinal traction (PSAST) as a supportive intervention. Remarkably, over the subsequent 21 months, she maintained oral intake and preserved respiratory function, an outcome atypical of the expected trajectory of bulbar-onset ALS. While this single case relies on provider reports for diagnostic confirmation, it raises the hypothesis that axial spinal traction may help sustain bulbar and respiratory function in ALS. Given the lack of effective treatment options, we present this case to raise awareness of a potential supportive approach that warrants further investigation.}, } @article {pmid40965373, year = {2025}, author = {Calcagno, N and Scirocco, E and Clampffer, E and Addy, G and Morgan, S and Parikh, N and Neel, DV and Scalia, J and Young, R and Locatelli, M and Mackie, DS and Berry, JD and Paganoni, S}, title = {Real-World Clinical Experience With Sodium Phenylbutyrate and Taurursodiol at a Single Amyotrophic Lateral Sclerosis Center in the United States.}, journal = {European journal of neurology}, volume = {32}, number = {9}, pages = {e70360}, pmid = {40965373}, issn = {1468-1331}, support = {//Amylyx Pharmaceuticals Inc/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; *Phenylbutyrates/therapeutic use/adverse effects ; Retrospective Studies ; Middle Aged ; Aged ; United States ; Adult ; }, abstract = {INTRODUCTION/AIMS: Sodium phenylbutyrate (PB) and taurursodiol (TURSO)-PB and TURSO-was approved as a treatment for amyotrophic lateral sclerosis (ALS) in the United States in 2022 based on the results of a phase 2 trial, but was voluntarily withdrawn from the market in 2024 after negative results from its phase 3 trial. The objective of our study was to describe the real-world clinical experience with PB and TURSO at one ALS clinic.

METHODS: This was a retrospective chart review of all ALS patients receiving a PB and TURSO prescription at the Massachusetts General Hospital ALS Clinic between October 1, 2022, and September 30, 2023. Data were extracted from patients' electronical medical records up to December 31, 2023.

RESULTS: A total of 441 ALS patients received a PB and TURSO prescription, with 329 (75%) initiating the medication. The average length of treatment was 285 days, and the rate of drug discontinuation during the study period was 41% (N=135). The most common reason for drug discontinuation was side effects (N=93, 69%), with the most common being gastrointestinal issues (N=69). No hospitalizations, deaths, or serious adverse events were considered related to treatment with PB and TURSO.

DISCUSSION: Experience in real-world clinical settings can help supplement trial data with information on the drug performance at various stages of disease progression. Adverse events impacted treatment persistence in routine clinical practice, underscoring the need for vigilant monitoring and tailored supportive interventions to optimize treatment adherence.}, } @article {pmid40974909, year = {2025}, author = {Fazeli, B and Botzenhardt, S and Bachhuber, F and Klassen, P and Klose, V and Dorst, J and Wiesenfarth, M and Uzelac, Z and Jesse, S and Brenner, D and Anderl-Straub, S and Ludolph, AC and Otto, M and Weishaupt, J and Tumani, H and Halbgebauer, S}, title = {Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain.}, journal = {EBioMedicine}, volume = {120}, number = {}, pages = {105930}, pmid = {40974909}, issn = {2352-3964}, mesh = {Humans ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Aged ; Middle Aged ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; ROC Curve ; Aged, 80 and over ; Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; }, abstract = {BACKGROUND: Neurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognised as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analysed its levels in ALS, Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated.

METHODS: In this study CSF levels of three neurofilament proteins were measured in 305 participants, including patients with ALS (n = 91), AD (n = 59), FTD (n = 38), LBD (n = 18), non-neurodegenerative controls (CTRL, n = 51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD). NfM levels were quantified using a homemade sandwich ELISA, while NfL and NfH were measured using commercialised Ella cartridges.

FINDINGS: All three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p < 0.0001 for both), with NfM and NfL also increased in FTD (p < 0.0001 for both) and AD (NfM, p < 0.0001; NfL, p = 0.0001) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p < 0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r = 0.93, 95% CI: 0.91-0.94, p < 0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.91; NfL, AUC: 0.89) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96).

INTERPRETATION: This study provides a quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases.

FUNDING: The present study was supported by the Else Kroener-Fresenius Foundation (2024-EKEA.126) and Chemische Fabrik Karl Bucher GmbH.}, } @article {pmid40976462, year = {2025}, author = {Shi, M and Chu, F and Zhu, J}, title = {Stem cells therapy in neurodegenerative and neuroimmune diseases: Current status of treatments and future prospects.}, journal = {Pharmacological research}, volume = {221}, number = {}, pages = {107960}, doi = {10.1016/j.phrs.2025.107960}, pmid = {40976462}, issn = {1096-1186}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative and neuroimmune diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share a common pathologic hallmark i.e. loss of neurons in the central nervous system (CNS), despite diverse pathological manifestations. These diseases present major challenges to global health due to incurable or extremely difficult to treat, imposing a heavy burden on society and families. Stem cell therapy, as a novel promising approach for treating various neurological diseases, harnesses the regenerative potential of stem cells to repair damaged neural tissues and circuits, and has become the only hope for patients to recover their health or delay the deterioration of disease symptoms. In recent years, researchers have successfully generated neurons from multiple types of stem cells, and good curative effects have been achieved in their animal models and in clinical trials. This comprehensive review elaborates on the relevant content of stem cell biology, focuses on conducting an in-depth analysis of the current application status of various stem cells in major neurodegenerative and neuroimmune diseases including MS, AD, PD and ALS, kindling the hope for the development of stem cell-based cell therapies in neurological diseases.}, } @article {pmid40979210, year = {2025}, author = {Grimm, T and Otto-Sobotka, F and Steinker, D and Summ, O and Timmer, A and Groß, M}, title = {Patients and treatments in a neuropalliative outpatient clinic: an analysis of clinical routine data from five years of care.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1616153}, pmid = {40979210}, issn = {1664-2295}, abstract = {INTRODUCTION: The increasing prevalence of life-threatening neurological diseases raises the need for neuropalliative care. Setting up neurological palliative outpatient clinics is one way of addressing this need. This study aims to describe the patient clientele of a neurological palliative outpatient clinic and the spectrum of necessary treatments and interventions.

METHODS: In this longitudinal analysis, clinical routine data from a single centre were collected retrospectively from adult patients. The patient characteristics related to disease and treatment were evaluated descriptively. Factors influencing the need for ventilation were modelled in a logistic regression. The required treatment effort was modelled with a zero-inflated Beta regression. Results were reported as odds ratios with 95% confidence intervals (CIs).

RESULTS: Two hundred and thirty-two patients were included in the study. Ninety-one patients were women, 141 were men, and the mean age was 55.42 years. Neuropalliative patients represented diagnoses such as amyotrophic lateral sclerosis (ALS) (n = 81), ischemic stroke (n = 15), intracerebral haemorrhage (n = 15), Duchenne muscular dystrophy (n = 12), or craniocerebral trauma (n = 10). Palliative care counselling was the most common intervention for patients (n = 203), their close relatives (n = 177), and their nursing services (n = 75). Respiratory therapy (n = 188), speech and language therapy (n = 145), and physiotherapy (n = 143) were also frequently applied interventions. Sixty patients received botulinum toxin A treatment for hypersalivation, and 32 for spasticity. The odds of needing invasive ventilation increased by 3.7 (CI 1.7-7.8), and the need for mechanical insufflation-exsufflation increased by 2.2 (CI 1.1-4.3) in patients previously discharged from early neurological-neurosurgical rehabilitation. Prior intensive care treatment increased the odds of invasive ventilation by 5.1 (CI 2.2-11.5) and the use of mechanical insufflation-exsufflation by 2.3 (CI 1.1-4.8).

CONCLUSION: Neuropalliative outpatient clinics demand a wide range of diagnostic measures and interventions as well as a multidisciplinary approach. Further research is necessary to investigate the relation between diagnosis and treatment needs.

CLINICAL TRIAL REGISTRATION: https://drks.de/search/en/trial/DRKS00030778, identifier DRKS00030778.}, } @article {pmid40981102, year = {2025}, author = {Juranek, JK and Kordas, B and Podlasz, P and Bossowska, A and Banach, M}, title = {Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {32}, number = {3}, pages = {}, pmid = {40981102}, issn = {1873-149X}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE-Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE-Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases.}, } @article {pmid40982298, year = {2025}, author = {Moojen, TB and Vlug, MS and Visser, E and Reijntjes, MA and Lange, JFM and Bislenghi, G and Carvello, M and Warusavitarne, J and Hompes, R and Stassen, LPS and Faiz, OD and Spinelli, A and D'Hoore, A and Bemelman, WA}, title = {Anastomotic leakage after ileoanal pouch surgery: risk factors and salvage rate.}, journal = {BJS open}, volume = {9}, number = {5}, pages = {}, pmid = {40982298}, issn = {2474-9842}, support = {974823//The Crohn's & Colitis Foundation/ ; }, mesh = {Humans ; *Anastomotic Leak/etiology/epidemiology/therapy/diagnosis ; Male ; Female ; Retrospective Studies ; *Proctocolectomy, Restorative/adverse effects ; Adult ; Risk Factors ; Middle Aged ; *Colonic Pouches/adverse effects ; *Salvage Therapy/statistics & numerical data ; *Colitis, Ulcerative/surgery ; Europe/epidemiology ; Anastomosis, Surgical/adverse effects ; }, abstract = {BACKGROUND: Chronic anastomotic leakage (AL) is the most common cause of pouch failure after restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. This study investigated factors associated with AL and successful salvage of leaking anastomoses after ileoanal pouch surgery.

METHOD: This multicentre retrospective cohort study included patients aged ≥ 18 years with ulcerative colitis or unclassified inflammatory bowel disease who underwent ileoanal pouch surgery between 2016 and 2021 in six European centres, with a > 12-month follow-up. The primary outcome was AL rate. Secondary outcomes included factors associated with AL occurrence, timing of AL diagnosis (early (< 21 days) versus late), AL management, AL salvage rate, and stoma-free survival.

RESULTS: Overall, 411 patients were included, of whom 13.6% (56) had a diagnosed AL. The rate of AL was significantly higher in low-volume (less than ten procedures annually) centres (28.0% versus 12.7%; P = 0.031). Of the 56 ALs, 44 were diagnosed as early leaks and 12 were diagnosed as late leaks. A three-stage approach was associated with late diagnosis and treatment. AL was managed using various techniques, including diverting ileostomy, antibiotics, and drainage. The overall AL salvage rate was 85.4%, but increased to 92% when diagnosed and treated early (compared with 60% when diagnosed and treated late; P = 0.010). Successful AL salvage was associated with long-term stoma-free status (P = 0.002). The median follow-up was 3.8 years (range 1.0-8.1 years). The long-term stoma-free rate was 95.5% in patients with AL diagnosed and treated early, but only 41.7% when diagnosed and treated late (P < 0.001).

CONCLUSION: Early diagnosis and treatment of AL diminishes the negative effect of AL after ileoanal pouch surgery. Proactive anastomotic assessment enable early diagnosis and management, especially in patients undergoing a three-stage approach.}, } @article {pmid40983218, year = {2025}, author = {Teixeira-Pinheiro, LC and Gonçalves, RGJ and Furtado, M and Decotelli, AB and Vasques, JF and Maturano, M and Quintanilha Barbosa, RA and Marques da Costa, FV and Souza, LRQ and de Lima, MN and Maron-Gutierrez, T and Gomes, HR and Pizzochero, M and Domizi, P and Santiago, MF and Mendez-Otero, R and Gubert, F}, title = {Regional modulation of neurodegeneration and microglial activation by intravenous Wharton's jelly mesenchymal stromal cell therapy in a mouse model of amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {586}, number = {}, pages = {110-120}, doi = {10.1016/j.neuroscience.2025.09.029}, pmid = {40983218}, issn = {1873-7544}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology ; *Mesenchymal Stem Cell Transplantation/methods ; *Microglia/pathology/metabolism/physiology ; Disease Models, Animal ; Female ; Motor Neurons/pathology ; Mice, Transgenic ; Mesenchymal Stem Cells ; Humans ; Mice ; *Wharton Jelly/cytology ; Spinal Cord/pathology ; *Nerve Degeneration/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition characterized by rapid degeneration of motoneurons (MNs), leading to progressive muscle atrophy and, ultimately, mortality within a few years of diagnosis. Although the precise mechanisms initiating MN degeneration are not fully understood, the involvement of non-neuronal cells, including microglia, in ALS pathophysiology is increasingly recognized. Mesenchymal stromal cell (MSC)-based therapies have emerged as a promising avenue for ALS treatment, yet clinical outcomes remain variable, underscoring the necessity for additional pre-clinical investigations. This study evaluated the therapeutic potential of human MSCs derived from Wharton's jelly (WJMSC) in the female SOD1[G93A] mouse model of ALS. Our results indicated that intravenous administration of WJMSC during the presymptomatic phase of the disease notably delayed the onset of motor deficits and extended the lifespan. This functional benefit was associated with the preservation of MNs in the cervical spinal cord. In the lumbar spinal cord, we did not observe MN neuroprotection, but we noted a temporary increase in microgliosis following WJMSC treatment. Our results supported the therapeutic benefits of human MSC in ALS, while also highlighting the differential responses of spinal-cord regions to the treatment during the disease progression. This study underscores the importance of targeting specific disease stages and regions for MSC therapy in ALS, paving the way for refined and potentially more effective therapeutic strategies.}, } @article {pmid40988456, year = {2025}, author = {Tian, J and Bai, D and He, S and Cao, Y and Liao, Y and Wang, J and Bai, L and Pan, L}, title = {Pro-197-his/ser mutation and the metabolic gene DsUGT84A1, synergistically confer resistance to tribenuron-methyl in Descurainia sophia.}, journal = {The Plant journal : for cell and molecular biology}, volume = {123}, number = {6}, pages = {e70487}, doi = {10.1111/tpj.70487}, pmid = {40988456}, issn = {1365-313X}, support = {2023YFD1401100//National Key Research and Development Program of China/ ; CARS-01//China Agriculture Research System/ ; CARS-16-E19//China Agriculture Research System/ ; 2022-31//Modern Agricultural Industrial Technology System of Hunan Province/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology/metabolism ; Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Plant Proteins/genetics/metabolism ; Mutation ; Cytochrome P-450 Enzyme System/genetics/metabolism ; *Plant Weeds/genetics/drug effects ; Plants, Genetically Modified ; Gene Expression Regulation, Plant ; }, abstract = {Descurainia sophia, an invasive weed in wheat fields of China, has developed notable resistance to the acetolactate synthase (ALS)-inhibiting herbicide tribenuron-methyl. In this study, a suspected resistant population (R) of D. sophia was investigated to assess its resistance level and elucidate the underlying mechanisms. Whole-plant bioassays revealed that the R population exhibited a 35.20-fold higher resistance index (RI) to tribenuron-methyl compared with a sensitive (S) population. Treatment with the cytochrome P450 inhibitor malathion partially reversed this resistance, indicating a metabolic component. Target-site resistance (TSR) analysis identified a mutation from proline (Pro) to histidine (His) or serine (Ser) at position 197 of the ALS gene in the R population. Additionally, high-performance liquid chromatography (HPLC) analysis indicated that enhanced tribenuron-methyl metabolism occurred in the R population compared with the S population. Three candidate P450 genes (CYP96A15, CYP81F1, CYP734A1), and one UDP-glycosyltransferase (UGT) gene (UGT84A1) were found to be upregulated in the R population, as verified by RNA sequencing and quantitative reverse transcription PCR (RT-qPCR). Candidate resistance genes were identified and expressed heterologously in Arabidopsis thaliana. Experimental data showed that compared with the green fluorescent protein (GFP) control group, the resistance of three transgenic Arabidopsis lines overexpressing the DsUGT84A1 gene to tribenuron-methyl was significantly increased. When all the plants in the GFP control group died, the fresh weight of these three transgenic lines remained above 20%. The above results fully confirm that the DsUGT84A1 gene demonstrates significant functions pertaining to resistance against tribenuron-methyl. However, the current data suggest that this novel metabolic gene (DsUGT84A1) may not confer cross-resistance among various ALS-inhibiting herbicides. In this respect, the TSR conferred by the Pro197His/Ser mutation may be responsible for cross-resistance. Additionally, antioxidant-related genes were upregulated in A. thaliana overexpressing DsUGT84A1, leading to a reduction in the toxicity level of reactive oxygen species (ROS). Notably, this study identifies and functionally characterizes the UGT gene DsUGT84A1 related to herbicide resistance in broadleaf weeds. This contributes to the understanding of herbicide resistance mechanisms, especially highlighting the role of UGT genes, and enhances the current understanding of resistance evolution in weeds.}, } @article {pmid40992657, year = {2025}, author = {Almaguer-Mederos, LE and Kandi, AR and Sen, NE and Canet-Pons, J and Berger, LM and Stokes, MP and Abell, K and Key, J and Gispert, S and Auburger, G}, title = {Spinal Cord Phosphoproteome of SCA2 Mouse Model Reveals Alteration of ATXN2-N-Term PRM-SH3-Actin Interactome and of Autophagy.}, journal = {Molecular & cellular proteomics : MCP}, volume = {24}, number = {11}, pages = {101072}, pmid = {40992657}, issn = {1535-9484}, mesh = {Animals ; *Autophagy ; *Ataxin-2/metabolism/genetics ; *Spinal Cord/metabolism/pathology ; Disease Models, Animal ; *Proteome/metabolism ; Mice ; Humans ; Phosphorylation ; *Spinocerebellar Ataxias/metabolism/pathology/genetics ; Peptides/metabolism ; Protein Interaction Maps ; }, abstract = {Toxic polyglutamine (polyQ) expansions in ataxin-2 (ATXN2) trigger neurodegenerative processes, causing spinocerebellar ataxia type 2, and enhancing TAR DNA-binding protein 43-dependent pathology in amyotrophic lateral sclerosis/frontotemporal dementia. Primary disease events can be compensated transiently, delaying disease manifestation. To define potential therapy targets, here we studied how cells modify phosphoprotein signals, using preferentially affected nervous tissue from end-stage Atxn2-CAG100-Knockin mice. The spinal cord phosphoproteome revealed massive hyperphosphorylations flanking the polyQ expansion in ATXN2 and for SQSTM1 and moderate hyperphosphorylations also for amyotrophic lateral sclerosis proteins, OPTN (optineurin), UBQLN2 (ubiquilin-2), TNIP1 (TNFAIP3 interacting protein 1), and TBK1-targeted TAX1BP1. Conversely, strong hypophosphorylations of WNK1 (protein kinase with no lysine 1), SPARCL1 (secreted protein acidic and cysteine rich-like 1), and PSMD9 (proteasome 19S regulator non-ATPase assembly chaperone P27) were found. Significant enrichments of SRC-homology domain type 3-containing proteins, autophagy/endocytosis factors, and actin modulators could be explained by N-terminal, polyQ-adjacent, proline-rich motifs in ATXN2, suggesting that spinocerebellar ataxia type 2 pathogenesis is highly similar to Huntington's disease, where neurotoxicity is mediated by abnormal polyQ-proline-rich motif-SRC-homology domain type 3 interactions. Validation of protein and mRNA levels was done in mouse spinal cord and embryonic fibroblasts or patient fibroblasts after bafilomycin or arsenite treatment, observing polyQ-dependent OPTN deficiency and SQSTM1 induction impairment. Overall, this phosphoproteome profile identified and quantified the main cellular efforts in adapting autophagy pathways to the aggregation propensity of the ATXN2-N-term.}, } @article {pmid40997459, year = {2025}, author = {de Oliveira Pires, L and Wasicki, B and Abaei, A and Scekic-Zahirovic, J and Roselli, F and Fernandes, S and Bączyk, M}, title = {A computational model of tsDCS effects in SOD1 mice: from MRI-based design to validation.}, journal = {Computers in biology and medicine}, volume = {197}, number = {Pt B}, pages = {111082}, doi = {10.1016/j.compbiomed.2025.111082}, pmid = {40997459}, issn = {1879-0534}, mesh = {Animals ; Mice ; *Magnetic Resonance Imaging ; *Superoxide Dismutase-1/genetics/metabolism ; *Models, Neurological ; *Spinal Cord/diagnostic imaging/physiology ; Computer Simulation ; Mice, Inbred C57BL ; Mice, Transgenic ; Membrane Potentials/physiology ; }, abstract = {During trans-spinal direct current stimulation (tsDCS) the transmembrane potential of neurons is modified by an electric field (EF) induced due to externally applied direct current (DC). The resultant functional effects are being harnessed in the treatment of various neurological conditions; however, the fundamental mechanisms of action underlying tsDCS remain unclear. This ambiguity is largely attributed to the limited knowledge of the geometrical constraints of the EF in the polarized spinal regions. It is, then, essential to develop tools that enable researchers to plan tsDCS approaches in a controlled and systematic manner, ensuring the reproducibility of stimulation effects at spinal targets. With this paper, we aim to provide a comprehensive computational model of tsDCS intervention in mice to support further fundamental research in this area. Our model was constructed using high-resolution MRI scans of C57/B6 mice, which were segmented and reconstructed into a realistic mouse computational model. In vivo electrophysiological measurements of voltage gradients in SOD1 G93A mice were used to validate our model predictions in real-life scenarios. In both the modeling and in vivo studies, we employed a rostrocaudal arrangement of DC electrodes to replicate stimulation parameters that have proven effective for modulating murine spinal circuits. Both the computational and in vivo approaches yielded highly consistent results, with EF parameters primarily influenced by the distance between the target site and the tsDCS electrodes. We conclude that this developed model offers high accuracy in EF distribution and can significantly substantiate basic research in tsDCS.}, } @article {pmid41002740, year = {2025}, author = {Bardhan, M and Anand, A and Javed, A and Chilo, MA and Khan, N and Garg, T and Surana, A and Huang, H and Samim, MM and Suresh, V and Khare, A and Menon, B and Kundu, T}, title = {Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {41002740}, issn = {2079-9721}, abstract = {Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.}, } @article {pmid41003732, year = {2025}, author = {Yang, X and Jia, Z and Lian, X and Zhang, R and Li, B and Tian, D and Gao, X and Guo, S and Wang, B and Liu, H and Long, Y and Wang, L and Zhang, J and Xue, Q and Liang, Z and Han, Y and Feng, H and Huang, L and Wang, P and Shao, N and Shi, FD and Zhang, C}, title = {Ofatumumab treatment in patients with neuromyelitis optica spectrum disorder: a retrospective multicenter cohort study.}, journal = {Journal of neurology}, volume = {272}, number = {10}, pages = {655}, pmid = {41003732}, issn = {1432-1459}, support = {82301469//National Natural Science Foundation of China/ ; 82171777//National Natural Science Foundation of China/ ; 20JCJQJC00280//Natural Science Foundation of Tianjin Municipal Science and Technology Commission/ ; 24ZXGZSY00030//Tianjin Public Health Science and Technology Major Project/ ; TJSQNYXXR-D2-120//Tianjin Health Research Project/ ; TJWJ2024RC001//Tianjin Health Research Project/ ; 2024CZLJ003//Leading Talent of Changzhou "The 14th Five-Year Plan" High-Level Health Talents Training Project/ ; }, mesh = {Humans ; Female ; Male ; *Neuromyelitis Optica/drug therapy ; Retrospective Studies ; Adult ; Middle Aged ; *Antibodies, Monoclonal, Humanized ; Aquaporin 4/immunology ; Treatment Outcome ; Cohort Studies ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Disability Evaluation ; }, abstract = {BACKGROUND: Ofatumumab is a fully human anti-CD20 monoclonal antibody that selectively and highly depletes B cells. However, limited data on ofatumumab treatment are available in patients with neuromyelitis optica spectrum disorders (NMOSD). In this study, we aimed to evaluate the efficacy and safety of subcutaneous ofatumumab in patients with NMOSD.

METHODS: We conducted a retrospective multicenter cohort study of patients with NMOSD who received ofatumumab treatment at 15 tertiary hospitals in China. The primary outcome was the annualized relapse rate (ARR). The secondary outcomes included disability measures (Expanded Disability Status Scale score, EDSS; the Aminoff-Logue Disability Scale, ALS), changes in aquaporin-4 IgG (AQP4-IgG) titers, and safety profiles during ofatumumab treatment.

RESULTS: A total of 112 patients (88% female, median age 44.0 years with interquartile range [IQR 29.5-57.5]) received ofatumumab treatment for a median of 1.7 years (IQR: 1.1-2.0). The median ARR decreased significantly from 2.0 (IQR 0.7-10.0) before ofatumumab to 0 (IQR 0.0-0.0; p < 0.001) after ofatumumab. Twenty-two patients (20%) experienced 25 relapses, with 20 (80%) occurring within the first year of initiating ofatumumab treatment and 19 (76%) classified as minor. The EDSS score from start to the last follow-up also improved significantly (median: pre-treatment 3.5, IQR 2.0-6.5, post-treatment: 2.0, IQR1.0-3.5, p < 0.001). Among 94 patients, 71 (76%) showed reduced AQP4-IgG titers at last follow-up. Injection-related reactions were reported in 13 (12%) of 112 patients. Twenty-four infections occurred in 20 patients (18%) during the ofatumumab treatment, with 92% (22/24) being grade 1 or 2 (CTCAE version 5.0). Only 2 patients (2%) experienced pneumonia requiring hospitalization and recovered after antibiotic treatment (grade 3). Hypogammaglobulinemia was recorded in 14% (13/95) of patients and was not associated with infection.

CONCLUSIONS: Subcutaneous ofatumumab treatment significantly reduces the relapse risk, limits worsening of disability, and reduces AQP4-IgG titers in NMOSD. Moreover, the safety profiles were generally acceptable. Further research is necessary to explore the sustained clinical response of ofatumumab in NMOSD.}, } @article {pmid41005474, year = {2025}, author = {Li, Y and Liu, D and Li, S}, title = {IRE1/Xbp1 promotes the clearance of poly(GR) dipeptide repeats in amyotrophic lateral sclerosis.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {11}, pages = {110764}, pmid = {41005474}, issn = {1083-351X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Humans ; *X-Box Binding Protein 1/metabolism/genetics ; C9orf72 Protein/genetics/metabolism ; *Dipeptides/metabolism/genetics ; *Endoribonucleases/metabolism/genetics ; Mice ; Disease Models, Animal ; Signal Transduction ; Drosophila melanogaster ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by the expansion of GGGGCC (G4C2) repeats in the C9orf72 gene and progressive motor neuron degeneration. A key pathological hallmark of these diseases is the accumulation and cytoplasmic mislocalization of dipeptide repeat (DPR) proteins, particularly poly(GR), which are neurotoxic. Enhancing the clearance of poly(GR) represents a promising therapeutic strategy; however, the molecular mechanisms regulating poly(GR) turnover are not fully understood. Our previous work demonstrated that translationally stalled poly(GR) is targeted by the ribosome-associated quality control (RQC) pathway. In the present study, we identify the IRE1/Xbp1s signaling axis as an essential regulator of poly(GR) degradation. Ectopic expression of IRE1 or its downstream effector Xbp1s, as well as pharmacological activation of IRE1 using IXA4, significantly reduces poly(GR) protein levels in a Drosophila disease model, mammalian cell lines, fibroblasts derived from patients with C9orf72-ALS, and a C9orf72 transgenic mouse model. Mechanistically, RNA-sequencing analysis reveals that IRE1/Xbp1s signaling upregulates heat shock protein Hsp70Ba, which plays a critical role in maintaining poly(GR) proteostasis. Additionally, we show that the Rictor/AKT/VCP pathway contributes to the translational regulation and turnover of poly(GR). Importantly, activation of IRE1, either through ectopic expression or IXA4 treatment, mitigates motor neuron loss in the C9orf72 mouse model. Collectively, our findings highlight the IRE1/Xbp1s axis as a key modulator of poly(GR) clearance and suggest its therapeutic potential in ALS/FTD.}, } @article {pmid41005925, year = {2026}, author = {Marín-García, M and Gonzalez-Olmos, R and Gómez-Canela, C}, title = {Direct UV photolysis of cloperastine in aqueous solution: Kinetic model and degradation pathway.}, journal = {Journal of environmental sciences (China)}, volume = {159}, number = {}, pages = {670-682}, doi = {10.1016/j.jes.2025.03.025}, pmid = {41005925}, issn = {1001-0742}, mesh = {*Photolysis ; *Water Pollutants, Chemical/chemistry/radiation effects ; *Ultraviolet Rays ; Kinetics ; *Piperidines/chemistry/radiation effects ; Models, Chemical ; }, abstract = {The increasing production and release of synthetic organic chemicals, including pharmaceuticals, into our environment has allowed these substances to accumulate in our surface water systems. Current purification technologies have been unable to eliminate these pollutants, resulting in their ongoing release into aquatic ecosystems. This study focuses on cloperastine (CPS), a cough suppressant and antihistamine medication. The environmental impact of CPS usage has become a concern, mainly due to its increased detection during the COVID-19 pandemic. CPS has been found in wastewater treatment facilities, effluents from senior living residences, river waters, and sewage sludge. However, the photosensitivity of CPS and its photodegradation profile remain largely unknown. This study investigates the photodegradation process of CPS under simulated tertiary treatment conditions using UV photolysis, a method commonly applied in some wastewater treatment plants. Several transformation products were identified, evaluating their kinetic profiles using chemometric approaches (i.e., curve fitting and the hard-soft multivariate curve resolution-alternating least squares (HS-MCR-ALS) algorithm) and calculating the reaction quantum yield. As a result, three different transformation products have been detected and correctly identified. In addition, a comprehensive description of the kinetic pathway involved in the photodegradation process of the CPS drug has been provided, including observed kinetic rate constants.}, } @article {pmid41008332, year = {2025}, author = {Bernetti, C and Cea, L and Buoso, A and Greco, F and Rossi, M and Pilato, F and Calandrelli, R and Di Gennaro, G and Di Lazzaro, V and Zobel, BB and Mallio, CA}, title = {A Comprehensive Overview of Subacute Combined Degeneration: MRI Diagnostic Challenges and Treatment Pathways.}, journal = {Brain sciences}, volume = {15}, number = {9}, pages = {}, pmid = {41008332}, issn = {2076-3425}, abstract = {Subacute combined degeneration (SCD) is a neurological disorder primarily caused by vitamin B12 deficiency. This condition leads to progressive demyelination and axonal damage, predominantly affecting the dorsal and lateral columns of the spinal cord. This review provides a comprehensive overview of SCD, detailing its complex etiology, pathophysiology, and clinical presentation. We highlight the critical role of magnetic resonance imaging (MRI) in the diagnostic process, discussing both the characteristic spinal cord findings and the more subtle intracranial abnormalities. Furthermore, we address the diagnostic challenges presented by conditions that mimic SCD in MRI, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). We conclude by outlining current treatment pathways and identifying key areas for future research, including the use of advanced neuroimaging techniques and the potential for new therapeutic approaches. This updated synthesis aims to provide a clear framework for clinicians and researchers to better understand and manage SCD.}, } @article {pmid41011076, year = {2025}, author = {Della Toffola, J and Ricci, E and Quagliotto, M and Manganotti, P and Benussi, A}, title = {Non-Invasive Brain Stimulation for Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {9}, pages = {}, pmid = {41011076}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; *Transcranial Magnetic Stimulation/methods/trends/standards ; *Transcranial Direct Current Stimulation/methods/trends/standards ; Brain/physiopathology ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, with a bleak prognosis and few treatment options. Non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), represent emerging approaches aimed at modulating cortical hyperexcitability, a relevant pathogenetic mechanism in ALS. Materials and Methods: A systematic review of the literature was conducted following the PRISMA guidelines, exploring the Scopus and PubMed databases from April to June 2025 with terms related to ALS and NIBS. A total of 18 relevant studies were selected from the initial 708 articles, analysing stimulation protocols, clinical and neurophysiological outcomes, and associated biomarkers; their validity was assessed using the revised Cochrane risk-of-bias (RoB2) tool. Results: The selected studies were extremely heterogeneous, with NIBS techniques, including magnetic (rTMS, cTBS, tSMS) and electrical (tDCS) stimulation, showing variable effects. Low-frequency protocols (1 Hz rTMS) and cTBS showed a slight slowing of clinical progression, while prolonged home stimulation with tDCS and tSMS showed more significant improvements in terms of efficacy, tolerability, and adherence. The main limitations concern the heterogeneity of patients and protocols and the lack of standardised biomarkers, which is why the analysis remained at a descriptive level. The use of telemonitoring and caregiver training are essential to ensure safety and accessibility. Conclusions: NIBS represents a promising therapeutic approach for ALS, but further multicentre, standardised studies with prolonged follow-up are needed. Future strategies should include customisation of stimulation, combination with other therapies, and extension of application to pre-symptomatic phases.}, } @article {pmid41017705, year = {2026}, author = {Wang, H and Wei, Y and Wang, J and Liu, J and Ou, S and Wang, J}, title = {Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.}, journal = {Neural regeneration research}, volume = {21}, number = {8}, pages = {3352-3362}, pmid = {41017705}, issn = {1673-5374}, abstract = {The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer's disease, Nav1.6 mediates amyloid-β oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson's disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na + /Ca 2+ exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-α signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood-brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.}, } @article {pmid41018945, year = {2025}, author = {Vucic, S and Shahrizaila, N and Kano, O and Menon, P and Agustini, S and Kulkantrakorn, K and Atchayaram, N and Lee, YC and Prado, MB and Ng, KWP and Chai, J and Son, B and Talman, P and Nghia, HTT and Tuan, LTQ and Shibuya, K and Izumi, Y and Atsuta, N and Henderson, RD and Cui, L and Liu, M and Ohnmar, O and Rabani, R and Hong, YH and Sung, JJ and Fan, D and Raykar, V and Kuwabara, S and Kim, SH and Sobue, G and Kiernan, MC}, title = {Pan-Asian consortium for treatment and research in ALS (PACTALS) guidelines for management of amyotrophic lateral sclerosis.}, journal = {The Lancet regional health. Western Pacific}, volume = {62}, number = {}, pages = {101684}, pmid = {41018945}, issn = {2666-6065}, abstract = {The Pan-Asian Consortium for Treatment and Research in ALS (PACTALS) guidelines were developed for the management of amyotrophic lateral sclerosis (ALS) patients living in the Asia-Pacific countries, taking into consideration the ethnic, racial and economic diversity of the region. The majority of patients reside in low-income (limited-resource setting) and middle-income countries. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was utilised for development of the PACTALS management guidelines. Nine broad research questions, divided into sections, were addressed. Evidence was derived from existing Cochrane reviews, systematic reviews, meta-analysis, and randomized controlled trials (RCT) along with consensus when evidence was limited. Recommendations were provided for diagnostic pathways, use of disease modifying therapies, appropriateness of multidisciplinary care models, management of respiratory dysfunction, communication and nutrition, addressing symptoms that affect the quality of life, managing cognitive, behavioural and emotional symptoms as well as appropriate implementation of palliative care services and addressing end-of-life issues. The PACTALS guidelines provide a much-needed framework for the management of ALS patients living in the Asia-Pacific region. The management guidelines will be updated as the treatment landscape evolves and evidence of novel management approaches becomes available.}, } @article {pmid41021147, year = {2025}, author = {Xie, X and Wu, P and Wen, T and Jia, R and Zhang, R and Hu, F and Jin, J and Qin, X and Chen, QY}, title = {Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {127}, pmid = {41021147}, issn = {1559-1166}, support = {82302973//National Natural Science Foundation of China/ ; YX6J010//Xi'an Jiaotong University "Young Talent Support Plan"/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; Male ; Female ; Middle Aged ; *Iron/blood ; *Ferritins/blood ; Aged ; Adult ; Homeostasis ; Sex Factors ; Age Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the "gene-time-environment" hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.}, } @article {pmid41026411, year = {2025}, author = {Eraslan, A and Kose, O}, title = {Prevalence and patterns of adductor lesions on MRI in athletes with osteitis pubis.}, journal = {Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology}, volume = {26}, number = {1}, pages = {65}, pmid = {41026411}, issn = {1590-9999}, mesh = {Humans ; Male ; Adult ; *Osteitis/diagnostic imaging/epidemiology ; Retrospective Studies ; Cross-Sectional Studies ; *Magnetic Resonance Imaging ; Adolescent ; Prevalence ; Young Adult ; Middle Aged ; *Athletic Injuries/diagnostic imaging/epidemiology ; Athletes ; Tendinopathy/diagnostic imaging/epidemiology ; *Tendon Injuries/diagnostic imaging/epidemiology ; }, abstract = {PURPOSE: Adductor lesions (ALs) frequently coexist with osteitis pubis (OP) in athletes, yet the prevalence and clinical impact of different AL types have not been comprehensively evaluated. This study aimed to determine the frequency of various AL types using magnetic resonance imaging (MRI) and to investigate their association with clinical outcomes in athletes with OP.

MATERIALS AND METHODS: This retrospective cross-sectional study included male athletes aged 18-45 years with MRI-confirmed OP. ALs were classified into four types on the basis of MRI: type 1 (strain), type 2 (tendon avulsion), type 3 (tendinopathy), and type 4 (secondary cleft sign). Types 1-2 were considered acute, and types 3-4 chronic lesions. The relationships between AL types, age, symptom side, return to sport (RTS), and hip outcome score (HOS) were analyzed.

RESULTS: Among 132 athletes with OP, 90% had concurrent AL, while 10% had isolated OP. Type 3 AL was the most frequent type (77.3%), followed by type 4 (23.5%), type 1 (15.9%), and type 2 (2.3%). Logistic regression revealed that type 3 was more likely to be found in younger athletes, while types 1 and 4 were found in older athletes. Although 95% of athletes had bilateral OP, 72% reported unilateral symptoms. The symptom side showed better consistency with the AL side than the OP side (Cohen's kappa = 0.489 versus 0.057). All athletes were treated conservatively, 50 chronic AL cases were applied also injection (31 corticosteroid-CS, 19 platelet reach plasma-PRP). Athletes with isolated OP achieved a higher RTS rate than those with AL (100% versus 75%, p = 0.033). RTS rates were higher in acute AL cases than in chronic cases (91% versus 72%) and in CS injections than in PRP injections (80% versus 63%), but without statistical significance. HOS scores were comparable across groups.

CONCLUSIONS: Adductor lesions, particularly chronic types, are highly prevalent in athletes with OP. While age influences the type of AL, the symptom side is compatible with the AL side, regardless of the type. RTS rates are more satisfactory in isolated OP and acute AL cases, but chronic AL cases were less successful in RTS outcomes despite injection treatments. These findings underscore the importance of identifying and classifying ALs for prognosis and treatment strategy in athletic groin pain.

LEVEL OF EVIDENCE: level IV, retrospective cohort study.}, } @article {pmid41028049, year = {2025}, author = {Spiteri, AG and Steele, JR and Lee, HC and Zhang, H and Sun, J and Schittenhelm, RB and Yu, CH and McLean, C and Masters, CL and Goudey, B and Jin, L and Pan, Y}, title = {Proteomic analysis of brain and spinal cord tissue reveals distinct immune and mitochondrial processes between human and mouse ALS models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33959}, pmid = {41028049}, issn = {2045-2322}, support = {GNT2007912//National Health and Medical Research Council/ ; GNT2022203//NHMRC-AMED 2022 Dementia Collaborative Research/ ; AARF1020292//Alzheimer's Association grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology/genetics ; *Spinal Cord/metabolism/pathology/immunology ; Humans ; Disease Models, Animal ; Mice ; *Proteomics/methods ; *Mitochondria/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; *Brain/metabolism/pathology/immunology ; *Proteome ; Motor Neurons/metabolism ; Male ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the progressive loss of motor neurons in the brain and spine. More than 95% of cases are pathologically characterized by the cytoplasmic accumulation of hyperphosphorylated and ubiquitinated transactive response DNA-binding protein 43 (TDP-43). Multiple mouse models with TDP-43 accumulation have been developed, however, whether they recapitulate molecular features of ALS pathology is unclear. Given the lack of curative treatment for ALS, there is an urgent need to identify the precise biological processes contributing to disease pathogenesis for the development of effective therapeutic treatments. Thus, in this study we employed label-based untargeted proteomics to characterize the ALS proteome and related biological processes in the spinal cord and brain of TDP-43[Q331K] mice, a transgenic mouse model of ALS and the motor cortex and the cervical, thoracic, and lumbar spinal cord regions from humans. In humans, we observed highly overlapping responses across the four tissues examined, primarily related to the upregulation of immune processes and the downregulation of mitochondrial function. In contrast, TDP-43[Q331K] mice demonstrate a lack of enrichment for immune activation and the opposite regulation of mitochondrial processes. A meta-analysis of previously published mouse datasets identified the Ubqln2 knock-out mouse model as showing stronger parallels with our late-stage human ALS. Overall, this study provides in-depth analysis of the site-specific dysregulated proteomes and their associated functional processes across species. Thereby, identifying potential therapeutic targets while emphasizing the limitations of specific mouse models at certain timepoints in recapitulating ALS-related processes for future model development.}, } @article {pmid41028829, year = {2025}, author = {Jiang, Q and Yang, D and Jiang, R and Wan, S and Wu, M and Xu, D and Zhou, J}, title = {Analysis of factors influencing sleep disorders in patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {34104}, pmid = {41028829}, issn = {2045-2322}, support = {2025AFD532//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; 2024AFD279//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; 2023AFD128//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; GZY-KJS-2025-008//Science and Technology Special Project of State Administration of Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Middle Aged ; *Sleep Wake Disorders/etiology/epidemiology/complications ; Cross-Sectional Studies ; Aged ; Fatigue/complications ; Adult ; Sleep Quality ; Anxiety/complications ; Disease Progression ; Pain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease frequently accompanied by sleep disorders. Conventional insomnia interventions are often unsuitable for ALS patients due to cognitive and respiratory impairments. There is a lack of targeted studies addressing sleep-related issues using multifactorial analyses specific to this group. This cross-sectional study included 266 ALS patients at the Motor Neuron Disease Rehabilitation and Treatment Center of Hubei Provincial Hospital of Traditional Chinese Medicine. Participants were evaluated using tools like the Pittsburgh Sleep Quality Index (PSQI) and ALS Functional Rating Scale-Revised (ALSFRS-R). Regression models identified factors affecting sleep disorders and quality. Patients with sleep disorders were more likely to have non-motor symptoms like anxiety, depression, pain, and excessive daytime sleepiness compared to those without. Fatigue severity and anxiety levels were identified as independent influencing factors of sleep disorders. Additionally, fatigue, anxiety, pain intensity, and disease progression rate were significantly linked to sleep quality. This study is the first comprehensive analysis of sleep-related factors in Chinese ALS patients, highlighting the crucial roles of fatigue, anxiety, pain, and disease progression rate. It provides a basis for future personalized, non-pharmacological interventions tailored to the specific needs of ALS patients.}, } @article {pmid41030970, year = {2025}, author = {Peethambaran Mallika, A and Yu, JG and Sitzman, O and Baghel, MS and Renganathan, S and Sinha, IR and Melnikova, T and Ling, JP and Wong, PC}, title = {Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41030970}, issn = {2692-8205}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43kDa (TDP-43) dysfunction is an early pathogenic mechanism that underlies amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder that lacks disease modifying therapies. We previously developed a mouse model in which TDP-43 is selectively deleted from motor neurons (ChAT-Cre;Tardbp [f/f]) that mimics the early stages of ALS. Here, we demonstrate that intravenous delivery of a blood-brain-barrier (BBB) permeable AAV capsid expressing our rationally designed splicing repressor CTR (AAV-PHP.eB-CTR) in symptomatic ChAT-Cre;Tardbp [f/f] mice markedly slowed disease progression and prevented paralysis. Systemic delivery of AAV-PHP.eB-CTR led to transduction of ~80% of spinal motor neurons, repression of TDP-43-associated cryptic exons within motor neurons expressing CTR, and attenuation of motor neuron loss. Notably, the addition of the TARDBP 3'UTR autoregulatory element to CTR maintained its expression within a physiological range. In control littermates that received AAV-PHP.eB-CTR and were monitored for >20 months, grip strength and body weight remained normal, and no histopathological abnormalities were observed, underscoring a favorable safety profile for this gene therapy. These results provide preclinical proof-of-concept that BBB-crossing AAV delivery of CTR can rescue motor neuron disease through the restoration of TDP-43 function, offering a promising mechanism-based therapeutic strategy for ALS.}, } @article {pmid41032491, year = {2025}, author = {Burkhill, L and Davies, TM}, title = {A case study exploring the management of dyspnoea in motor neurone disease.}, journal = {British journal of community nursing}, volume = {30}, number = {10}, pages = {488-492}, doi = {10.12968/bjcn.2025.0023}, pmid = {41032491}, issn = {1462-4753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/nursing ; Analgesics, Opioid/therapeutic use ; *Dyspnea/etiology/therapy/nursing ; *Motor Neuron Disease/complications ; Quality of Life ; United Kingdom ; }, abstract = {Motor neurone disease affects around 5000 people in the UK at any given time. It is a progressive disease with a poor prognosis and carries a high symptom burden. Dyspnoea (breathlessness) is one of its most challenging yet common symptoms and occurs because of a weakening of the muscles that control breathing. This case study explores the management of a man diagnosed with amyotrophic lateral sclerosis in the community. His advance decision to refuse treatment directive to avoid non-invasive ventilation during the day was managed through a combination of opioid medication, breath stacking, positioning and other strategies recommended by the National Institute for Health and Care Excellence. Individualised care planning and maintaining quality of life was key in his management.}, } @article {pmid41035727, year = {2025}, author = {Wanner, GK and Dworkin, M and Rosenbaum, RA}, title = {Statewide Prehospital Buprenorphine in Delaware: Two-Years of Paramedic-Initiated Medication for Opioid Use Disorder After Overdose.}, journal = {Delaware journal of public health}, volume = {11}, number = {3}, pages = {24-28}, pmid = {41035727}, issn = {2639-6378}, abstract = {The Delaware Division of Public Health, Office of Emergency Medical Services (EMS) implemented the first statewide program enabling paramedics throughout the state to initiate buprenorphine treatment for opioid use disorder (OUD) in the prehospital setting. Building on a model from Camden, New Jersey, this protocol was approved in 2022 in response to rising overdose deaths and was fully implemented across Delaware's advanced life support (ALS) EMS agencies in April 2023. Eligible patients-those 18 years or older, resuscitated with naloxone, and able to consent-received up to 24 mg of sublingual buprenorphine along with ondansetron for nausea. Between April 2023 and May 2025, paramedics administered 118 buprenorphine doses to 105 patients, with improvement in withdrawal symptoms reported after 63.6% of doses. Despite a rise in patient ineligibility due to altered mental status-likely linked to sedating adulterants,such as xylazine and medetomidine,in regional street drugs-paramedics increased the percentage of eligible patients accepting offered buprenorphine from 19.0% to 22.8% between the first and second year of the program. This protocol not only addresses acute overdose management in the field but also connects patients to ongoing care, aiming to reduce mortality and expand access to medications for opioid use disorder.}, } @article {pmid41036176, year = {2025}, author = {Toro, CA and Zhao, W and Garcia Silva, P and Retamal-Santibáñez, D and Rojas, F and Pan, J and Johnson, N and Duarte, Y and Cardozo, CP and Sáez, JC and van Zundert, B}, title = {Boldine as a neuroprotective agent against motor neuron degeneration in models of amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1640590}, pmid = {41036176}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Current FDA-approved treatments offer only modest benefits. Connexins (Cx), proteins that mediate intercellular communication have emerged as potential therapeutic targets, with increased Cx hemichannel (HC) activity observed in ALS models, and blocking Cx HC activity prevents motor neuron loss in vitro. Boldine, a natural compound with both Cx HC-blocking and antioxidant properties, has shown neuroprotective potential. This study investigated boldine's effects in ALS models. In vitro, spinal cord cell cultures exposed to conditioned media from mutant SOD1[G93A] astrocytes showed a 50% reduction in motor neuron survival, elevated Cx HC activity, and increased reactive oxygen species (ROS). Boldine treatment significantly reduced Cx HC activity and ROS, and increased motor neuron viability. In vivo, oral boldine was well-tolerated in male mutant SOD1[G93A] mice starting at 7 weeks of age. Mice receiving 50 mg/kg/day showed a median survival increase of 9 days (132 vs. 123 days), though not statistically significant. Functional assessments revealed delayed disease progression: in the horizontal ladder rung walk test, boldine-treated mice exhibited a 36.8% reduction in crossing time and 21.2% fewer stepping errors. Improved scores were also observed on the Basso Mouse Scale at later stages, indicating preserved locomotor function. However, boldine had no significant effect in the rotarod test. These results support boldine's neuroprotective effects in ALS, particularly in fine motor coordination and locomotor performance. Its reduction of Cx HC activity and oxidative stress highlights boldine's promise as a potential therapeutic candidate for ALS.}, } @article {pmid41040684, year = {2025}, author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP}, title = {Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41040684}, support = {ZIA NS003169/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluate five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 2-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.}, } @article {pmid41041029, year = {2024}, author = {Zareei, A and Razeghinejad, R and Talebnejad, MR and Khalili, MR and Masoumpour, MS and Shayan, Z and Mahdaviazad, H and Keshtkar, M and Mohammadi, E and Tajbakhsh, Z and Shahmohammadi, M and Nowroozzadeh, MH}, title = {Macular Sublayer Thickness in Healthy Iranian Children: An Optical Coherence Tomography Study from the Population-Based Shiraz Pediatric Eye Study.}, journal = {Journal of current ophthalmology}, volume = {36}, number = {4}, pages = {393-399}, pmid = {41041029}, issn = {2452-2325}, abstract = {PURPOSE: To establish normative values for macular sublayer thickness in healthy Iranian children using optical coherence tomography (OCT) and to assess the effects of age and gender.

METHODS: This study was part of the population-based Shiraz pediatric eye study. Of 2400 children aged 6-12 years invited, 480 were randomly selected for optical biometry and macular spectral-domain OCT (SD-OCT) imaging. Finally, 431 OCT scans from children with medium axial length (AL; 21.5-26.5 mm) were analyzed. The OCT device automatically segmented seven retinal sublayers, and their thickness was measured across Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. Thickness in the central 1-mm subfield was assessed by gender and age groups (6-9 vs. 10-12 years), adjusted for AL. Regression analysis examined the impact of age, sex, and AL on retinal sublayer thickness. Only data from the right eye were used.

RESULTS: The mean age of participants was 9.12 ± 1.59 years (range, 6-12), with 254 (58.9%) being girls. The mean AL was 22.91 ± 0.71 mm, and the mean foveal thickness was 258 ± 8 µm. A normative database was created for the total retinal thickness and the seven retinal sublayers across the nine ETDRS subfields. Boys had longer globes (by approximately 0.4 mm; P < 0.001) and thicker foveae (by about 5 µm; P = 0.001) compared to girls. Among the seven sublayers studied, boys had a thicker ganglion cell complex layer (P = 0.014) and outer nuclear layer (ONL; P = 0.012), while girls had a thicker retinal pigment epithelium (RPE; P = 0.029). The inner nuclear layer and outer plexiform layer showed no significant differences (P = 0.075 and P = 0.810, respectively). The mean AL was 22.78 ± 0.68 mm in the 6-9 age group and 23.10 ± 0.72 mm in the 10-12 age group (P < 0.001). The older age group (10-12 years) exhibited thicker ONL (P = 0.009) and RPE (P = 0.002) layers compared to the younger group.

CONCLUSIONS: This study provides normative data for macular sublayer thickness in Iranian children aged 6-12 years using Heidelberg SD-OCT. Boys had longer ALs and thicker maculae, while girls had a thicker RPE layer. Older children had longer globes and thicker retinas, mainly due to increased ONL and RPE thickness.}, } @article {pmid41042311, year = {2025}, author = {Ouyang, C and Jin, X and Zhao, H and Chen, S and Zhao, G and Li, D and Liu, W and He, X and Wu, Y and Yang, J and An, B}, title = {Generating Broad-Spectrum Resistance to ALS-Inhibiting Herbicides in Rice by CRISPR/Cas9-Mediated NHEJ.}, journal = {Rice (New York, N.Y.)}, volume = {18}, number = {1}, pages = {86}, pmid = {41042311}, issn = {1939-8425}, support = {2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; }, abstract = {Herbicides are pivotal for modern agriculture, but challenges like weed resistance and crop rotation issues necessitate the development of herbicide-resistant genetic resources. This study focused on acetolactate synthase (ALS), a key enzyme targeted by numerous herbicides. Using CRISPR/Cas9-mediated non-homologous end joining (NHEJ) and combining with whole-stage selection, we induced mutations in the OsALS gene of indica rice and identified novel in-frame mutations at the P171 and S627 sites, respectively. Among them, one mutation at the P171 site, the triple mutation P171T/R172G/M174L (ALS-TM) conferred broad-spectrum resistance to Imidazolinones Pyrimidinylthiobenzoates Sulfonylaminocarbonyltriazolinones and Sulfonylureas herbicides. Compared to wild-type (WT) rice, ALS-TM showed 1153-fold higher resistance to imazethapyr (IMT) than WT based on GR50 values (The herbicide dose causing a 50% reduction in growth), with minimal growth inhibition at 10-fold IMT treatment. Enzymatic assays revealed that ALS-TM maintained catalytic efficiency while reducing herbicide binding, which validated the resistance at the protein level. Field trials showed that ALS-TM mutant retained normal agronomic traits even after IMT spraying, indicating no yield penalty. Additionally, ALS mutations were validated as effective transgenic selection markers, enabling efficient rice transformation under different selection systems. These results demonstrated that ALS-TM could also serve as a reliable tool in basic research, facilitating the selection and identification of transgenic materials in laboratory studies. This study provided a robust method for generating herbicide-resistant rice germplasm and highlighted the potential of CRISPR-mediated NHEJ for creating novel resistant mutations.}, } @article {pmid41051689, year = {2025}, author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A}, title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6277-6319}, pmid = {41051689}, issn = {1590-3478}, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/therapy/genetics/metabolism ; Biomarkers/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.}, } @article {pmid41053519, year = {2025}, author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S}, title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {24}, pages = {5435-5448}, pmid = {41053519}, issn = {1618-2650}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Biomarkers/analysis ; Nanotechnology/methods ; }, abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.}, } @article {pmid41057909, year = {2025}, author = {Hunter, E and Alshaker, H and Bundock, O and Weston, C and Bautista, S and Gebregzabhar, A and Virdi, A and Croxford, J and Dring, A and Powell, R and Vugrinec, D and Kingdon, C and Wilson, C and Dowrick, S and Green, J and Akoulitchev, A and Pchejetski, D}, title = {Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch[®] 3-dimensional genomic regulatory immuno-genetic profiling.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1048}, pmid = {41057909}, issn = {1479-5876}, support = {6514//Oxford BioDynamics plc, Oxford UK/ ; }, mesh = {Humans ; *Fatigue Syndrome, Chronic/genetics/blood/diagnosis/immunology ; *Biomarkers/blood ; *Gene Expression Profiling ; *Genomics/methods ; Reproducibility of Results ; Male ; Female ; Middle Aged ; }, abstract = {Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.}, } @article {pmid41058966, year = {2024}, author = {Donohue, C and Perry, B and Focht Garand, KL}, title = {A Clinical Focus on Shared Decision Making in Clinical Practice When Providing Dysarthria and Dysphagia Services to Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Perspectives of the ASHA special interest groups}, volume = {9}, number = {4}, pages = {1003-1015}, pmid = {41058966}, issn = {2381-4764}, support = {K23 NS123369/NS/NINDS NIH HHS/United States ; L30 NS123988/NS/NINDS NIH HHS/United States ; }, abstract = {PURPOSE: Traditional health care decision-making models center on clinicians making decisions for patients/caregivers based on the best available research evidence. However, this diminishes patient/caregiver involvement in their care and hinders the ability to align care plans with patient values and preferences. Shared decision making is a potentially beneficial process to implement with individuals with amyotrophic lateral sclerosis (ALS) to provide more holistic, patient-centered dysarthria and dysphagia treatment. Shared decision making promotes active involvement by patients/caregivers by informing them of potential treatment options, understanding their values and preferences, and aligning their desires with treatment options to determine the most optimal individualized care plan.

CONCLUSIONS: The benefits and barriers to incorporating shared decision making within ALS multidisciplinary clinics are discussed in this clinical focus article. Furthermore, a fictional case study example of how to apply shared decision making to dysarthria and dysphagia management of individuals with ALS is provided.}, } @article {pmid41061670, year = {2026}, author = {James, RE and Bekier, M and Lee, PJ and Schroeder, FA and Evans, LT and Wagner, FF and Hickman, D and Richardson, T and Hatzipetros, T and Vieira, F and Callizot, N and Modi, S and Hooker, JM and Kranz, JE and Brown, RH and Barmada, SJ and Gilbert, TM}, title = {A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {5}, pages = {1586-1603}, pmid = {41061670}, issn = {1460-2156}, support = {//Eikonizo Therapeutics, Inc/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase 6/antagonists & inhibitors/metabolism ; Animals ; *Frontotemporal Dementia/drug therapy/metabolism/genetics ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; Humans ; Mice, Transgenic ; Male ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; }, abstract = {Dysregulated proteostasis and intracellular transport contribute to neurodegeneration. Histone deacetylase 6 (HDAC6), a therapeutic target of interest for neurodegenerative diseases, acts at a nexus modulating both proteostasis and intracellular transport. Inhibition of HDAC6 deacetylase activity promotes autophagic clearance of protein aggregates and increases α-tubulin acetylation, thereby enhancing microtubule resiliency and motor protein-microtubule binding, which facilitates intracellular transport and, subsequently, proteostasis. Despite these benefits, advancement of HDAC6 inhibitor therapeutics for neurodegenerative disease has been hindered by inadequate selectivity and CNS-penetrance of first-generation compounds. Here, we characterize a next-generation small molecule HDAC6 inhibitor, EKZ-438, in preclinical models of amyotrophic lateral sclerosis and frontotemporal dementia. We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8500-fold selectivity for HDAC6 versus all other HDAC6 paralogues), low nanomolar potency (12 nM) for HDAC6, and importantly, CNS-penetrance (unbound brain-to-plasma partition coefficient [Kp,uu,brain] ≥ 0.55) and high oral bioavailability (fraction of dose absorbed [F%] = 70). In complementary preclinical in vitro and in vivo immunolabelling and live imaging studies we tested the hypothesis that selective inhibition of HDAC6 deacetylase activity is sufficient to improve pathophysiological proteostasis and intracellular transport deficits in animal models of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. EKZ-438 treatment rescued superoxide dismutase 1 (SOD1) (q < 0.0001) and transactive response DNA binding protein 43 kDa (TDP-43) (q < 0.001) proteostasis defects following an excitotoxic glutamate challenge, and increased survival of SOD1G93A and wild-type motor neurons by 59% (q < 0.0001) and 37% (q < 0.01), respectively, demonstrating in vitro neuroprotection. In SOD1G93A mice, EKZ-438 improved axonal transport by 16% (q < 0.05), motor performance by ∼40% (q < 0.05) and decreased plasma neurofilament light chain levels by 35% (q < 0.05), demonstrating in vivo neuroprotection. In a TDP-43 mouse model, EKZ-438 reduced TDP-43 pathology by ∼30% (q < 0.05) and neuroinflammation by ∼26% (q < 0.05) in the brain, supporting HDAC6 inhibition for sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Furthermore, EKZ-438 treatment improved intracellular transport by 39% (q < 0.001), rescued cytoplasmic TDP-43 accumulation by 87% (q < 0.0001) and restored nuclear TDP-43 splicing activity (P < 0.05) in human TARDBP neurons. These mechanistic improvements aligned with nearly complete rescue of human TARDBP and C9orf72 mutant neuron survival (P < 0.0001). We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.}, } @article {pmid41065069, year = {2026}, author = {Shan, Y and Jing, W and Zhang, H and Liu, Y and Wei, S and Wu, F and Pan, W}, title = {Amyotrophic lateral sclerosis rehabilitation management and non-pharmacological symptomatic treatment: A review.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {64}, number = {1}, pages = {38-46}, doi = {10.5414/CP204744}, pmid = {41065069}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/diagnosis/psychology/therapy ; Quality of Life ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options for the prevention of progression. Relieving swallowing difficulties, reducing breathing difficulties, and alleviating muscle spasms are essential to improving the quality of life in patients with ALS. Many symptoms can be treated clinically with medication; however, the evidence level of related research is relatively low. Rehabilitation management can aid in improving various functional impairments and enhancing quality of life. This review introduces and describes the relevant evaluations of rehabilitation and nonpharmacological symptomatic treatment methods for functional disorders from the perspectives of motor and nonmotor symptoms. This review may promote the popularization of ALS rehabilitation management and provide an additional reference for ALS treatment.}, } @article {pmid41066153, year = {2025}, author = {Su, W and Zhang, C and Sun, L and Xu, H and Zhang, G and Xue, F and Leng, Q and Niu, Y and Wu, R}, title = {Multifaceted Mechanisms of Cyprosulfamide in Mitigating Mesosulfuron-Methyl Phytotoxicity in Maize Seedlings: GST Activation, Oxidative Stress Alleviation, and Target-Site Competition.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {42}, pages = {26584-26594}, doi = {10.1021/acs.jafc.5c07590}, pmid = {41066153}, issn = {1520-5118}, mesh = {*Zea mays/drug effects/metabolism/genetics/enzymology/growth & development ; Oxidative Stress/drug effects ; *Herbicides/toxicity ; *Sulfonylurea Compounds/toxicity ; *Plant Proteins/metabolism/genetics ; *Glutathione Transferase/metabolism/genetics ; Seedlings/drug effects/metabolism/genetics/growth & development/enzymology ; Superoxide Dismutase/metabolism/genetics ; *Sulfonamides/pharmacology ; Malondialdehyde/metabolism ; Acetolactate Synthase/metabolism/genetics ; }, abstract = {Mesosulfuron-methyl (MS), a sulfonylurea herbicide used in wheat, poses significant residual phytotoxicity risks to subsequent maize (Zea mays L.) crops. This study evaluated the protective role of the safener cyprosulfamide (CSA) through physiological, biochemical, and molecular analyses. MS treatment drastically reduced maize shoot length and fresh weight by 80.74% and 74.24%, respectively, while CSA pretreatment significantly relieved these inhibitory effects, with the mitigation rates of shoot length and fresh weight reaching 66.3% and 63.57%, respectively. Physiologically, CSA alleviated MS-induced chlorophyll and carotenoid losses and reduced oxidative stress by lowering malondialdehyde (MDA) levels (23.39% at 6 days after sowing) while enhancing superoxide dismutase (SOD) and glutathione S-transferase (GST) activity. Molecularly, CSA upregulated nine GST genes, competitively bound to ZmALS1/2, increasing acetolactate synthase (ALS) activity by 70-146%, and reduced MS residues in shoots (4.02%) and roots (33.78%). These findings demonstrate CSA's multifunctional detoxification mechanism, combining gene activation, antioxidant regulation, and target-site competition, offering a viable strategy to mitigate herbicide carryover in crop rotations. CSA application could significantly reduce MS phytotoxicity, advancing sustainable herbicide management.}, } @article {pmid41073493, year = {2025}, author = {Montazeri, S and Bijani, S and Rashidzadeh, H and Ramazani, A and Andalib, S and Kalantari-Hesari, A and Cheraghi, G and Hosseini, MJ}, title = {Application of edaravone-loaded nanogel in alleviating behavioral deficits and oxidative stress in schizophrenia rat model.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {35468}, pmid = {41073493}, issn = {2045-2322}, support = {4000397//National Institute for Medical Research Development/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; *Schizophrenia/drug therapy/metabolism ; *Edaravone/administration & dosage/pharmacology ; Rats ; Disease Models, Animal ; *Nanogels/chemistry ; Male ; Glutathione/chemistry ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Prefrontal Cortex/drug effects/metabolism ; }, abstract = {Schizophrenia is considered as a main one of the public health issues, and imposes numerous burdens on patients and society. We previously reported, the pathophysiology of schizophrenia is influenced by inflammation and mitochondrial dysfunction. Edaravone (EDV) as a potent antioxidant with neuroprotective traits, has been approved for the treatment of amyotrophic lateral sclerosis (ALS), effecting through neutralizing soluble/insoluble peroxyl radicals. However, the main disadvantages of EDV are its low stability in aqueous media, poor water solubility, and un-optimized bioavailability. To effectively address these obstacles, nanogel was utilized as the drug vehicle. The decoration of nanogel surface with glutathione (GSH) was carried out to elevate edaravone's brain delivery. The probable improvement in drug delivery of edaravone loaded GSH-nanogel is the main hypothesis of this study. In order to mimic schizophrenia-like behaviors, we applied two month of post-weaning social isolation stress (PWSI) to rodent model. The choice of PWSI model was made due to the maturation and development of prefrontal cortex and hippocampus during adolescence. In addition to causing oxidative stress and upregulating genes linked to innate immunity in the prefrontal cortex (PFC), the data showed that PWSI triggered schizophrenia-like behaviors in rats. This study demonstrated that treatment with edaravone loaded GSH-nanogel decreased the impact of PWSI on behavioral dysfunctions and oxidative stress in the PFC of rats. Edaravone loaded GSH-nanogel (GSH-PMAA-EDV) down-regulated Toll-like receptor 4 (Tlr-4) and AMP-activated protein kinase (Ampk) gene expression which are involved in inflammation and cellular energy homeostasis, respectively. Increase immunoreactivity feedback and Brain-derived neurotrophic factor (Bdnf) as direct impact in neurogenesis and neural cell plasticity was observed in EDV loaded GSH-nanogel treated groups. edaravone loaded GSH-nanogel (100 µg/kg) in comparison to free form of edaravone (5 mg/kg) revealed more beneficial effects, which might be useful for future clinical use especially for the treatment of schizophrenia.}, } @article {pmid41074071, year = {2025}, author = {Cole, A and Chege, T and Aman, R and Githuka, G and Muga, R and Aspinall, A and Kokwaro, G}, title = {Health system challenges and facilitators associated with adaptive cycling deployment of multiple first-line treatment for uncomplicated malaria: a pilot study in a malaria-endemic region of Kenya.}, journal = {Malaria journal}, volume = {24}, number = {1}, pages = {328}, pmid = {41074071}, issn = {1475-2875}, support = {PO20/00538//Medicines for Malaria Venture/ ; }, mesh = {Kenya ; Pilot Projects ; *Antimalarials/therapeutic use/administration & dosage ; Humans ; Artemisinins/therapeutic use ; *Malaria/drug therapy ; Female ; Adult ; Male ; Drug Combinations ; Young Adult ; Drug Therapy, Combination ; Adolescent ; Middle Aged ; Artemether, Lumefantrine Drug Combination/therapeutic use ; Amodiaquine/therapeutic use ; }, abstract = {BACKGROUND: Artemisinin-based combination therapy (ACT) has been first-line treatment for uncomplicated malaria in sub-Saharan Africa for over two decades. However, emerging artemisinin partial resistance threatens efficacy. Multiple first-line treatments (MFTs) represent a proposed mitigation strategy, though associated health systems challenges remain unknown. This study evaluated health systems challenges and facilitators for MFT implementation in western Kenya.

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

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

CONCLUSION: Adaptive cycling MFT implementation is feasible in Kenya with adequate planning and addressing health systems challenges. Stakeholder engagement and continuous training were critical for success. Policy implications and regional cooperation potential warrant exploration in other sub-Saharan African countries with different deployment contexts.}, } @article {pmid41075758, year = {2026}, author = {Gery, KL and Ramos, S and Lee, JC}, title = {Correlative Raman and immunofluorescence imaging reveals different protein abundance between stress granules induced by oxidative damage.}, journal = {Journal of inorganic biochemistry}, volume = {274}, number = {}, pages = {113091}, pmid = {41075758}, issn = {1873-3344}, support = {ZIA HL006236/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *Stress Granules/metabolism/drug effects ; *Spectrum Analysis, Raman/methods ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Hydrogen Peroxide/pharmacology ; Cell Line, Tumor ; Fluorescent Antibody Technique/methods ; Poly-ADP-Ribose Binding Proteins/metabolism ; Reactive Oxygen Species/metabolism ; RNA Recognition Motif Proteins/metabolism ; DNA Helicases/metabolism ; RNA Helicases ; }, abstract = {Heavy metal toxicity generates reactive oxygen species (ROS) that can contribute to neurodegeneration. Oxidative damage from exposure to metals such as sodium arsenite will activate the integrated stress response and may result in the cytosolic formation of stress granules (SGs), which have been implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis. Here, two different ROS sources, sodium arsenite and hydrogen peroxide, under acute (1 h) and chronic (24 h) conditions, were used to induce SG formation in human osteosarcoma (U-2 OS) cells and investigate if characteristics of SGs could depend on the induction. Specifically, correlative Raman and immunofluorescence imaging (CRIFI) was developed to evaluate the relative protein abundance found in SGs to ascertain their potential as loci for protein accumulation. Interestingly, while there are differences in the punctate-staining phenotypes for different stressors, two types of puncta visualized by CRIFI were common to all treatment conditions, where notably a subset exhibited protein concentration above cytosolic background, indicating that only some SGs are composed of protein-rich, dense phases. Differences in protein abundance between SGs were also observed within a single cell, suggesting that individual SGs can develop differently. These results demonstrate the versatility and the strength of pairing Raman spectroscopy, which allows for probe-free detection of different chemical functional groups, with specific protein localization granted by immunofluorescence, providing new cellular insights unattainable by either modality alone.}, } @article {pmid41082679, year = {2025}, author = {Tabor Gray, L and Sullivan, S and O'Brien, M and Costello, J and Plowman, E and Garand, KLF}, title = {International Survey of Practice Patterns of Speech-Language Pathologists Working With Patients With Amyotrophic Lateral Sclerosis.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {6}, pages = {3343-3354}, doi = {10.1044/2025_AJSLP-25-00064}, pmid = {41082679}, issn = {1558-9110}, support = {R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology/complications ; *Speech-Language Pathology/trends ; *Deglutition Disorders/therapy/diagnosis/etiology/physiopathology ; *Practice Patterns, Physicians'/trends ; Health Care Surveys ; United States ; Male ; Female ; Surveys and Questionnaires ; *Communication Disorders/therapy/diagnosis/etiology ; }, abstract = {BACKGROUND: Speech-language pathologists (SLPs) evaluate and treat swallowing and communication impairments in individuals with amyotrophic lateral sclerosis (ALS). Standardized clinical practice guidelines for the evaluation and management of bulbar dysfunction in ALS have not yet been established. This study aimed to describe current international practice patterns of SLPs evaluating and treating bulbar dysfunction in ALS.

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

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

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

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

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.30249997.}, } @article {pmid41083392, year = {2025}, author = {Guo, Y and Li, CJ and Wei, H and Ding, Y and Guo, LJ and Gao, YN}, title = {[Clinical analysis of a motor neuron disease-like phenotype associated with anti-IgLON5 disease].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {10}, pages = {977-983}, doi = {10.3760/cma.j.cn112138-20241018-00695}, pmid = {41083392}, issn = {0578-1426}, mesh = {Aged ; Female ; Humans ; Amyotrophic Lateral Sclerosis/immunology/diagnosis ; *Autoantibodies/blood ; *Cell Adhesion Molecules, Neuronal/immunology ; Electromyography ; *Motor Neuron Disease/immunology/diagnosis ; Phenotype ; }, abstract = {We report a case of anti-IgLON5 disease with a motor neuron disease-like presentation admitted to the Department of Neurology, Xuanwu Hospital, Capital Medical University in July 2021. The patient was a 71-year-old female who presented with the chief complaint of limb weakness persisting for 4 months. She showed progressive limb weakness accompanied by muscle atrophy. Electromyography (EMG) revealed extensive neurogenic damage. Initial serum evaluation for neural-specific autoantibodies was positive for IgLON5-Ab (1∶100). Repeat testing confirmed IgLON5-Ab positivity with a titer of 1∶1 000. The patient was diagnosed with anti-IgLON5 disease and treated with methylprednisolone and immunoglobulin, leading to clinical improvement. We found four relevant articles reporting a total of 11 similar cases. Thus, in this study, we analyzed a total of 12 cases, including our patient. Based on their clinical manifestations, these cases can be categorized into two types: amyotrophic lateral sclerosis(ALS)type and isolated bulbar type. Six cases-three males and three females-presented with the ALS type. Of these, three cases had diffuse limb weakness accompanied by muscle atrophy(two cases had diffuse hyperreflexia and one had a normal tendon reflex); one case presented with neck extensor weakness and bilateral asymmetric upper extremity weakness and was hyperreflexic at the bilateral patellar tendons; one case displayed asymmetric weakness in both lower limbs with normal deep reflexes, and one case exhibited neck weakness with hyperreflexia. EMG revealed diffuse lower motor neuron disease involving two or three regions. All patients tested positive for serum anti-IgLON5 antibodies. Four were also positive for anti-IgLON5 antibodies in cerebrospinal fluid, two were negative, and six were not tested. Among the 11 patients who received immunotherapy, 4 showed partial improvement in clinical symptoms, 2 exhibited transient improvement, 2 remained stable, and 3 showed no improvement. Testing for IgLON5-Ab should be considered among patients presenting with bulbar symptoms or ALS-like features, especially those with acute or subacute onset, rapid progression, autonomic dysfunction, vocal cord paralysis requiring tracheotomy, cognitive impairment, or involuntary movements. Early diagnosis and treatment may improve clinical symptoms and reduce adverse outcomes.}, } @article {pmid41086149, year = {2025}, author = {Clackson, O and Hamid, MR and Wijesekera, A and Kulick, D and O'Neil, AL}, title = {Exposure to the organochlorine pesticide cis-chlordane induces ALS-like mitochondrial perturbations in stem cell-derived motor neurons.}, journal = {PloS one}, volume = {20}, number = {10}, pages = {e0332422}, pmid = {41086149}, issn = {1932-6203}, mesh = {*Chlordan/toxicity ; Pesticides/toxicity ; *Amyotrophic Lateral Sclerosis/chemically induced/pathology ; *Mitochondria/drug effects/metabolism ; *Motor Neurons/cytology/drug effects/pathology ; Reactive Oxygen Species/metabolism ; Adenosine Triphosphate/biosynthesis ; Membrane Potential, Mitochondrial/drug effects ; Oxygen Consumption/drug effects ; Sequence Analysis, RNA ; Cell Line ; Humans ; Induced Pluripotent Stem Cells ; Human Embryonic Stem Cells ; Cell Differentiation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a debilitating and incurable neurodegenerative disease with unsolved etiology. Due to the large proportion of patients lacking direct disease inheritance, understanding the environmental factors that contribute to ALS development is of high priority. Epidemiological studies have implicated pesticides and other environmental exposures as possible contributors to ALS pathogenesis. Recently, our group determined that the organochlorine pesticide cis-chlordane is toxic to human motor neurons in a dose-dependent manner, causing an ALS-like phenotype in culture and animals with a mode of action independent of its known GABAA antagonism. Here, we aimed to characterize downstream motor neuron phenotypes associated with cis-chlordane treatment. We performed bulk RNA sequencing, live imaging, immunofluorescent labeling, and real-time metabolic assays on stem cell-derived motor neurons to assess chlordane-associated phenotypes in vitro. We demonstrate that cis-chlordane treatment causes a highly altered mitochondrial phenotype in motor neurons, including increased production of reactive oxygen species, decreased oxygen consumption rate and ATP production, and loss of mitochondrial membrane potential. We further implicate cis-chlordane as a possible mediator of potent motor neuron damage, with exposure to the pesticide inducing mitochondrial phenotypes akin to those seen in ALS. Our findings contribute to the growing body of evidence that future studies of investigating the role of pesticides in ALS development should focus on organochlorine molecules.}, } @article {pmid41088992, year = {2026}, author = {Essa, SM and Khosa, NA and Kakar, A and Ozturk, B and Ibrahim, IA and Haq, N}, title = {Unraveling the Potential of Stem Cell Therapy in Motor Neuron Disease: A Narrative Review.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {6}, pages = {403-415}, pmid = {41088992}, issn = {1996-3181}, mesh = {Humans ; *Motor Neuron Disease/therapy ; Animals ; *Stem Cell Transplantation/methods ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Motor neuron disorders (MNDs), including ALS, are deadly neurodegenerative conditions that cause progressive motor neuron degeneration. With neuroprotection and the potential for neuron regeneration employing MSCs, ESCs, iPSCs, and NSCs, stem cell treatment presents a viable alternative to current medicines, which only control a limited number of symptoms. Following PRISMA criteria, this narrative review methodically screened 1248 records from the Cochrane, Web of Science, PubMed, and Scopus databases. Following a thorough screening process, 22 studies, including preclinical models and 19 clinical trials, were analysed to assess the therapeutic mechanisms, safety, and efficacy of stem cell therapies for MNDs. Mesenchymal stem cell (MSC) therapy has shown a promising safety profile and possible therapeutic efficacy in ALS, with no substantial transplant-related toxicity noted. ALS functional rating scale-revised (ALSFRS-R) scores and forced vital capacity (FVC) assessments from clinical trials, such as those evaluating autologous bone marrow-derived MSCs, demonstrated stabilisation in ALS development. Studies have also emphasised as to how immunomodulation and neurotrophic factors play a part in MSC-based therapies. Recent data indicate that repeated intrathecal MSC injection could extend the duration of therapeutic advantages. Clinical trials have shown safety and early efficacy signals for motor neurons produced from embryonic stem cells (ESCs), especially using AstroRx®. This suggests that ESCs could be a viable option for regenerative medicine. Nonetheless, issues, like host integration and differentiation optimisation, still exist. Although clinical translation is still in its early stages, induced pluripotent stem cells (iPSCs) and their derivatives provide disease modelling and patient-specific therapeutic applications. Stem cell therapy holds promise for treating MND, with MSCs leading the way in current trials. It is necessary to enhance ESC- and iPSC-based techniques to tackle integration issues. To ensure long-term safety and efficacy, therapies must be developed using standardised protocols, patient stratification, optimised delivery, and large-scale studies.}, } @article {pmid41090678, year = {2025}, author = {Jing, W and Shan, Y and Wu, H and Li, T and Tang, H and Sun, Y and Napattharin, V and Loong, S and Qin, B and Pan, W}, title = {Integrative treatment of the motor neuron disease amyotrophic lateral sclerosis, efficacy of pharmacotherapy, traditional Chinese medicine and importance of respiratory support, life-style, and gastrostomy-assisted nutrition: A review.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {63 (Suppl. 1)}, number = {}, pages = {S14-S25}, pmid = {41090678}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/etiology/physiopathology ; *Gastrostomy ; *Medicine, Chinese Traditional ; *Life Style ; *Integrative Medicine/methods ; Treatment Outcome ; }, abstract = {Currently, there are no effective treatments for amyotrophic lateral sclerosis (ALS), a chronic progressive neurodegenerative disease. Although the etiology of ALS is unknown, it is thought that factors such as diet, the environment, and lifestyle habits play a role. The pathogenesis of ALS includes alterations in glutamate neurotransmission, oxidative stress, mitochondrial dysfunction. Drugs such as riluzole, edaravone, dextromethorphan/quinidine combinations, and the administration of tofersen by injection are approved treatment options for ALS although a number of other agents are being examined in clinical trials. Despite these developments, the availability of effective treatment options is limited. This review summarizes the etiology and pathogenesis of ALS and describes treatments in detail as an integrative medicine approach and including traditional Chinese medicine together with the importance of the timing for interventions, precautions necessary for noninvasive ventilator and gastrostomy surgery, and precautions for dealing with respiratory issues with the overall aim of providing state-of-the-art clinical recommendations for the care and therapy of ALS patients.}, } @article {pmid41093062, year = {2026}, author = {Bunick, CG and Yang, K and Jafarian, F and Barbieri, JS}, title = {Response to Veenstra et al's "Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis" on statistical design.}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e125-e127}, doi = {10.1016/j.jaad.2025.10.042}, pmid = {41093062}, issn = {1097-6787}, } @article {pmid41094045, year = {2025}, author = {Li, A and Huang, S and Cao, SQ and Lin, J and Zhao, L and Yu, F and Huang, M and Yang, L and Xin, J and Wen, J and Yan, L and Zhang, K and Jiang, M and Le, W and Li, P and Liu, YU and Qin, D and Lu, J and Lu, G and Shen, H and Yao, X and Fang, EF and Su, H}, title = {Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.}, journal = {EMBO molecular medicine}, volume = {17}, number = {11}, pages = {3139-3173}, pmid = {41094045}, issn = {1757-4684}, support = {#282952; #284930//Cure Alzheimer's Fund (CAF)/ ; #281931//civitan norges forskningsfond for Alzheimer skydom/ ; #262175,#334361//research council of Norway/ ; TO01000215//Ministerstvo Práce a Sociálních Věcí České Republiky (Ministry of Labour and Social Affairs of the Czech Republic)/ ; #81971327//MOST | National Natural Science Foundation of China (NSFC)/ ; #119986//NordForsk/ ; #82271448//MOST | National Natural Science Foundation of China (NSFC)/ ; /WT_/Wellcome Trust/United Kingdom ; SKL-QRCM(UM)-2023-2025//Science and Technology Development Fund, MAR/ ; 001/2023/ALC//Science and Technology Development Fund, MAR/ ; #101073251//horizon-TMA-MSCA-DN/ ; 2020001,#2021021,#2023093//HELSE SOR-OST/ ; 269901,#261973,#262960//Høgskolen i Oslo og Akershus (HiOA)/ ; #282942//Molecule AG/VITADAO/ ; #104617//Burroughs Wellcome Fund (BWF)/ ; MYRGGRG2023-00152-ICMS-UMDF//MOST | National Natural Science Foundation of China (NSFC)/ ; 0093/2024/AFJ//Macau University of Science and Technology (MUST)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Mitophagy/drug effects ; *Ubiquitin-Protein Ligases/metabolism ; Animals ; Humans ; *Protein Kinases/metabolism ; *Induced Pluripotent Stem Cells/drug effects ; Mice ; Caenorhabditis elegans ; Disease Models, Animal ; Mitochondria/drug effects/metabolism ; PTEN-Induced Putative Kinase ; }, abstract = {Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.}, } @article {pmid41095520, year = {2025}, author = {Whelan, BM and Aldridge, D and Ruhle, J and Whitelock, P and Taubert, S and Collins, A and Kearney, E and Charania, S and Henderson, RD and Wallace, SJ and Mitchell, C and Stipancic, KL and Kuruvilla-Dugdale, M and Vogel, AP}, title = {To Treat or Not to Treat: A Scoping Review of Speech Treatment for Dysarthria in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {19}, pages = {}, pmid = {41095520}, issn = {2227-9032}, support = {N/A//University of Queensland, School of Health and Rehabilitation Sciences, New Staff Research Start-Up Fund/ ; }, abstract = {BACKGROUND: Speech loss is recognised as one of the most devastating outcomes for individuals with ALS, yet active speech intervention is rarely targeted in this population. Clinicians face significant challenges in managing dysarthria associated with ALS due to the rapidly progressive nature of the disease, historical concerns around intensive exercise accelerating decline, and an absence of direction on restorative and compensatory intervention strategies in current clinical care guidelines. This review evaluates the scope and quality of evidence for speech treatments in ALS to identify knowledge gaps and establish research priorities to guide clinical care.

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

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

CONCLUSIONS: Despite the prevalence and impact of dysarthria in this population, evidence for speech treatment remains sparse, of generally low quality, and provides limited guidance for clinical practice. The changing perspective on exercise in ALS warrants rigorous investigation of tailored dysarthria interventions for this population that are minimally fatiguing and enhance speech by making use of residual physiologic support.}, } @article {pmid41095781, year = {2025}, author = {Ferreira Laurentino, EK and Maldaner da Silva, VZ and Costa Meneses, WR and da Costa, LM and Otto-Yañez, M and Vera-Uribe, R and Torres-Castro, R and Carneiro de Sousa, BR and de Abreu Freitas, RP and Menezes Mateus, SR and Vasconcellos, IF and Fernandes Franco, HC and Pinto Nagem, DA and Medeiros Valentim, RA and Dourado Júnior, ME and Rodrigues Lindquist, AR and Santos Andrade, SMMD and Medeiros Fonseca, JD and Resqueti, VR and Freitas Fregonezi, G}, title = {High-Definition Transcranial Direct Current Stimulation (HD-tDCS) Therapy in Amyotrophic Lateral Sclerosis: Study Protocol for a Multicenter Randomized Controlled Clinical Trial.}, journal = {Journal of clinical medicine}, volume = {14}, number = {19}, pages = {}, pmid = {41095781}, issn = {2077-0383}, support = {1748/22//Financiadora de Estudos e Projetos/ ; 88887.692599/2022-00 (JDMF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 305960/2021-0 (VRR)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 316937/2021-5 (GF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (EKFL)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (WRCM)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (LMC)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (BRCS)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; }, abstract = {Background/Objectives: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron loss, muscle weakness, and respiratory dysfunction, often culminating in ventilatory failure. Evidence suggests that High-Definition Transcranial Direct Current Stimulation (HD-tDCS) may modulate motor cortical excitability and potentially influence motor and respiratory function in ALS. This study aims to evaluate the effects of home-based HD-tDCS applied over the primary diaphragmatic motor cortex on respiratory parameters and disease progression in individuals with ALS. Methods: This is a multicenter, randomized, controlled clinical trial. Eligible participants (aged 18-80, both sexes, diagnosed with ALS) will be randomized into an active HD-tDCS group (gTDCS) or a sham group (gSham). The intervention consists of 30 min daily HD-tDCS sessions (3 mA) applied for two weeks (5 days/week), using a 4 × 1 ring configuration targeting the diaphragmatic motor cortex. Sham stimulation includes an identical setup but only delivers ramp currents (30 s) with a minimal ongoing current (0.1 mA). Results: Pre-, intra-, and post-intervention evaluations will include measures of cortical excitability, cerebral and tissue perfusion, surface electromyography, respiratory and pulmonary function, fatigue, sleep quality, pain, motor performance, dyspnea, quality of life, and adverse effects. All procedures will be conducted at participants' homes with appropriate safety monitoring. Conclusions: This study will investigate the effects of HD-tDCS on respiratory and motor function in ALS and explore the feasibility of a home-based neuromodulation intervention. The outcomes may provide insight into non-pharmacological strategies for respiratory management in ALS.}, } @article {pmid41096646, year = {2025}, author = {García-Criado, F and Hurtado-García, L and Rojano, E and Esteban-Martos, Á and Pérez-García, J and Seoane, P and Ranea, JAG}, title = {Integrative Transcriptomic and Network-Based Analysis of Neuromuscular Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096646}, issn = {1422-0067}, support = {PID2019-108096RB-C21, PID2022-140047OB-C21, CPP2022-010108//Ministerio de Ciencia, Innovación y Universidades/ ; IMP/00019, ACCI-05-703, ACCI-02-770//Instituto de Salud Carlos III/ ; HORIZON-HLTH-2022-DISEASE-06, 101080580//European Union/ ; RH-0079-2021//Fundación Progreso y Salud/ ; PI RARE 24-03//Instituto de Investigación Biomédica de Málaga/ ; FPU21/01449, PRE2022/000510//Ministerio de Ciencia, Innovación y Universidades/ ; }, mesh = {Humans ; *Transcriptome ; *Neuromuscular Diseases/genetics/metabolism ; *Gene Regulatory Networks ; Protein Interaction Maps/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Muscular Dystrophy, Duchenne/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle/genetics/metabolism ; Computational Biology/methods ; }, abstract = {Neuromuscular diseases (NMDs) like Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), and amyotrophic lateral sclerosis (ALS) are rare, progressive disorders with complex molecular mechanisms. Traditional transcriptomic analyses often struggle to capture systems-level dysregulation, especially given the small sample sizes typical of rare disease studies. Our differential expression analysis of eight public RNA-seq datasets from various cell types in DMD, LGMD, and ALS revealed not only disease-relevant pathways but also unexpected enrichments, such as renal development, suggesting systemic impacts beyond muscle tissue. To address limitations in capturing broader molecular mechanisms, we applied an integrative systems biology approach combining differential expression data, protein-protein interaction (PPI) networks, and network embedding techniques. Comparative functional enrichment revealed shared pathways, including glycosaminoglycan binding in both DMD and FUS-related ALS, implicating extracellular matrix-protein interactions in FUS mutation effects. Mapping DEGs onto the human PPI network and assessing their proximity to causal genes uncovered dysregulated non-coding RNAs, such as PAX8-AS1, SBF2-AS1, and NEAT1, potentially indicating common regulatory roles. We also found candidate genes within disease-proximal clusters, like HS3ST3A1, which may contribute to pathogenesis. Overall, this integrative approach reveals shared transcriptional programs and novel targets, advancing our understanding and potential treatment strategies for NMDs.}, } @article {pmid41096667, year = {2025}, author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096667}, issn = {1422-0067}, mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; }, abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.}, } @article {pmid41097004, year = {2025}, author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41097004}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; }, abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.}, } @article {pmid41101301, year = {2025}, author = {Sasidharan, A and Somayaji, Y and Fernandes, R}, title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4147-4158}, doi = {10.1021/acschemneuro.5c00159}, pmid = {41101301}, issn = {1948-7193}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; Animals ; Phenotype ; Neuroinflammatory Diseases/metabolism ; Phagocytosis/physiology ; }, abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.}, } @article {pmid41101465, year = {2026}, author = {Veenstra, J and Ozog, D and Stephens, A}, title = {Response to Bunick et al, "Response to Veenstra et al's 'Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis' on statistical design".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {2}, pages = {e129-e130}, doi = {10.1016/j.jaad.2025.09.104}, pmid = {41101465}, issn = {1097-6787}, } @article {pmid41103971, year = {2025}, author = {Arachchige, ASPM}, title = {Rethinking ALS: Current understanding and emerging therapeutic strategies.}, journal = {AIMS neuroscience}, volume = {12}, number = {3}, pages = {391-405}, pmid = {41103971}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, which leads to muscle atrophy, spasticity, and ultimately respiratory failure. The etiology of ALS remains unclear, though a combination of genetic and environmental factors is suspected. Advances in understanding ALS pathophysiology, including the role of RNA metabolism, mitochondrial dysfunction, and glutamate toxicity, have paved the way for new research directions. While Riluzole offers limited survival benefits, there is no cure, and treatment remains mostly supportive. This article summarizes the current understanding of ALS in terms of its pathophysiology, epidemiology, risk factors, clinical presentation, and treatment strategies.}, } @article {pmid41114109, year = {2025}, author = {Zhou, QQ and Ren, YM and Shi, SM and Liu, TF}, title = {Microenvironmental code of pancreatic ductal adenocarcinoma: The prognostic symphony of budding, matrix and lymphocytes.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {10}, pages = {110523}, pmid = {41114109}, issn = {1948-5204}, abstract = {This editorial discusses Alpsoy et al's significant study of prognosis of pancreatic ductal adenocarcinoma (PDAC), which lacks histopathological markers. This study evaluated the synergistic prognolymphocytes. Peritumoral budding is significantly correlated with tumor volume, while intratumoral budding is closely related to lymph node metastasis. Peritumoral budding and intratumoral budding are confirmed as independent adverse prognostic factors, and their high levels of expression are associated with immature stromal phenotypes, suggesting the key role of epithelial-mesenchymal transition. These breakthrough findings provide a new multidimensional biomarker system for the prognostic assessment of PDAC, and promote the clinical transformation process of incorporating tumor budding indicators into the pathological reporting process. However, the complexity and spatiotemporal heterogeneity of the tumor microenvironment require us to go beyond traditional morphological analysis and move towards multiomics integration and dynamic monitoring. Through standardized pathological assessment, innovative treatment strategies and interdisciplinary collaboration, it is expected to transform tumor microenvironment-related markers into clinically applicable indicators, ultimately improving the treatment predicament of PDAC. This editorial intended to summarize relevant studies and share some of our views, in order to offer perspectives for future research.}, } @article {pmid41117127, year = {2025}, author = {Kim, H and Uhm, JE and Park, J and Kim, YS and Sung, W and Lee, S and Kim, SH and Oh, KW}, title = {Monoclonal Gammopathy in Amyotrophic Lateral Sclerosis: No Impact on Clinical Progression and Immunotherapy Outcomes.}, journal = {European journal of neurology}, volume = {32}, number = {10}, pages = {e70376}, pmid = {41117127}, issn = {1468-1331}, support = {RS-2023-00265515//K-Brain Project of the National Research Foundation(NRF) Korean government (MSIT) (RS-2023-00265515)./ ; RS-2024-00348451//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (RS-2024-00348451)./ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/complications ; Female ; Disease Progression ; Aged ; *Immunotherapy/methods ; Middle Aged ; *Paraproteinemias/epidemiology/therapy/complications ; Republic of Korea/epidemiology ; Registries ; Prevalence ; Treatment Outcome ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: The association between amyotrophic lateral sclerosis (ALS) and monoclonal gammopathy has been proposed, but evidence on its prevalence, clinical relevance, and treatment response remains limited, especially in Asian populations. This study aimed to investigate the prevalence of monoclonal gammopathy in Korean patients with ALS and evaluate the impact of immunotherapy.

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

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

CONCLUSION: Monoclonal gammopathy in Korean patients with ALS was not more prevalent than in the general population, and immunotherapy did not impact ALS progression or survival. Clinical features may vary by immunoglobulin subtype. This collectively suggests minimal clinical significance of monoclonal gammopathy in ALS.}, } @article {pmid41117139, year = {2025}, author = {Pedro, KM and Alvi, MA and Goulart, GR and Fehlings, MG}, title = {Riluzole as a pharmacological therapy for spinal cord injury: where does this therapy stand?.}, journal = {Current opinion in neurology}, volume = {38}, number = {6}, pages = {625-634}, doi = {10.1097/WCO.0000000000001434}, pmid = {41117139}, issn = {1473-6551}, mesh = {*Riluzole/therapeutic use/pharmacology ; Humans ; *Spinal Cord Injuries/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; }, abstract = {PURPOSE OF REVIEW: Spinal cord injury (SCI) remains a disabling condition associated with long term neurological impairment, functional disability, and reduced quality of life. Despite decades of research, pharmacological interventions with proven clinical efficacy remain limited. This review critically evaluates the current evidence supporting riluzole as a neuroprotective agent for acute traumatic and nontraumatic SCI. We synthesize findings from preclinical and clinical studies, assess the progress towards clinical translation, and outline key challenges and research opportunities for future implementation.

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

SUMMARY: Riluzole represents a promising candidate for neuroprotection in traumatic and nontraumatic SCI. The consistency of favorable trends across multiple domains and strong support from preclinical studies highlight riluzole's value in orphan diseases such as SCI. Future directions should focus on refining the therapeutic window, optimizing PK/PD modeling, and identifying patient subgroups most likely to benefit. Its implementation in a multimodal treatment paradigm for acute SCI will be crucial for optimizing management protocols in this highly disabling condition.}, } @article {pmid41117572, year = {2025}, author = {Soar, J and Böttiger, BW and Carli, P and Jiménez, FC and Cimpoesu, D and Cole, G and Couper, K and D'Arrigo, S and Deakin, CD and Ek, JE and Holmberg, MJ and Magliocca, A and Nikolaou, N and Paal, P and Pocock, H and Sandroni, C and Scquizzato, T and Skrifvars, MB and Verginella, F and Yeung, J and Nolan, JP}, title = {European Resuscitation Council Guidelines 2025 Adult Advanced Life Support.}, journal = {Resuscitation}, volume = {215 Suppl 1}, number = {}, pages = {110769}, doi = {10.1016/j.resuscitation.2025.110769}, pmid = {41117572}, issn = {1873-1570}, mesh = {Humans ; *Advanced Cardiac Life Support/standards/methods ; *Cardiopulmonary Resuscitation/standards/methods ; Adult ; Europe ; *Heart Arrest/therapy ; *Out-of-Hospital Cardiac Arrest/therapy ; }, abstract = {These European Resuscitation Council (ERC) Guidelines 2025 Adult Advanced Life Support (ALS) are based on the International Liaison Committee on Resuscitation (ILCOR) Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations (CoSTR). The evidence informing the ALS Guidelines is also included. When ILCOR has not addressed a specific topic, the ERC ALS Writing Group has provided its own guidance and the evidence supporting it. This section provides recommendations for ALS for adults with in- or out-of-hospital cardiac arrest. The ERC Guidelines 2025 ALS emphasise providing early and effective ALS interventions to improve survival from cardiac arrest in adults.}, } @article {pmid41132886, year = {2025}, author = {Agüera-Morales, E and Fernández-Sánchez, VE and Navarro-Mascarell, G and Cabezas-Rodríguez, JA and Peña-Toledo, MÁ and Reyes-Rodríguez, V and Postigo-Pozo, MJ and Patrignani-Ochoa, G and Geniz-Clavijo, MÁ and Márquez-Infante, C and Tallon-Aguilar, L and Tinoco-González, J and Padillo-Ruiz, J and Valladares-Sánchez, A and Caballero-Eraso, C and López-Ramírez, C and Mata Alcázar-Caballero, R and Leyva-Fernández, L and Rodríguez-Acosta, A and Maldonado-Sánchez, R and García-Martín, ML and Somoza-Ramírez, M and Quijano-Ruiz, B and Macías-Sánchez, MDM and Carmona-Sánchez, G and Fernández-López, O and Fernández-Fernández, Ó}, title = {Adipose-derived mesenchymal stem cells for the treatment of Amyotrophic Lateral Sclerosis. A phase I/II safety and efficacy clinical trial.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1655124}, pmid = {41132886}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with few treatments available. Mesenchymal stem cells have arisen as a potential treatment option for ALS due to their immune system modulation and their neuroprotective effects. This clinical trial aimed to evaluate the safety, efficacy and feasibility of three intravenous doses of autologous adipose-derived mesenchymal stem cells (AdMSC) in ALS patients.

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

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

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

CLINICAL TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-006254-85.}, } @article {pmid41135686, year = {2026}, author = {Columbro, SF and Tortarolo, M and Re Cecconi, AD and Piccirillo, R and Bendotti, C and Biasini, E and Pasetto, L and Bonetto, V}, title = {Beneficial effects of synthetic torpor in a fast-progressing mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115521}, doi = {10.1016/j.expneurol.2025.115521}, pmid = {41135686}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Torpor/physiology ; Disease Progression ; Superoxide Dismutase-1/genetics ; Motor Neurons/pathology/metabolism ; Male ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss, muscle atrophy, and progressive paralysis. Currently approved treatments provide only limited benefits. Due to the complex and multifactorial nature of ALS pathology, therapies targeting multiple pathways may prove more effective. Synthetic torpor, a state that mimics natural hibernation, has shown promise in promoting neuroprotection by modulating metabolism, reducing inflammation, and preserving both neurons and muscles. In this study, synthetic torpor was induced using 5'AMP combined with environmental cooling in the fast-progressing SOD1[G93A] ALS mouse model on the 129SvHsd genetic background, known for its aggressive disease course, early metabolic dysfunction and unresponsiveness to treatments. Synthetic torpor was highly effective in preserving motor neurons. The treatment significantly delayed disease onset and extended survival, although mildly, without altering overall disease duration. In the spinal cord, synthetic torpor increased glucose transporters, reduced markers of oxidative stress, decreased glial activation and sustained upregulation of neuroprotective proteins, such as RBM3 and PPIA. This occurred despite an increased SOD1 aggregation in a later phase of the disease. Muscles display clear protective effects across disease progression with preservation of mass, reduced atrogin-1, lower PDK4 and oxidative stress markers, associated with improvements in markers of axonal integrity and muscle denervation. This study provides proof-of-concept that activating multiple protective molecular pathways, particularly those involved in glucose metabolism and protein folding, can mitigate the pathological processes in ALS, especially in rapidly progressing forms of the disease.}, } @article {pmid41135742, year = {2025}, author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y}, title = {Multi-omics analysis reveals the protective role of transcriptional enhancer factor and the pathogenic mechanism of monocytes in Parkinson's disease.}, journal = {Brain research bulletin}, volume = {232}, number = {}, pages = {111594}, doi = {10.1016/j.brainresbull.2025.111594}, pmid = {41135742}, issn = {1873-2747}, mesh = {Animals ; *Parkinson Disease/genetics/metabolism ; Humans ; *Monocytes/metabolism/pathology ; Mice ; Mendelian Randomization Analysis ; *Transcription Factors/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Cell Line, Tumor ; Multiomics ; }, abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.}, } @article {pmid41136425, year = {2025}, author = {Vokali, E and Chevalier, E and Dreyfus, N and Charmey, D and Melly, T and Kocher, J and Ratnam, M and Serra, AM and Jaquier, T and Delgado, C and Ravache, M and Scialò, C and Cappelli, S and Kroth, H and Capotosti, F and Luthi-Carter, R and Afroz, T and Derouazi, M and Constantinescu, CC and Seelaar, H and Buratti, E and Nelson, PT and Polymenidou, M and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T}, title = {Development of [[18]F]ACI-19626 as a first-in-class brain PET tracer for imaging TDP-43 pathology.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {9358}, pmid = {41136425}, issn = {2041-1723}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {*Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism/pathology ; Humans ; *DNA-Binding Proteins/metabolism ; Animals ; *Radiopharmaceuticals/pharmacokinetics/chemistry ; Fluorine Radioisotopes ; *TDP-43 Proteinopathies/diagnostic imaging/metabolism/pathology ; Mice ; Male ; Frontotemporal Dementia/diagnostic imaging/metabolism/pathology ; Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/pathology ; Female ; }, abstract = {Aggregated TDP-43 is a hallmark of frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and limbic-predominant age-related TDP-43 encephalopathy (LATE), and a common co-pathology in other neurodegenerative diseases. Currently, no specific biomarkers exist to assess TDP-43 pathology in vivo. We developed two small-molecule radiopharmaceuticals, [[18]F]ACI-19278 and [[18]F]ACI-19626, for visualizing TDP-43 inclusions by positron emission tomography (PET). Both ligands bind with high affinity to aggregated, but not soluble, TDP-43 in patient brain samples from diverse TDP-43 proteinopathies, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), ALS, and LATE, and in cell models. Both compounds display excellent selectivity for TDP-43 over Aβ, Tau, and α-synuclein aggregates. In non-human primates, [[18]F]ACI-19278 and [[18]F]ACI-19626 show a pharmacokinetic profile suitable for brain PET imaging (rapid brain uptake; fast and complete washout). ACI-19278 and ACI-19626 are promising first-in-class TDP-43 PET tracers with the potential to revolutionize the diagnosis and treatment of neurodegenerative proteinopathies, enabling a precision medicine approach.}, } @article {pmid41137739, year = {2026}, author = {van Wijk, IF and Kraneburg, L and van Eijk, RPA and Veldink, JH and van Es, MA and Westeneng, HJ and van den Berg, LH}, title = {Prodromal symptoms in amyotrophic lateral sclerosis from the perspective of the patient and of the caregiver.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {263-273}, doi = {10.1080/21678421.2025.2574687}, pmid = {41137739}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/physiopathology ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; *Prodromal Symptoms ; Aged ; Adult ; Surveys and Questionnaires ; Registries ; }, abstract = {OBJECTIVE: Clinically manifest ALS is preceded by a prodromal phase in gene mutation carriers, characterized by mild motor impairment. A well-defined prodromal phase could enable earlier diagnosis and treatment. We investigated the presence of a prodromal phase in sporadic ALS, from the perspective of patients and caregivers.

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

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

CONCLUSIONS: In sporadic ALS, approximately a quarter of patients report a prodromal phase characterized primarily by mild motor symptoms. However, mild motor symptoms alone are unlikely to contribute to earlier disease recognition. Cognitive or behavioral symptoms are often not recognized as part of the clinical spectrum. These findings emphasize the need for reliable biomarkers to detect ALS pathology at an early stage.}, } @article {pmid41141079, year = {2025}, author = {Jeong, E and Li, D}, title = {Antisense Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis (ALS): An Umbrella Review.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e93140}, pmid = {41141079}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is a fatal neurodegenerative disease prominent in the elderly population. To this point, no completely effective treatments have been procured; however, antisense oligonucleotide therapies, or ASOs, are a promising venue. In order to investigate the efficacy of ASOs in the treatment of ALS by targeting specific genetic mutations, we conducted an umbrella review utilizing keywords such as "ALS" and "ASO" in the PubMed database, excluding sources published more than 10 years ago for relevance. Results revealed that of multiple tentative ASO treatments, for multiple specific gene mutations, only one, Tofersen, was approved for the wider population. The main cause of failure was an inability to meet efficacy endpoints, resulting in the discontinuation of the product. Tofersen is able to treat mutations in the SOD1 gene, but not any others. While initially discouraging, the production of ASOs is a relatively new and advanced process, and slow progress is expected. However, there remains the problem of identifying and treating the much more prevalent sporadic ALS, which is much more common compared to familial ALS.}, } @article {pmid41141812, year = {2025}, author = {Cobos, SN and Fisher, RMA and Bennett, SA and Janani, C and Dansu, DK and Cleere, MM and Yeasmin, A and Cruz, G and Qureshi, S and Villasi, W and Frederic, R and Chen, K and Mirzakandova, M and Angelakakis, G and Son, E and Elgendy, A and Torrente, MP}, title = {C9orf72 Dipeptide Repeat Proteinopathy Is Linked to Increased Histone H3 Phosphorylation on Serine 10.}, journal = {ACS omega}, volume = {10}, number = {41}, pages = {48395-48411}, pmid = {41141812}, issn = {2470-1343}, support = {K12 GM102778/GM/NIGMS NIH HHS/United States ; R15 NS125394/NS/NINDS NIH HHS/United States ; T34 GM149490/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal illnesses forming a neurodegenerative disease continuum. While most ALS/FTD cases are sporadic, a small proportion of cases are linked to mutations in many genes. Among these, hexanucleotide repeat expansions in the C9orf72 gene are the most common and lead to the formation of dipeptide repeat proteins (DPRs), including a proline-arginine dipeptide (PR), which aggregate in the cytoplasm of decaying neurons. As genetics alone fails to explain the etiology of ALS/FTD, it is possible that epigenetic mechanisms - such as histone post-translational modifications (PTMs) - are involved in disease processes. A Saccharomyces cerevisiae (PR)50 overexpression model displays overt growth suppression and aggregation. Here, we exploit this model as a discovery platform to comprehensively characterize changes in the levels of PTMs on Histones H3 and H4. We find that overexpression of (PR)50 is associated with increased levels of phosphorylation on Histone H3 at Serine 10 (H3S10ph). Furthermore, (PR)50 overexpression revealed modest increases in the levels of other marks associated with increased gene expression. Remarkably, decreased abundance of Ipl1, the kinase responsible for phosphorylating H3S10 in yeast, leads to amelioration of the growth suppression phenotype and restores H3S10ph levels even in the context of (PR)50 overexpression. Recapitulating our results in yeast, several c9orf72 ALS patient-derived fibroblasts and induced pluripotent stem cell (iPSCs) lines display similar increases in H3S10ph levels. Altogether, these findings reveal a previously undiscovered connection between H3S10ph and c9 ALS/FTD proteinopathy that could reveal novel targets for the treatment of this disease.}, } @article {pmid41143669, year = {2025}, author = {Morley, M and Aurora, M and Gustafson, K and Seals, CS and Feuer, A and Datar, S and Parvanta, S and Thakur, N and Dave, KD}, title = {Medicare expenditures in the first year of amyotrophic lateral sclerosis diagnosis.}, journal = {The American journal of managed care}, volume = {31}, number = {10}, pages = {e308-e312}, doi = {10.37765/ajmc.2025.89813}, pmid = {41143669}, issn = {1936-2692}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/economics/therapy ; *Health Expenditures/statistics & numerical data ; *Medicare/economics/statistics & numerical data ; *Fee-for-Service Plans/economics/statistics & numerical data ; Edaravone/economics/therapeutic use ; Riluzole/economics/therapeutic use ; Neuroprotective Agents/economics/therapeutic use ; Drug Costs/statistics & numerical data ; Administrative Claims, Healthcare/economics/statistics & numerical data ; Financial Stress/epidemiology ; Cost of Illness ; Retrospective Studies ; Hospitalization/economics/statistics & numerical data ; Humans ; Male ; Female ; Aged ; }, abstract = {OBJECTIVES: To determine Medicare expenditures and potential beneficiary out-of-pocket liability for Medicare beneficiaries with amyotrophic lateral sclerosis (ALS), including costs related to drug treatments.

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

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

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

CONCLUSIONS: Approximately one-third of people with ALS on Medicare receive disease-modifying medication. ALS is a burdensome disease with significant financial implications for people with ALS and the Medicare program. Treatment for ALS presents affordability challenges, and policy makers must consider how current Medicare policy addresses the costs of care.}, } @article {pmid41144002, year = {2025}, author = {Vidovic, M and Lapp, HS and Dittes, I and Leuchten, N and Aringer, M and Günther, C and Günther, R}, title = {Methotrexate therapy as a promising long-term treatment approach for immune-mediated adverse reactions of tofersen in SOD1-ALS: a case report.}, journal = {Journal of neurology}, volume = {272}, number = {11}, pages = {732}, pmid = {41144002}, issn = {1432-1459}, } @article {pmid41148458, year = {2025}, author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK}, title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {16}, pmid = {41148458}, issn = {1573-4978}, mesh = {Humans ; Animals ; *MicroRNAs/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Signal Transduction ; Gene Regulatory Networks ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.}, } @article {pmid41149102, year = {2025}, author = {Mauriello, L and Cuozzo, A and Pezzella, V and Isola, G and Spagnuolo, G and Iorio-Siciliano, V and Ramaglia, L and Blasi, A}, title = {Oral Health Status in Patients with Amyotrophic Lateral Sclerosis: A Scoping Review.}, journal = {Dentistry journal}, volume = {13}, number = {10}, pages = {}, pmid = {41149102}, issn = {2304-6767}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome which often leads to progressive muscular dysfunction and therefore oral health deterioration. The aim of this scoping review is to evaluate oral health status in ALS patients focusing on the importance of dental care in improving patient's quality of life. Methods: A comprehensive literature search was conducted on PubMed, Scopus, Web of Science, and Embase databases until June 2025 using a combination of keywords and MeSH terms related to ALS and oral health. Studies were screened and selected based on inclusion and exclusion criteria, focusing on human clinical data reporting oral health outcomes in ALS. Results: Eight studies met the inclusion criteria. The findings showed a high prevalence of oral complications in bulbar-onset ALS patients. Common issues included reduced tongue mobility, poor oral hygiene, sialorrhea, and decreased masticatory function were evaluated. Conclusions: Oral health impairment in ALS patients frequently contributes to systemic risks and reduced quality of life. A dental expert may play an important role in multidisciplinary care teams in terms of early diagnosis and conservative treatment of oral diseases ranging from periodontal disease to temporomandibular disorders (TMD). Personalized oral hygiene strategies and adjunctive therapies may serve as key elements in maintaining overall health and patient comfort in ALS. Therefore, the objective of the following review was to evaluate oral health complication in patients with ALS, highlighting the impact of oral care on patients' quality of life.}, } @article {pmid41152189, year = {2025}, author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY}, title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70786}, pmid = {41152189}, issn = {1552-5279}, support = {U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911//The National Institute on Aging/ ; U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U01 AG045390/AG/NIA NIH HHS/United States ; //The Intramural Research Program of the National Institutes of Health/ ; U54 NS092089/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures.

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

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

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

HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.}, } @article {pmid41155480, year = {2025}, author = {Turpo-Peqqueña, AG and Valencia-Arce, RJ and Del-Carpio-Carrazco, FL and Quispe-Ppacco, DJ and Carbajal-Llerena, PF and Loza-Chipa, HR and Vásquez-Macedo, AS and Gómez, B}, title = {Inhibition of Casein Kinase 1δ as a Novel Therapeutic Strategy for Amyotrophic Lateral Sclerosis: A Theoretical Study.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155480}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/enzymology ; *Casein Kinase Idelta/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Molecular Dynamics Simulation ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Protein Binding ; }, abstract = {Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1δ) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1δ using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1δ (-46.53±1.94 kcal/mol). An inverse correlation was observed between theoretical affinity and experimental IC50 values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood-brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1δ inhibitors for future experimental validation in the treatment of ALS.}, } @article {pmid41155541, year = {2025}, author = {Perez, DM}, title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155541}, issn = {1424-8247}, support = {R01 AG066627/AG/NIA NIH HHS/United States ; RO1AG066627/GF/NIH HHS/United States ; }, abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.}, } @article {pmid41165282, year = {2025}, author = {Roedl, K and Genbrugge, C}, title = {Managing cardiac arrest in the intensive care unit.}, journal = {Current opinion in critical care}, volume = {31}, number = {6}, pages = {729-734}, doi = {10.1097/MCC.0000000000001319}, pmid = {41165282}, issn = {1531-7072}, mesh = {Humans ; *Heart Arrest/therapy/epidemiology/etiology/mortality ; *Intensive Care Units ; *COVID-19/epidemiology ; *Cardiopulmonary Resuscitation/methods ; SARS-CoV-2 ; *Critical Care/methods ; }, abstract = {PURPOSE OF REVIEW: This review aims to explore the distinct clinical characteristics, epidemiology, treatment approaches, and research needs concerning cardiac arrest in the intensive care unit (ICU-CA), a specific subset of in-hospital cardiac arrest (IHCA). While IHCA remains a major cause of mortality, recent data indicate improved outcomes, with a notable variation in incidence and survival depending on the location, particularly within the ICU setting.

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

SUMMARY: In summary, ICU-CA represents a distinct clinical entity requiring tailored research. Future directions should prioritize international registries, validation of predictive models using artificial intelligence, and clarification of do-not-resuscitate practices to improve outcomes and resource allocation in this critically ill population.}, } @article {pmid41169216, year = {2026}, author = {Chisholm, CG and McAlary, L and Lum, JS}, title = {From translation to stabilization and degradation: A multifaceted approach for the treatment of superoxide dismutase 1-associated amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {21}, number = {7}, pages = {2946-2947}, pmid = {41169216}, issn = {1673-5374}, } @article {pmid41171075, year = {2025}, author = {Cazzola, J and Talpo, F and Faravelli, G and Donati, C and Maramai, S and Saletti, M and Giuliani, G and Paolino, M and Cappelli, A and Anzini, M and Sommi, P and Vitali, A and Sala, A and Trucco, A and Biella, GR and Spaiardi, P}, title = {Evaluation of a New Riluzole-Based Compound VA945 on Sodium and Potassium Conductances Expressed by SH-SY5Y- Derived Neurons.}, journal = {Journal of neurochemistry}, volume = {169}, number = {11}, pages = {e70280}, pmid = {41171075}, issn = {1471-4159}, mesh = {*Riluzole/pharmacology/analogs & derivatives ; Humans ; *Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; Potassium/metabolism ; *Potassium Channels ; Sodium/metabolism ; Membrane Potentials/drug effects ; Patch-Clamp Techniques ; *Sodium Channels ; Dose-Response Relationship, Drug ; }, abstract = {Riluzole (Rilutek), a derivative of benzothiazole, acts as a neuroprotective agent by inhibiting voltage-dependent sodium (Na[+]) and delaying rectifier potassium (K[+]) currents. By doing so, it helps reduce excitotoxicity, a key pathogenetic mechanism in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although riluzole is a clinically approved treatment for ALS, it is not fully effective, particularly in advanced stages of the disease. In this study, we functionally characterized a newly synthetized riluzole-based compound, VA945, with potentially enhanced neuroprotective effects. By means of SH-SY5Y human neuroblastoma cells differentiated into neurons, we assessed using whole-cell patch-clamp techniques the effects of VA945 on voltage-dependent Na[+] and K[+] currents at extracellular concentrations of 5, 50, and 100 μM. The compound reduced maximal activation and inactivation of Na[+] conductance, as well as maximal activation of K[+] conductance, across all tested concentrations. We also observed shifts of the activation and inactivation curves to more hyperpolarized potentials along with changes in the slope factor (k), indicating an altered voltage sensitivity of voltage-dependent K[+] and Na[+] channels. While the activation kinetics of both channels remained unaffected, and the inactivation kinetics of Na[+] were unchanged, we noted a slowdown in the deactivation kinetics of the K[+] channels. Altogether, these findings suggest that VA945 exerts multi-target pharmacological effects on neuronal voltage-dependent ion currents critically involved in excitotoxicity and neurodegeneration, across a wide range of concentrations. This warrants further ex vivo and/or in vivo studies to explore its potential as a neuroprotective agent.}, } @article {pmid41175647, year = {2025}, author = {Singh, A and Gupta, I and Saha, P and Hole, A and Anthony, F and Natu, A and Smoot, DT and Ashktorab, H and Chilakapati, MK and Gupta, S}, title = {Raman spectroscopy for detecting gastric and liver cancer cells that entered a tolerant persistence state to survive cisplatin chemotherapy.}, journal = {Biochemical and biophysical research communications}, volume = {790}, number = {}, pages = {152891}, doi = {10.1016/j.bbrc.2025.152891}, pmid = {41175647}, issn = {1090-2104}, mesh = {Humans ; *Cisplatin/pharmacology/therapeutic use ; *Stomach Neoplasms/drug therapy/pathology ; *Drug Resistance, Neoplasm/drug effects ; *Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; *Spectrum Analysis, Raman/methods ; *Liver Neoplasms/drug therapy/pathology ; Cell Survival/drug effects ; Neoplasm, Residual ; }, abstract = {The persistence of minimal residual disease (MRD), a small population of tumor cells that survive therapy but remain below the limit of conventional detection methods, often leads to relapse. The residual disease is attributed to drug-tolerant persister (DTP) cells at the cellular level. In the present study, the differences in drug-tolerant persister cells, which represent a transient, reversible survival state, and drug-resistant cells, which reflect a stable, fixed phenotype of gastric and liver cancer cell lines, were investigated. The ultramicroscopic and confocal studies revealed a phenotypic shift in DTP cells induced upon drug treatment, characterized by cytoplasmic expansion, enhanced mitochondrial biogenesis, and active intercellular communication, potentially contributing to the survival of the drug-tolerant cells. The observed morphological alterations in a cell's physical characteristics are associated with underlying biochemical changes. Further, Raman spectroscopy provides a non-invasive method for studying biochemical alterations; Raman spectral analysis demonstrated precision in distinguishing with significant accuracy between DTP cells compared to resistant and parental cells. Multivariate Curve Resolution-alternating least squares (MCR-ALS) analysis showed alteration of lipid, nucleic acid, and protein-related features. The accumulation of lipid vacuoles inside the cytoplasm of DTP cells, and gene set enrichment analysis (GSEA) showed significant downregulation of metabolic pathways purine and pyrimidine, highlighting the potential metabolic shift in imparting a survival advantage to DTP cells. Thus, Raman analysis has confirmed the biochemical changes and provides proof of concept for identifying cisplatin-induced DTP and resistant tumor cells for a better therapeutic approach in resistant and relapse management.}, } @article {pmid41181835, year = {2025}, author = {Keritam, O and Erdler, M and Fasching, B and Zulehner, G and Rath, J and Krenn, M and Waldhör, T and Gruber, VA and Langweil, N and Kiss, C and Griedl, TA and Gold, V and Wanschitz, J and Hotter, A and Kleinveld, VEA and Horlings, CGC and Erber, A and Schernhammer, E and Troger, J and Grinzinger, S and Müller, P and Langenscheidt, D and Rappold, M and Wiesenhofer, A and Gosk-Tomek, M and Knipp, F and Mahal, S and Bernert, G and Baumann, M and Zimprich, F and Topakian, R and Eggers, C and Quasthoff, S and Löscher, W and Cetin, H}, title = {Efficacy and safety of risdiplam in adults with 5q-associated spinal muscular atrophy: a nationwide observational cohort study in Austria.}, journal = {EClinicalMedicine}, volume = {88}, number = {}, pages = {103536}, pmid = {41181835}, issn = {2589-5370}, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic motor neuron disease marked by the progressive decline of motor function. Risdiplam, an orally administered SMN2 splicing modifier, was approved for the treatment of 5q-associated SMA (5q-SMA) across all age groups. However, clinical trial data have primarily focused on paediatric populations, with limited evidence available for adult patients. This study aimed to evaluate the efficacy and safety of risdiplam in treatment-naïve adults with 5q-SMA in a real-world, multicentre setting.

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

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

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

FUNDING: This study was financially supported by F. Hoffmann-La Roche Ltd.}, } @article {pmid41182353, year = {2026}, author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X}, title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.}, journal = {Psychopharmacology}, volume = {243}, number = {6}, pages = {1377-1396}, pmid = {41182353}, issn = {1432-2072}, support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; }, mesh = {Humans ; *Piwi-Interacting RNA/genetics/metabolism ; Animals ; *Brain/metabolism ; *Brain Diseases/genetics/physiopathology/drug therapy ; }, abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.}, } @article {pmid41184709, year = {2025}, author = {Kiecka, A and Szczepanik, M}, title = {Dietary modulation of the gut microbiome as a supportive strategy in the treatment of amyotrophic lateral sclerosis - a narrative review.}, journal = {Pharmacological reports : PR}, volume = {77}, number = {6}, pages = {1514-1526}, pmid = {41184709}, issn = {2299-5684}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/therapy/diet therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use/administration & dosage ; Fecal Microbiota Transplantation/methods ; Animals ; Prebiotics/administration & dosage ; *Diet ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to permanent damage to the central and peripheral motor neurons. Currently, there is no effective treatment for ALS, and therapy focuses solely on slowing the progression of the disease. Recent studies show that gut microbiota plays an important role in the development of neurodegenerative diseases. Altered gut microbiota has also been found in ALS. These changes have prompted the search for alternative forms of ALS treatment, focusing on changing the microbial composition of the gut. It has been noted that diet, probiotics, prebiotics and vitamins can all influence the course of ALS. Another interesting issue is fecal microbiota transplantation, which is already used in the treatment of certain intestinal diseases and could potentially be useful in the treatment of ALS. This review summarizes current knowledge on the impact of gut microbiota on the neurodegenerative process in ALS, with particular emphasis on the role of diet and probiotics. It also discusses potential mechanisms and highlights future research directions in this emerging field.}, } @article {pmid41191158, year = {2025}, author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK}, title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {49}, pmid = {41191158}, issn = {1573-4978}, mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.}, } @article {pmid41196032, year = {2026}, author = {Mansoor, N and Heiman-Patterson, T and Feldman, EL and Wicks, P and Benatar, M and Vieira, F and Glass, J and Levine, T and Bertorini, T and Barkhaus, P and Mascias Cadavid, J and Jackson, C and Jhooty, S and Brown, A and Pattee, G and Sane, H and Mcdermott, CJ and Carter, G and Beauchamp, M and Wang, O and Ratner, D and Bedlack, R and Li, X}, title = {ALSUntangled #81: Pyridostigmine (mestinon[®]).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {487-491}, doi = {10.1080/21678421.2025.2582830}, pmid = {41196032}, issn = {2167-9223}, mesh = {Humans ; *Pyridostigmine Bromide/therapeutic use/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Neuromuscular Junction/drug effects ; Animals ; Disease Progression ; }, abstract = {Pyridostigmine (Mestinon[®], Bausch Health, Canada Inc.) increases acetylcholine availability at the neuromuscular junction, enhancing transmission. Preclinical studies suggest that neuromuscular junction dysfunction develops early in ALS, and pyridostigmine may temporarily improve neuromuscular transmission. However, altered neuromuscular junction transmission has uncertain benefits in ALS progression. Pyridostigmine does not have other plausible mechanisms that truly modify ALS pathophysiology. People with ALS (PALS) who have positive acetylcholine receptor autoantibodies and no myasthenia symptoms are unlikely to respond to pyridostigmine treatment. Clinical trials on pyridostigmine in PALS are lacking, but two clinical trials of other similar anticholinesterase agents did not effectively slow ALS progression. Muscarinic cholinergic side effects, including gastrointestinal symptoms, are common. Given the lack of mechanistic plausibility and efficacy, we do not support the use of pyridostigmine for slowing ALS progression.}, } @article {pmid41202295, year = {2025}, author = {Sales de Campos, P and Smith-Hublou, M and Olsen, WL and Souza Leite, W and Wymer, JP and Napoli, NJ and Vose, AK and Pulley, MT and Mitchell, GS and Smith, BK}, title = {Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e76105}, pmid = {41202295}, issn = {1929-0748}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; 22-CTA-611//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/therapy ; Double-Blind Method ; *Hypoxia/physiopathology ; Purines/therapeutic use/pharmacology ; *Respiration/drug effects ; *Neuronal Plasticity/drug effects ; *Purinergic P1 Receptor Antagonists/therapeutic use ; Randomized Controlled Trials as Topic ; Male ; Adult ; Middle Aged ; Female ; }, abstract = {BACKGROUND: Respiratory impairment is a major concern in amyotrophic lateral sclerosis (ALS), shortening survival and lowering quality of life. One therapy with promise to delay respiratory decline in ALS is acute intermittent hypoxia (AIH), consisting of alternating periods of breathing mildly hypoxic (9%-12% O2) and normoxic (21% O2) gas. AIH stimulates spinal, serotonin-dependent neuroplasticity in rodent models, conferring functional benefits in diverse physiological systems without detectable pathology. However, in rodent models, AIH-induced neuroplasticity is constrained by distinct signaling cascades initiated by spinal adenosine.

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

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

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

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

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

DERR1-10.2196/76105.}, } @article {pmid41203507, year = {2025}, author = {Zhang, YP and Kedia, S and Klenerman, D}, title = {Rethinking neurodegeneration through a co-proteinopathy lens.}, journal = {Trends in neurosciences}, volume = {48}, number = {12}, pages = {952-963}, doi = {10.1016/j.tins.2025.10.006}, pmid = {41203507}, issn = {1878-108X}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.}, } @article {pmid41206134, year = {2025}, author = {Allel, K and Palmer, T and Abou Jaoude, GJ and Korotych, O and Yedilbayev, A and Vilc, V and Corloteanu, A and Macari, M and Evghenia, C and Laticevschi, D and Shakhimurat-Shaimovich, I and Anar-Saduakasovna, R and Gulzhan-Elbrusovna, T and Anatolievna-Ryazanet, D and Shahrizada-Yergalymovna, A and Yatskevich, N and Skrahina, A and Zhurkin, D and Avaliani, Z and Kiria, N and Lomtadze, N and Kiria, N and Avaliani, T and Khonelidze, I and Danelia, M and Maxim, C and Haghparast-Bidgoli, H and Skordis, J}, title = {Cost-effectiveness of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis in Belarus, Georgia, Kazakhstan and the Republic of Moldova.}, journal = {BMJ global health}, volume = {10}, number = {11}, pages = {}, pmid = {41206134}, issn = {2059-7908}, support = {001/WHO_/World Health Organization/International ; D43 TW007124/TW/FIC NIH HHS/United States ; }, mesh = {Humans ; Cost-Benefit Analysis ; *Tuberculosis, Multidrug-Resistant/drug therapy/economics ; Moldova ; Kazakhstan ; Quality-Adjusted Life Years ; Male ; *Rifampin/therapeutic use/administration & dosage ; Republic of Belarus ; Female ; Adult ; *Antitubercular Agents/economics/administration & dosage/therapeutic use ; Administration, Oral ; Georgia (Republic) ; Middle Aged ; }, abstract = {INTRODUCTION: Prior to 2020, treatment options for multidrug-resistant tuberculosis (MDR-TB) were limited and typically involved long treatment durations and high financial burdens. In the eastern European and central Asian (EECA) region, traditional inpatient tuberculosis (TB) care models, alongside high MDR-TB rates, escalate nosocomial transmission risks and treatment costs. Modified, fully oral, shorter treatment regimens (mSTR) implemented in the WHO European Region under operational research conditions offered a potential reduction in the burden of MDR-TB treatment for both patients and health systems.

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

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

CONCLUSIONS: Compared with SOC, mSTR is a more cost-effective treatment option for MDR/RR-TB, which should be considered by policymakers in the EECA region. Using insights from current implementations to scale up, plan operational changes and reallocate savings from mSTR could greatly enhance TB services and patient care.}, } @article {pmid41209384, year = {2025}, author = {Han, K and Yan, SG and Liu, F and Li, L and Zhou, D and Li, L and Liu, N and Dong, J}, title = {The Alterations in the Osteoimmune Microenvironment of STZ-Induced Type 2 Diabetic Mice:A Single-Cell RNA Sequencing Analysis.}, journal = {Journal of inflammation research}, volume = {18}, number = {}, pages = {15309-15327}, pmid = {41209384}, issn = {1178-7031}, abstract = {BACKGROUND: This study aimed to delineate the single-cell transcriptome of bone marrow (BM) cells from wild-type (WT) and type 2 diabetic (T2D) mice, revealing distinct immune microenvironment features.

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

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

CONCLUSION: Single-cell RNA sequencing provides a comprehensive profile of bone marrow immune cells in T2D mice and has highlighted their heterogeneity, population shifts, and intercellular interactions. These findings highlight critical alterations in immune cell functions that may contribute to T2D progression and suggest possible avenues for future therapeutic investigation. Future research should continue to leverage scRNA-seq technology to refine treatment strategies and enhance patient outcomes by addressing immune dysfunction and chronic inflammation.}, } @article {pmid41210444, year = {2025}, author = {Khan, S and Wennberg, B and Hooda, F and Witkowska, M}, title = {Delayed treatment and diagnostic challenges in differentiating multifocal acquired demyelinating sensory and motor neuropathy from lupus: a case report and literature review.}, journal = {AME case reports}, volume = {9}, number = {}, pages = {111}, pmid = {41210444}, issn = {2523-1995}, abstract = {BACKGROUND: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is a rare autoimmune-mediated inflammatory response with negative antibodies which causes demyelination of multiple peripheral nerves in an asymmetric distribution with both motor and sensory deficits. Diagnosis for MADSAM can be clinically challenging, relies on a combination of clinical and electrodiagnostic studies, and symptoms can overlap with other neurological conditions such as systemic lupus erythematosus (SLE). MADSAM is typically asymmetric, demyelinating, and limited to peripheral nerves, whereas SLE is systemic, more commonly axonal, and has vasculitic features. SLE is treated with steroids and immunosuppressants while MADSAM is treated with intravenous immunoglobulin (IVIG), steroids, or plasmapheresis. There is a good short-term prognosis for MADSAM with early treatment, but prognosis can worsen with delayed or inappropriate therapy.

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

CONCLUSIONS: The case highlights the importance of understanding the various causes of weakness and neuropathy, particularly with an atypical presentation, to pursue the correct diagnostic tests and treatment. The case particularly focuses on the difference between MADSAM and SLE. There is significant clinical overlap between the two, and a misdiagnosis can delay effective treatment and worsen outcomes by allowing progression to more debilitating stages of the illness.}, } @article {pmid41213077, year = {2025}, author = {Cai, S and Liu, Y and Liu, B and Liao, H and Li, K}, title = {Hexokinase as a Central Hub in Neurodegeneration: From Metabolic Dysfunction to Therapeutic Innovation.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.0891}, pmid = {41213077}, issn = {2152-5250}, abstract = {Neurodegenerative diseases represent an escalating global health crisis affecting more than 55 million people worldwide; however, underlying mechanisms remain unclear, and therapeutic breakthroughs are elusive. Emerging evidence indicates that hexokinase (HK), the rate-limiting glycolytic enzyme, functions as a master regulator orchestrating neuronal survival through metabolic‒mitochondrial coupling. This review consolidates emerging paradigms revealing that HK maintains neuronal viability through its obligate interaction with mitochondrial VDAC1, forming a metabolic checkpoint that integrates energy status with survival signaling. Disease-specific HK dysfunction patterns precede clinical manifestations and drive pathological cascades across primary neurodegenerative conditions. Pathological proteins characteristic of neurodegeneration-amyloid-β in AD, α-synuclein in PD, mutant SOD1 in ALS, and huntingtin in HD-converge to disrupt the HK-VDAC1 axis through distinct molecular mechanisms, triggering mitochondrial permeabilization, bioenergetic collapse, and inflammatory activation. This uncoupling event promotes VDAC1 oligomerization, enabling the cytosolic release of mtDNA, which in turn activates the NLRP3 inflammasome while depleting antioxidant capacity, establishing self-perpetuating neuroinflammatory cycles. The literature reveals that HK functions as a molecular rheostat, determining neuronal fate through glucose-6-phosphate-mediated feedback control, modulation of growth factor signaling, and regulation of apoptosis/survival pathways. Therapeutic targeting of HK through peptide interventions, enzymatic modulation, and gene therapy demonstrates robust neuroprotective effects across multiple disease models. Meanwhile, combination strategies addressing metabolic-inflammatory networks show synergistic efficacy. These insights position HK as a convergent therapeutic nexus offering unprecedented opportunities for precision intervention in neurodegeneration, with potential for early diagnostic applications and preventive strategies that could transform treatment paradigms for conditions affecting millions worldwide.}, } @article {pmid41222589, year = {2026}, author = {Heyming, T and Knudsen-Robbins, C and Kain, A and Morphew, T and Ta-Perez, Z and Darabpour, A and Lee, H and Brukman, S and Shelton, SK}, title = {Prehospital Pediatric Assessment Triangle-Real World Data: Emergency Medical Services Use of the Pediatric Assessment Triangle in the Prehospital Environment.}, journal = {Prehospital emergency care}, volume = {30}, number = {6}, pages = {828-836}, doi = {10.1080/10903127.2025.2581753}, pmid = {41222589}, issn = {1545-0066}, mesh = {Humans ; *Emergency Medical Services/methods/statistics & numerical data ; Retrospective Studies ; Child, Preschool ; Female ; Infant ; Child ; Male ; Adolescent ; *Pediatrics/methods ; Infant, Newborn ; }, abstract = {OBJECTIVES: Emergency medical services (EMS) clinicians report lack of training and experience with children, leading to discomfort and uncertainty regarding assessment and treatment. The Pediatric Assessment Triangle (PAT) was designed to provide a rapid and standardized approach. Despite widespread adoption, literature examining EMS implementation of PAT remains limited. We examined EMS use of PAT and assessment of clinical stability and the association between EMS use of PAT and prehospital interventions, EMS transport decisions (advanced life support [ALS] vs basic life support [BLS]), emergency department (ED) interventions, and ED disposition.

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

RESULTS: A total of 2929 patients were included. Most patients, 65.9%, had a PAT score of 0; for those with non-zero PATs, abnormalities in the appearance domain were most prevalent, 50.7%. A PAT score of 1 or higher was associated with transport via ALS (OR 67.9; 95% CI 32.0, 144.1) compared to a PAT of 0. Most patients, 62.2%, received an EMS intervention; the most common was diagnostics (blood glucose or electrocardiogram [EKG]). The EMS administered medications to 22% of patients. PAT scores of ≥2 were associated with double the odds of admission to the floor (OR 2.09; 95% CI 1.4, 3.0) and quadruple the odds of admission to ICU level of care/direct to surgery/expired (OR 4.9; 95% CI 2.9, 8.3); PATs abnormal for work of breathing only were associated with increased odds of admission to the floor (OR 2.5; 95% CI 1.8, 3.6).

CONCLUSIONS: This study suggests that EMS PAT assessment in the field appropriately reflects patient stability and may be associated with EMS intervention en-route. The EMS PAT scores demonstrate promise as an adjunct to ED assessment, alerting clinicians to increased likelihood of admission. The PAT has potential to serve as a practical mechanism for EMS feedback and quality improvement studies.}, } @article {pmid41224202, year = {2026}, author = {Metelmann, M and Heyne, S and Peuker, M and Claßen, J and Mehnert-Theuerkauf, A and Esser, P}, title = {[Experiences with the Application of Short-Term Psychotherapy in Patients with Amyotrophic Lateral Sclerosis: What Can We Learn from It?].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {76}, number = {2}, pages = {86-94}, doi = {10.1055/a-2711-2085}, pmid = {41224202}, issn = {1439-1058}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; Male ; Female ; Middle Aged ; Aged ; *Psychotherapy, Brief/methods ; Palliative Care ; Adult ; Feasibility Studies ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is associated with elevated distress, but evidence on psychosocial interventions is limited. We tested the feasibility of a psychotherapy for palliative cancer patients in ALS patients.We applied CALM (Managing Cancer and Living Meaningfully), an effective psychodynamic short-term therapy for advanced cancer patients, within a pre-post study among patients with ALS. We provided patient flow and formal treatment information. Based on the treatment protocols, the therapist reflected on the applicability of the treatment structure, specifics in the psychosocial work with ALS patients and suggestions for treatment modification.Among 15 eligible patients, five participated. Three patients completed the treatment, two patients provided complete study data. The trial was prematurely stopped due to issues in feasibility. Six (22%) sessions were conducted via telephone, 10 (37%) were attended by family caregivers. The structure showed limited applicability largely because fear-laden topics including suffering and death were extensively avoided. Compared to palliative cancer patients, ALS patients fluctuated more strongly in their psychological and physical symptom burden and were more strongly distressed by disease-related practical issues. Recommendations included a multi-professional team, booster sessions and a direct support for caregivers.A psychotherapy effective for cancer patients showed features that limit its applicability among ALS patients. Some of these limitations are treatment-inherent and thus hard to adapt. Rather than modifying the program, we suggest to develop a specific supportive psychotherapeutic intervention within a participatory approach.}, } @article {pmid41228121, year = {2025}, author = {Wityshyn, S and Sanghai, N and Tranmer, GK}, title = {My Amyotrophic Lateral Sclerosis (ALS) Journey from Weakness to Diagnosis: A Journey of Hope.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {21}, pages = {}, pmid = {41228121}, issn = {2227-9032}, support = {202210PJT-495295/CAPMC/CIHR/Canada ; }, abstract = {Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a progressive neurodegenerative disease that attacks and kills motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy, eventually causing respiratory failure and death within 2-5 years after diagnosis. By 2040, the global population of individuals living with ALS is projected to approach 400,000. Since ALS was discovered by Charcot 150 years ago, only two drugs (Edaravone and Riluzole) have been available, offering modest clinical benefits in slowing disease progression. The increasing number of cases, along with the high costs of treatment and care, creates a growing burden on communities and the healthcare system. However, despite this rising burden and the failure of most clinical trials, the ALS community remains hopeful because of the patients themselves. ALS patients are the beating heart of the ALS community. They engage in efforts to improve lives for others, raising awareness through their real-life experiences, participating in research activities, fundraising, providing samples for research, and advocating strongly in front of communities and governments to raise funds. Their engagement is highly valuable, and collaboration with the research community is essential to understanding the disease process and developing effective disease-modifying therapies. Here, we share the story of Mrs. Sherry Wityshyn, an ALS patient and a true ALS warrior from Winnipeg, Manitoba, Canada. We believe her story will inspire and motivate the entire community to learn more about ALS. Furthermore, her story gives hope to everyone impacted. In this manuscript, we also emphasize the different stages of Sherry's journey from weakness to diagnosis and our efforts to share her enduring words with policymakers in the government.}, } @article {pmid41228180, year = {2025}, author = {Taubert, S and Collins, A and Henderson, R and McCombe, P and Tang, L and Kramer, K and Wishart, L and Burns, C}, title = {Co-Design and Non-Randomised Pilot Evaluation of Resources Developed to Optimise Saliva Management in People with Motor Neurone Disease.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {21}, pages = {}, pmid = {41228180}, issn = {2227-9032}, support = {EOGR-2022-01//Royal Brisbane and Women's Hospital Foundation/ ; }, abstract = {Background/Objectives: People living with MND (plwMND) commonly develop difficulty swallowing and subsequent difficulty clearing saliva from the airway. Medical saliva interventions include pharmacological agents, botulinum toxin injections, and radiation to salivary glands, with associated side effects. Non-invasive behavioural strategies and natural remedies are also recommended. Saliva symptom management is guided by the multidisciplinary MND team (typically through a three-monthly clinic) alongside community clinicians. Some plwMND report difficulty recalling and implementing treatments between clinics. This study aimed to enhance the content and method of providing recommendations for self-management of saliva symptoms by (i) developing MND-specific resources and (ii) evaluating resource use and preliminary clinical benefit. Methods: In Phase 1 plwMND, caregivers, and clinicians co-designed saliva management resources. Phase 2 examined the use of these resources via a hospital-based MND clinic with 28 plwMND, their caregivers, and community clinicians. In the clinic, plwMND were given a written treatment plan and relevant resources. During reviews at weeks 2, 6, and 12 saliva treatment was adjusted and clinical outcomes evaluated using the Clinical Saliva Scale for MND (CSS-MND). Community clinicians, plwMND, and caregivers were surveyed regarding the resource utility. Results: People living with MND reported the resources assisted saliva symptom self-management. Community clinicians found the resources informative and beneficial in supporting patient care. All plwMND required multiple treatment strategies and adjustments to manage symptoms. Of the treatments prescribed, 91% were non-invasive and 9% were medical interventions. For 54% (n = 15) of plwMND, improved CSS-MND scores were sustained over the three-month evaluation. Conclusions: Co-designed saliva resources and regular reviews assisted plwMND to implement their individualised saliva treatment, to self-manage saliva symptoms between clinics.}, } @article {pmid41229135, year = {2025}, author = {Vacchiano, V and Ragucci, C and Rizzo, G and Di Stasi, V and Pastorelli, F and Rinaldi, R and Provini, F and Postiglione, E and Fiorentino, A and Carelli, V and Liguori, R}, title = {Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With SOD1-Linked Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {11}, pages = {e70434}, pmid = {41229135}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/pathology/physiopathology/diagnosis ; Male ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Aged ; *Spinal Nerve Roots/pathology/diagnostic imaging ; Adult ; *Cerebrospinal Fluid Proteins/cerebrospinal fluid ; }, abstract = {INTRODUCTION: The superoxide dismutase type 1 (SOD1) gene has been implicated in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). We report four ALS cases carrying pathogenic or likely pathogenic SOD1 variants, characterized by albuminocytologic dissociation and nerve root enhancement.

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

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

CONCLUSION: Albuminocytologic dissociation and nerve root enhancement may occur in SOD1-related ALS, expanding the spectrum of atypical ALS phenotypes.}, } @article {pmid41233143, year = {2026}, author = {Cook, BE and McLaren, DG and Sullivan, JM and El Fakhri, G and Yokell, DL and Freeman, MW and Currier, N and Oestergaard, ME and Dobson, H and Hesterman, J and Salem, N and Nestorov, I and Monine, M and Martarello, L and Evans, KC and Fradette, S and Ferguson, TA and Graham, D and Passamonti, L}, title = {Central Nervous System Biodistribution and Pharmacokinetics of Radiolabeled Tofersen in Rodents, Nonhuman Primates, and Humans.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {67}, number = {1}, pages = {139-144}, pmid = {41233143}, issn = {1535-5667}, mesh = {Animals ; Humans ; Tissue Distribution ; Rats ; Male ; Female ; Single Photon Emission Computed Tomography Computed Tomography ; *Central Nervous System/metabolism/diagnostic imaging ; Adult ; *Oligonucleotides, Antisense/pharmacokinetics/chemistry ; Isotope Labeling ; Rats, Sprague-Dawley ; }, abstract = {Antisense oligonucleotides (ASOs) are an important therapeutic modality across several therapeutic areas, offering currently available and potential future treatment options for patients. ASO pharmacokinetics, biodistribution, and regional brain uptake are not fully characterized, particularly in humans. Here, we report preclinical studies and the first-in-human imaging trial measuring the biodistribution of [[99m]Tc]Tc-MAG3-tofersen. The tracer was designed to be a proxy for tofersen (Qalsody; Biogen), an ASO approved for the treatment of amyotrophic lateral sclerosis in adults who have a variant in the SOD1 gene (SOD1-ALS). Methods: Tofersen was conjugated to a MAG3 moiety, which chelates [99m]Tc to yield [[99m]Tc]Tc-MAG3-tofersen. [[99m]Tc]Tc-MAG3-tofersen and unlabeled tofersen were intrathecally injected in rats, nonhuman primates (NHPs), and healthy human volunteers (n = 3) via lumbar puncture, followed by SPECT/CT imaging. Tofersen was coadministered at a therapeutic dose. The tracer [[99m]Tc]Tc-MAG3-tofersen was prepared with greater than 99% purity. Results: Findings in rats demonstrated that [[99m]Tc]Tc-MAG3-tofersen was a proxy measure of unlabeled tofersen, and dosimetry was calculated from NHP imaging data. In a clinical study, unlabeled tofersen coadministered with a microdose of [[99m]Tc]Tc-MAG3-tofersen (≤129.5 MBq [3.5 mCi]) was well-tolerated. Human dosimetry estimates were within safe radiation dose levels. Imaging showed consistent distribution of radiolabeled ASO throughout the spinal cord and brain across species, with clearance patterns diverging in humans. Although rats and NHPs demonstrated declining brain concentrations over the study duration, human brain uptake increased during the first 4 h after injection. Additionally, tracer clearance from the spine in rodents and NHPs plateaued after 6 h but continued to decrease in humans. Radiolabeled ASO clearance from the lumbar spine was observed across all species, with peripheral clearance mediated primarily through the liver and kidneys. Broad uptake of the ASO in the brain and spinal cord is consistent with the clinical effects of tofersen observed in individuals with the SOD1-ALS variation. Conclusion: In preclinical and human SPECT/CT studies, [[99m]Tc]Tc-MAG3-tofersen mirrored unlabeled drug distribution, showing broad spinal cord and brain uptake, with some differences in kinetics among species.}, } @article {pmid41233462, year = {2025}, author = {Cattaneo, M and Bonanomi, M and Chirizzi, C and Malacarne, C and Giagnorio, E and Farinazzo, G and Bonanno, S and Porro, D and Lauria, G and Metrangolo, P and Bombelli, FB and Gaglio, D and Marcuzzo, S}, title = {Metabolic reprogramming in amyotrophic lateral sclerosis ependymal stem cells by FM19G11 nanotherapy.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39847}, pmid = {41233462}, issn = {2045-2322}, support = {1157625//Fondazione Regionale per la Ricerca Biomedica POR FESR/ ; IR0000010//Italian Ministry of University and Research (MIUR)-ELIXIR-IT through the empowering project ELIXIRNextGenIT/ ; T4-AN-09//CALabria HUB per Ricerca Innovativa ed Avanzata/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; Animals ; Mice ; Male ; *Nanoparticles/chemistry ; *Ependyma/metabolism/cytology/pathology/drug effects ; *Stem Cells/metabolism/drug effects ; Metabolomics ; Metabolome/drug effects ; Mice, Transgenic ; Disease Models, Animal ; *Cellular Reprogramming/drug effects ; Motor Neurons/metabolism ; Humans ; Metabolic Reprogramming ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the motor cortex, brainstem, and the spinal cord. In response to neurodegeneration, spinal cord exhibits ineffective regenerative attempt, thus suggesting that therapeutic strategies aimed at enhancing regenerative capacity of ependymal stem/progenitor cells (epSPCs), residing in the spinal cord, could promote neurogenesis. Dysregulated levels of metabolites might disturb epSPC differentiation, and their restoration might favour neurogenesis. This study aimed to investigate the metabolomic profile of epSPCs from ALS mice to identify altered metabolites as novel therapeutic targets for precision treatment. We performed a metabolome analysis to investigate changes in epSPCs from ALS compared to control male mice (B6SJL-Tg (SOD1*G93A)1Gur/J) and treated the epSPCs with FM19G11-loaded nanoparticles (NPs) to reestablish metabolic balance. Metabolomics analysis revealed significant changes in ALS epSPCs compared to controls. In vitro treatment with FM19G11-loaded nanoparticles (NPs) restored key metabolic networks, particularly in pathways related to glucose, glutamate and glutathione metabolism. These findings highlight the potential of FM19G11-loaded NPs to revert metabolic dysregulation in ALS epSPCs, providing a basis for innovative metabolic therapies and precision medicine approaches to counteract motor neuron degeneration in ALS and other motor neuron diseases.}, } @article {pmid41234489, year = {2025}, author = {Chan, JM and Romano, C and Lee, AY and Wang, S and Lombardo, D and Kamdar, F and Dora, M and Khan, S and Mammen, P and Kimonis, V}, title = {Cardiomyopathy in valosin-containing protein multisystem proteinopathy: Evaluation, diagnosis, and management.}, journal = {American heart journal plus : cardiology research and practice}, volume = {60}, number = {}, pages = {100644}, pmid = {41234489}, issn = {2666-6022}, support = {UM1 TR004927/TR/NCATS NIH HHS/United States ; }, abstract = {Valosin-containing protein (VCP)-associated multisystem proteinopathy is a rare, autosomal dominant disease that affects skeletal muscle, bone, central nervous system, and the heart. While VCP mutations are well established as causing inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, their role in cardiomyopathy remains underrecognized. This review aims to evaluate the pathophysiology, diagnostic approach, and management of VCP-associated cardiomyopathy to provide a framework for clinical care and future research. Emerging evidence from animal models and human case studies suggests that VCP dysfunction disrupts cardiomyocyte homeostasis, impairs protein degradation, and alters mitochondrial function, leading to maladaptive cardiac remodeling and susceptibility to dilated or hypertrophic cardiomyopathy. Echocardiographic studies in patients with VCP variants reveal a significant prevalence of diastolic dysfunction, conduction abnormalities, and variable degrees of systolic impairment. Despite these findings, there are no standardized guidelines for the diagnosis and management of VCP-associated cardiomyopathy. Current treatment strategies are extrapolated from heart failure guidelines, incorporating neurohormonal blockades with angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Our review highlights the need for systematic screening protocols, genotype-phenotype correlation studies, and the development of targeted therapies. Future research should focus on identifying biomarkers for early detection, elucidating the molecular mechanisms underlying cardiac dysfunction, and assessing the efficacy of novel treatment strategies. Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.}, } @article {pmid41238102, year = {2026}, author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q}, title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.}, journal = {Metabolism: clinical and experimental}, volume = {175}, number = {}, pages = {156436}, doi = {10.1016/j.metabol.2025.156436}, pmid = {41238102}, issn = {1532-8600}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Lipid Metabolism/drug effects/physiology ; Animals ; Brain/metabolism ; }, abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.}, } @article {pmid41238318, year = {2025}, author = {Soriani, MH and Blasco, H and Corcia, P and Danel-Brunaud, V and Desmaison, A and Pradat, PF and Querin, G and Vourch, P and Guy, N}, title = {Markers of presymptomatic amyotrophic lateral sclerosis: State of the art, practical implications and perspectives.}, journal = {Revue neurologique}, volume = {181}, number = {9}, pages = {893-908}, doi = {10.1016/j.neurol.2025.07.008}, pmid = {41238318}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/blood ; *Biomarkers/analysis/blood ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an identified genetic origin in 10-15% of cases, mainly involving C9orf72 and SOD1 mutations. The increasing number of genetically confirmed ALS cases has led to a growing identification of asymptomatic mutation carriers. While riluzole remains the standard treatment, mutation-specific therapies such as tofersen, that was recently approved in SOD1-ALS, are emerging. In this context, the identification of presymptomatic biomarkers is crucial for monitoring genetically at-risk individuals. Plasma neurofilament light chain can increase up to 3.5years before symptom onset in C9orf72 carriers. Metabolic and neuroimaging alterations together with cognitive or behavioral changes, that are sometimes detectable decades prior to diagnosis, have also been observed. These biomarkers may support early surveillance and intervention strategies. The present review provides an overview of current evidence on presymptomatic biomarkers in ALS mutation carriers and their potential role in genetic counseling, monitoring, and early therapeutic decisions.}, } @article {pmid41238422, year = {2026}, author = {Liguori, F and Amadio, S and Angioli, C and Ferriero, A and Passaro, I and Alberti, F and Vernì, F and Volonté, C}, title = {Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00793}, pmid = {41238422}, issn = {1878-7479}, mesh = {Animals ; *Clomipramine/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; Humans ; *Drug Repositioning/methods ; Disease Models, Animal ; Drosophila ; *Computer Simulation ; Animals, Genetically Modified ; Drosophila melanogaster ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2-5 years of symptom onset. Current Food and Drug Administration-approved drugs -riluzole, edaravone, and tofersen - offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1[A4V] or SOD1[G85R] mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.}, } @article {pmid41238908, year = {2026}, author = {Le, Y and Liu, G and Wu, S and Nissenbaum, M and Kusnecov, AW and Furmanski, P and Birge, RB and Zhou, R}, title = {AAV-mediated BDNF and GAS6 muscle delivery delays disease onset in SOD1[G93A] ALS mice.}, journal = {Gene therapy}, volume = {33}, number = {4}, pages = {462-473}, pmid = {41238908}, issn = {1476-5462}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; Female ; Male ; *Genetic Therapy/methods ; Mice ; *Brain-Derived Neurotrophic Factor/genetics/metabolism ; *Dependovirus/genetics ; Genetic Vectors/administration & dosage ; Disease Models, Animal ; *Intercellular Signaling Peptides and Proteins/genetics/metabolism ; Muscle, Skeletal/metabolism ; Growth Arrest-Specific Protein 6 ; Gene Therapy Agents ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Humans ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, with limited treatments. Gene therapy offers an alternative strategy for treating a large portion of ALS patients, however, the disparate genetic alterations in ALS complicate the development of gene therapies. Tyrosine receptor kinase B (TRKB) and Tyro3 receptors are highly expressed in mouse spinal cord motor neurons, suggesting that their ligands, brain-derived neurotrophic factor (BDNF) and growth arrest-specific 6 (GAS6), respectively, are crucial for neuronal survival. In this study, we tested whether genetically induced and muscle tissue-specific expression of such survival-enhancing ligands would ameliorate symptom development in the SOD1[G93A] ALS mouse model. The therapeutic vectors (AAV-Pmus7-HuBDNF-teLuc or AAV-Pmus7-HuGAS6), or a control vector (AAV-Pmus7-teLuc) were injected intravenously via the retro-orbital route and intramuscularly into the hindlimb skeletal muscle of six-week-old mice. Treatment with the therapeutic vectors delayed disease onset and slowed progression in both male and female mice. Interestingly, a sex-specific response was observed, with female mice benefiting more from the treatments than males. Lumbar motor neuron survival was more sustained in the therapeutic vector-treated group compared to control vector group. No statistically significant extension of lifespan was observed in the treated groups.}, } @article {pmid41239797, year = {2025}, author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG}, title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {25}, number = {4}, pages = {496-512}, pmid = {41239797}, issn = {1875-6166}, mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.}, } @article {pmid41241727, year = {2025}, author = {Sironi, F and Tortarolo, M and Mazzucchi, S and Camporeale, L and Freschi, M and Arcadipane, E and De Giovanetti, G and Kurosaki, M and Terao, M and Parlanti, P and Podini, P and Gentile, F and Bonetto, V and Cappello, V and Riva, N and Quattrini, A and Bendotti, C}, title = {Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {272}, pmid = {41241727}, issn = {1742-2094}, support = {Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/immunology/metabolism ; *C9orf72 Protein/genetics/deficiency/metabolism ; Mice ; *Superoxide Dismutase-1/genetics ; Disease Progression ; Mice, Transgenic ; *Neuromuscular Junction/pathology/metabolism/immunology ; Disease Models, Animal ; Mutation/genetics ; Motor Neurons/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder where neuromuscular health is central to disease progression. The degeneration of motor neurons (MNs) leads to muscle weakness and paralysis, underscoring the critical importance of neuromuscular junctions (NMJs) and axonal integrity. Among the genetic contributors to ALS, mutations in the C9orf72 gene are the most common, accounting for both ALS and frontotemporal dementia (FTD). While the role of C9orf72 has been studied across various cells and compartments, its function in the peripheral nervous system (PNS), a compartment crucial for maintaining neuromuscular connectivity in ALS,remains largely unexplored.

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

CONCLUSION: Our findings underscore the critical role of C9orf72 in maintaining neuromuscular health through its influence on myelination, immune response regulation, and NMJ integrity. Loss of C9orf72 function exacerbates ALS progression by promoting SC dysfunction and immune dysregulation. This highlights the significance of preserving normal C9orf72 function in ALS therapies through antisense oligonucleotides strategies. Furthermore, targeting immune responses and myelination pathways may offer novel avenues for ALS treatment strategies.}, } @article {pmid41244779, year = {2025}, author = {Sun, Z and Liu, C and Liu, W and Zhang, M and Ren, S and Gao, L and Ji, Z}, title = {Surgical treatment of autosomal recessive bestrophinopathy with angle-closure glaucoma: vitreous liquefaction as the key to correcting postoperative malignant glaucoma-three case reports.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1560475}, pmid = {41244779}, issn = {2296-858X}, abstract = {PURPOSE: This study aimed to evaluate the surgical treatment of autosomal recessive bestrophinopathy (ARB) combined with angle-closure glaucoma (ACG) through a retrospective case series.

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

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

CONCLUSION: For ACG/ARB patients, the risk of developing malignant glaucoma after glaucoma surgery is very high. Surgical intervention, such as anterior vitrectomy, is needed to increase vitreous fluidity, eliminate vitreous block, assist the formation of the anterior chamber, and stabilize the IOP to save the patient's vision. Long-term, close follow-up is essential due to the risk of recurrence in the operated eye and occurrence in the non-operated eyes.}, } @article {pmid41246229, year = {2025}, author = {Şahin, TÖ and Cemali, Ö and Özdemir, M and Ayten, Ş and Ağagündüz, D}, title = {Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.}, journal = {Turkish journal of biology = Turk biyoloji dergisi}, volume = {49}, number = {5}, pages = {635-659}, pmid = {41246229}, issn = {1303-6092}, abstract = {BACKGROUND/AIM: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.

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

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

CONCLUSION: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.}, } @article {pmid41246746, year = {2025}, author = {Bethea, JP and Sharma, H and Doberstein, N and Shenker, T and Gregory, B and Hoffman, R and Aizenman, D and Guirguis, G and Hoffmann, J and Tazani, S and Harris, Z and Costin, J}, title = {Application of Osteopathic Manipulative Treatment (OMT) in Neurodegenerative Disorders: A Scoping Review.}, journal = {Cureus}, volume = {17}, number = {10}, pages = {e94748}, pmid = {41246746}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are comprised of a host of chronic conditions that impair the central nervous system. Osteopathic manipulative treatment (OMT) consists of many non-invasive modalities that can be used to treat a wide variety of ailments and conditions. OMT is reported to increase the range of motion and lymphatic flow, as well as decrease pain in a wide array of disorders. However, the efficacy of using OMT in neurodegenerative disorders has not been well established. The objective of this scoping review is to map the evidence that pertains to the application of OMT in treating neurodegenerative disorders and identify the gaps in the literature on this subject. This study was designed according to the Joanna Briggs Institute (JBI) guidelines for scoping reviews to gather information on OMT's potential efficacy in managing Parkinson's disease (PD), Alzheimer's disease (AD) dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Peer-reviewed literature was collected through the Excerpta Medica database (EMBASE), Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. The criteria were limited to papers in English published between 1999 and 2023. The following search string was utilized: "osteopathic manipulative treatment" OR "osteopathic manipulation" AND "neurodegenerative disorders" OR "Alzheimer's disease" OR "dementia" OR "amyotrophic lateral sclerosis" OR "Parkinson's disease" OR "Huntington's chorea". One hundred and forty-three articles were identified following final screening and critical appraisal, with eleven articles selected for analysis in this study. Data from the selected articles demonstrated that OMT can possibly attenuate symptoms in patients diagnosed with neurodegenerative diseases. Studies in rats showed that OMT techniques were found to alter cholinergic neuronal genes, improve spatial learning and memory, reduce amyloid β protein levels, modulate synaptic transmission, and increase levels of the cytokines IL-1, IL-10, IL-13, RANTES, IL-17A, and EOTAXIN effects in AD dementia. ALS patients demonstrated a high level of satisfaction with OMT and did not report any adverse effects, though there was no decrease in pain or increased quality of life reported. PD patients reported improved postural stability, balance, and gait after OMT. No results were returned regarding OMT's effects on HD. Preliminary results in human PD and ALS patients who received OMT as an adjunct to traditional treatment regimens showed promising results, though few studies were found that address the topic, and the sample sizes of the studies that were found were small. There were no studies of the effects of OMT on human patients with AD or HD found, though preclinical studies in rats supported their trial in subsequent human studies. While current research on the impact of OMT on these neurodegenerative diseases is promising, there remain large gaps in the literature. Further research is necessary to support the use of and long-term efficacy of OMT in neurodegenerative diseases.}, } @article {pmid41251254, year = {2025}, author = {Staehr-Rye, AK and Küchen, SHL and Salvesen, L and Blicher, J and Strange, DG and Svenstrup, K}, title = {[Chronic respiratory insufficiency in amyotrophic lateral sclerosis].}, journal = {Ugeskrift for laeger}, volume = {187}, number = {44}, pages = {}, doi = {10.61409/V03250140}, pmid = {41251254}, issn = {1603-6824}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Respiration, Artificial/methods ; Chronic Disease ; Noninvasive Ventilation ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. As the disease progresses, respiratory function becomes increasingly compromised. Supporting respiratory function is the treatment with the greatest potential impact on life expectancy and should align with the patient's wishes to ensure quality of life. Optimal secretion management is essential for effective non-invasive mechanical ventilation therapy, as argued in this review. Home invasive mechanical ventilation is reserved for a small subset of patients.}, } @article {pmid41252371, year = {2025}, author = {Lillelund, CM and Kalra, S and Greiner, R and , }, title = {A meaningful prediction of functional decline in amyotrophic lateral sclerosis based on multi-event survival analysis.}, journal = {PloS one}, volume = {20}, number = {11}, pages = {e0336476}, pmid = {41252371}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/drug therapy ; Male ; Female ; Survival Analysis ; Middle Aged ; Aged ; Kaplan-Meier Estimate ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of the motor neurons that causes progressive paralysis in patients. Current treatment options aim to prolong survival and improve quality of life. However, due to the heterogeneity of the disease, it is often difficult to determine the optimal time for potential therapies or medical interventions. In this study, we propose a novel method to predict the time until a patient with ALS experiences significant functional impairment (ALSFRS-R ≤ 2) for each of five common functions: speaking, swallowing, handwriting, walking, and breathing. We formulate this task as a multi-event survival problem and validate our approach in the PRO-ACT dataset ([Formula: see text]) by training five covariate-based survival models to estimate the probability of each event over the 500 days following the baseline visit. We then predict five event-specific individual survival distributions (ISDs) for a patient, each providing an interpretable estimate of when that event is likely to occur. The results show that covariate-based models are superior to the Kaplan-Meier estimator at predicting time-to-event outcomes in the PRO-ACT dataset. Additionally, our method enables practitioners to make individual counterfactual predictions-where certain covariates can be changed-to estimate their effect on the predicted outcome. In this regard, we find that Riluzole has little or no impact on predicted functional decline. However, for patients with bulbar-onset ALS, our model predicts significantly shorter time-to-event estimates for loss of speech and swallowing function compared to patients with limb-onset ALS (log-rank p < 0.001, Bonferroni-adjusted [Formula: see text]). The proposed method can be applied to current clinical examination data to assess the risk of functional decline and thus allow more personalized treatment planning.}, } @article {pmid41253081, year = {2026}, author = {Okagaki, N and Tsuboi, T and Chihara, Y and Sumi, K and Takeuchi, H and Yamamoto, K and Hajiro, T and Sato, A}, title = {Impact of pneumothorax on clinical course of patients with amyotrophic lateral sclerosis on long-term ventilation.}, journal = {Respiratory investigation}, volume = {64}, number = {1}, pages = {101329}, doi = {10.1016/j.resinv.2025.11.008}, pmid = {41253081}, issn = {2212-5353}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Pneumothorax/etiology ; Retrospective Studies ; Male ; Female ; Middle Aged ; Longitudinal Studies ; *Positive-Pressure Respiration/adverse effects ; Aged ; Prognosis ; Time Factors ; Tracheostomy ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Numerous clinical studies have shown that long-term positive pressure ventilation (PPV) improves quality of life and prognosis in patients with amyotrophic lateral sclerosis (ALS). Pneumothorax is an important complication of PPV; however, few studies investigated pneumothorax in patients with ALS on long-term PPV.

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

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

CONCLUSIONS: Pneumothorax should be recognized as a serious complication that can occur in patients with ALS on PPV. Higher inspiratory positive airway pressure and support pressure settings on long-term PPV may be significant risk factors for pneumothorax.}, } @article {pmid41255457, year = {2025}, author = {Hu, Y and Lu, Y and Lan, D}, title = {Early Multidisciplinary Rehabilitation Improves Swallowing and Speech Function in a Patient With Amyotrophic Lateral Sclerosis.}, journal = {Clinical case reports}, volume = {13}, number = {11}, pages = {e71486}, pmid = {41255457}, issn = {2050-0904}, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease for which there is a lack of effective treatment. This case report describes a 49-year-old male with ALS who presented with dysphagia, dysarthria, dyskinesia, sleep disorders, anxiety, and depression. Following 45 days of early multidisciplinary rehabilitation, the patient demonstrated significant improvement in swallowing and speech function, alleviation of non-motor symptoms, and maintenance of motor function. Notably, he retained the ability to consume soft foods at a two-year follow-up. This case highlights the vital role of early multidisciplinary rehabilitation in the comprehensive management of ALS.}, } @article {pmid41258507, year = {2025}, author = {Hashizume, A and Hanazawa, R and Yamada, S and Ito, D and Kishimoto, Y and Komori, S and Kawase, T and Iida, M and Kondo, A and Mori, Y and Obara, K and Morita, M and Yamamoto, T and Sato, H and Hirakawa, A and Katsuno, M}, title = {Therapeutic impact of leuprorelin acetate on spinal and bulbar muscular atrophy: pre- and post-marketing observational study.}, journal = {Journal of neurology}, volume = {272}, number = {12}, pages = {772}, pmid = {41258507}, issn = {1432-1459}, support = {24ek0109588//Japan Agency for Medical Research and Development/ ; 24K10658//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Leuprolide/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; Adult ; *Product Surveillance, Postmarketing ; Disease Progression ; *Bulbo-Spinal Atrophy, X-Linked/drug therapy ; Treatment Outcome ; *Muscular Atrophy, Spinal/drug therapy ; Japan ; }, abstract = {Although leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, has been approved based on short-term clinical trials conducted in Japan, its long-term efficacy on physical function remains unclear. We aimed to evaluate the long-term therapeutic efficacy of leuprorelin acetate using real-world clinical data through a self-controlled trend-shift analysis. The analysis included 91 genetically confirmed patients with spinal and bulbar muscular atrophy, with follow-up data collected before and after treatment initiation. The functional outcomes assessed included the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and modified Norris scales, grip power, and serum creatinine levels. Leuprorelin acetate significantly slowed disease progression. For instance, the annual ALSFRS-R decline rate improved from approximately 0.5 points pre-treatment to 0.2 points post-treatment. The subgroup analysis supported the potential benefit of early intervention. These findings highlight the value of leveraging patient registries and post-marketing real-world data to evaluate treatment efficacy in slowly progressive diseases, such as SBMA, where traditional randomized controlled trials are often limited by insufficient statistical power to detect therapeutic efficacy. They also underscore the need for innovative methodologies to assess post-approval drug performance, paving the way for improved clinical outcomes for neurodegenerative diseases.}, } @article {pmid41263806, year = {2025}, author = {Kalkowski, K}, title = {[Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge].}, journal = {Postepy biochemii}, volume = {71}, number = {3}, pages = {252-259}, doi = {10.18388/pb.2021_599}, pmid = {41263806}, issn = {0032-5422}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; Genetic Therapy ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to progressive degeneration of motor neurons, muscle weakness and respiratory failure. Despite intensive research, the pathomechanisms of ALS have not been fully elucidated. This article presents the current state of knowledge on the genetic and molecular mechanisms of this disease, with a focus on mutations in the SOD1, C9ORF72, TARDBP, FUS, TBK1 genes, as well as recent discoveries in this area. Key pathogenetic processes are discussed, including disruption of RNA homeostasis, oxidative stress, mitochondrial dysfunction and protein aggregation. In addition, current therapeutic strategies are reviewed, including both registered drugs, such as riluzole and edaravone, and modern approaches, such as gene therapy, antisense oligonucleotides, immunotherapy and gene editing technologies, including CRISPR/Cas9. Special attention was given to clinical trials and their potential impact on future treatment options for ALS.}, } @article {pmid41268542, year = {2025}, author = {Baird, LA and Teener, SJ and Webber-Davis, IF and Carter, AD and Huang, F and Jang, DG and Famie, JP and Piecuch, CE and Guo, K and Feldman, EL and Murdock, BJ}, title = {Tofacitinib extends survival in a mouse model of ALS through NK cell-independent mechanisms.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1662197}, pmid = {41268542}, issn = {1664-3224}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality/pathology ; *Pyrimidines/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; *Killer Cells, Natural/immunology/drug effects ; Mice, Transgenic ; *Protein Kinase Inhibitors/pharmacology ; Superoxide Dismutase-1/genetics ; Spinal Cord/drug effects/immunology ; Motor Neurons/drug effects/immunology ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with few treatment options, rendering the development of new, effective therapeutics of critical importance. The immune system plays a substantial role in ALS pathology, with multiple cell populations implicated in disease progression. Natural killer (NK) cells are innate immune cells that accumulate in the brain and spinal cord during ALS, increasing neuroinflammation and killing motor neurons. Depleting NK cells extends survival in mouse models of ALS. Tofacitinib, an FDA-approved janus kinase (Jak) and signal transducer and activator (STAT) pathway inhibitor, reduces NK cytotoxicity and decreases overall levels in peripheral blood and may represent a potential ALS therapy. Therefore, we aimed to evaluate the effects of tofacitinib treatment on survival and phenotype in an ALS mouse model. Additionally, we sought to determine the impact of dose and regimen on efficacy.

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

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

CONCLUSIONS: These data support the repurposing of tofacitinib as a potential ALS treatment.}, } @article {pmid41269403, year = {2025}, author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA}, title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {121}, pmid = {41269403}, issn = {1559-1182}, mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; }, abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.}, } @article {pmid41272780, year = {2025}, author = {Kumar, A and Shukla, S and Rai, A and Pathak, P and Narayan, KP}, title = {Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen).}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {598}, pmid = {41272780}, issn = {1750-1172}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Genetic Therapy/methods ; Orphan Drug Production ; *Oligonucleotides/therapeutic use ; United States Food and Drug Administration ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord. With a global incidence of 1.9 to 6 per 100,000 people, ALS is slightly more common in men and prevalent in individuals over 60. However, this review provides a concise update on the regulatory landscape and therapeutic advancements in managing ALS, focusing on the recent approval of Tofersen, the first gene therapy specifically targeting SOD1 mutation-related ALS.

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

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

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

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

CONCLUSION: Intranasally-instilled AlloEx Exosomes[®] are completely safe, attenuate progression, and improve strength in ALS, Kennedy Disease, CMS, and LBD.}, } @article {pmid41280004, year = {2025}, author = {Rao, PP and Herbert, C and Azeem, SM and Gary, E and Ho, G and Munira, R and Askarifirouzja, H and Haimovitz-Friedman, A and Mahajan, SS}, title = {Riluzole as a Dual-Targeted Radiosensitizer for Osteosarcoma: Targeting Tumor Cells and Angiogenic Vasculature to Enhance Single High Dose Radiotherapy Efficacy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41280004}, issn = {2692-8205}, support = {SC1 GM131929/GM/NIGMS NIH HHS/United States ; }, abstract = {Osteosarcoma is a highly aggressive bone malignancy primarily affecting children and young adults. It presents significant treatment challenges due to its inherent resistance to conventional fractionated radiotherapy (CFRT). Single high dose radiation therapy (SDRT) has promise for the treatment of radioresistant sarcomas, especially those characterized with extensive vascularity. However, its clinical application is severely constrained by toxicity to adjacent critical tissues. Radiosensitizers can enhance tumor cell susceptibility to radiation-induced DNA damage, improving therapeutic efficacy and potentially reducing collateral toxicity. Monotherapies targeting tumor vasculature alone in solid tumors have shown limited success as radiosensitizers in clinical settings. This highlights the importance of compounds that can simultaneously target both tumor cells and its associated microvasculature to maximize the therapeutic outcome to SDRT. Riluzole, the FDA-approved drug for Amyotrophic Lateral Sclerosis, is currently under investigation as a therapeutic agent for osteosarcoma. Riluzole acts to inhibit glutamate release, reduce glutathione levels in cancer cells, and mitigate tumor angiogenesis, positioning it as a potent radiosensitizing agent for the treatment of osteosarcoma. We hypothesize that Riluzole enhances osteosarcoma radiosensitivity to SDRT by simultaneously targeting intrinsic tumor radioresistance and pro-angiogenic signaling. Our findings demonstrate that Riluzole radiosensitizes osteosarcoma cells in vitro by reducing clonogenic survival and enhancing apoptosis. Mechanistically, Riluzole potentiates irradiation-induced reactive oxygen species (ROS) production, induces G2/M phase cell cycle arrest, inhibits DNA repair, and thereby amplifies radiation-induced DNA damage. Additionally, Riluzole suppresses radiation-induced Vascular Endothelial growth factor A (VEGFA) expression indicating its ability to overcome endothelial cell mediated radioresistance. Collectively, these results establish Riluzole as a promising radiosensitizer for osteosarcoma, with the potential to improve SDRT efficacy by overcoming both tumor-intrinsic and microvasculature-mediated radioresistance.}, } @article {pmid41281478, year = {2025}, author = {Kumar, S}, title = {Artificial intelligence powered radiomics model for the assessment of colorectal tumor immune microenvironment.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {11}, pages = {108576}, pmid = {41281478}, issn = {1948-5204}, abstract = {Zhou et al's investigation on the creation of a non-invasive deep learning (DL) method for colorectal tumor immune microenvironment evaluation using preoperative computed tomography (CT) radiomics published in the World Journal of Gastrointestinal Oncology is thorough and scientific. The study analyzed preoperative CT images of 315 confirmed colorectal cancer patients, using manual regions of interest to extract DL features. The study developed a DL model using CT images and histopathological images to predict immune-related indicators in colorectal cancer patients. Pathological (tumor-stroma ratio, tumor-infiltrating lymphocytes infiltration, immunohistochemistry, tumor immune microenvironment and immune score) parameters and radiomics (CT imaging and model construction) data were combined to generate artificial intelligence-powered models. Clinical benefit and goodness of fit of the models were assessed using receiver operating characteristic, area under curve and decision curve analysis. The developed DL-based radiomics prediction model for non-invasive evaluation of tumor markers demonstrated potential for personalized treatment planning and immunotherapy strategies in colorectal cancer patients. The study, involving a small group from a single medical center, lacks inclusion/exclusion criteria and should include clinicopathological features for valuable therapeutic practice insights in colorectal cancer patients.}, } @article {pmid41281507, year = {2025}, author = {Lucke-Wold, B and Salam, HD and Karayi, G}, title = {Behavioral analysis of insomnia sufferers to acupuncture treatment.}, journal = {World journal of psychiatry}, volume = {15}, number = {11}, pages = {108630}, pmid = {41281507}, issn = {2220-3206}, abstract = {In this commentary, we respond to Zhao et al's recent paper which focuses on mechanisms underlying insomnia sufferers' engagement with acupuncture. Insomnia, a prevalent condition characterized by difficulty falling asleep and poor sleep quality, is associated with increased risk of cardiovascular disease, diabetes, and psychiatric illness. Acupuncture, a method involving the therapeutic placement of needles, has been widely accepted as a treatment for insomnia with minimal side effects. In fact, clinical trials suggest auricular acupuncture may improve sleep duration more than cognitive behavioral therapy. However, responses to acupuncture vary. Some patients find it extremely beneficial, while others view it as a routine treatment-or avoid it altogether due to needle phobia. Patient engagement is influenced by cultural beliefs, encouragement, motivation, prior experiences, and recommendations from peers or clinicians. Trust in the physician and testimonials from recovered patients are particularly important facilitators. Looking ahead, a holistic approach - integrating acupuncture with meditation, pranayama, yoga, and other restorative practices - may enhance treatment effectiveness and help patients achieve restorative sleep.}, } @article {pmid41283303, year = {2025}, author = {Bartoshyk, P and O'Caoimh, R}, title = {Update on Disease-Modifying Pharmacological Treatments for Frontotemporal Dementia (FTD): A Scoping Review of Registered Trials.}, journal = {NeuroSci}, volume = {6}, number = {4}, pages = {}, pmid = {41283303}, issn = {2673-4087}, abstract = {Frontotemporal dementia (FTD) represents a cluster of adult-onset neurodegenerative diseases resulting from a combination of genetic and epigenetic factors. Currently, treatment is symptomatic and there are no licensed disease-modifying therapies available. The aim of this review was to provide an overview of ongoing or recently completed clinical studies targeting disease modification in FTD. A structured search of interventional trials of pharmacological compounds was conducted on three clinical trial registries (National Library of Medicine Clinical Trials, European Union Clinical Trials, and the Australian New Zealand Clinical Trials registries) up to September 2025. Twelve interventional trials were found. Half targeted autosomal-dominant progranulin (GRN) mutations (n = 6) and half examined therapies targeting neuroinflammatory-induced sporadic FTD (n = 6). The interim results of the early-phase (1/2) randomized controlled trials (RCTs), comprising three ongoing gene replacement studies (PROCLAIM, ASPIRE-FTD, upliFT-D) and one immune-modulating monoclonal antibody (INFRONT, now in phase 3)-all targeting the FTD-GRN mutation-show safety, tolerability, and effectiveness in restoring progranulin levels. Two recently completed phase 2 RCTs for sporadic FTD targeting neuroinflammation, the PEA-FTD and C9orf72 ALS/FTD trials, show disease-modifying potential. While interim results from six trials suggest clear mechanistic efficacy, prospective high-quality later-phase RCTs are required to ascertain long-term clinical efficacy. Since familial FTD encompasses less than half of the people with this disease, it is important to continue exploring the underlying pathophysiology, neuroimmunology, and treatment of epigenetic-induced sporadic FTD.}, } @article {pmid41283860, year = {2026}, author = {Varline, J and Enfinger, M and Kavanaugh, MS}, title = {Mental health treatment of persons with ALS & their families: implementing an intervention to support practitioners.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {602-607}, doi = {10.1080/21678421.2025.2593304}, pmid = {41283860}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; *Caregivers/psychology/education ; *Family/psychology ; Female ; Male ; *Mental Health Services ; Surveys and Questionnaires ; Mental Health ; Middle Aged ; Adult ; *Mental Disorders/therapy/etiology ; }, abstract = {Objective: Given the limited education available to practitioners who provide mental health care for persons with amyotrophic lateral sclerosis (ALS) and their family members, a partnership between Mental Health America, Global Neuro YCare, and the ALS Association developed a web-based education programme providing discussions addressing ALS background, lived experience, and impact of caregiving, to increase confidence in care and access to resources when serving persons living with ALS and their caregivers. Methods: A pre/post survey was utilized to assess the webinar's impact on provider confidence in their knowledge and experience of ALS, access to ALS information and resources, and the ability to refer persons with ALS to care. The percentage change from pretest to post-test, frequency of knowledge, and qualitative analyses were conducted. Results: The findings indicated a 24% increase in practitioners' confidence in working with people with ALS and their family members, a 19% increase in providing mental health care to a family member, and a 20% increase in assessing resource information about ALS. Qualitative data highlighted several categories of responses, including increases in knowledge from the workshop, the need for individuals to be treated as more than just ALS, and a continuing need for training, and additional emotional support for practitioners. Conclusion: The online training increased confidence in providing mental health care to people living with ALS and their family members, adding to this understudied area. Still, additional research is needed to increase confidence in referring people to care, accessing information, and growing knowledge about ALS.}, } @article {pmid41289739, year = {2026}, author = {Dakroub, F and Awada, B and Abdelhady, S and Shaito, AA and Eid, AH and Walker, J and Mondello, S and Bondi, CO and Moro, F and Elgendy, B and Wang, KK and Zanier, ER and Mechref, Y and Kobeissy, F}, title = {Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action.}, journal = {Pharmacological reviews}, volume = {78}, number = {1}, pages = {100101}, doi = {10.1016/j.pharmr.2025.100101}, pmid = {41289739}, issn = {1521-0081}, support = {1R01GM112490-08,/NH/NIH HHS/United States ; 1R01GM130091-05/NH/NIH HHS/United States ; 1U01CA225753-05/NH/NIH HHS/United States ; }, mesh = {Humans ; *Edaravone/pharmacology/therapeutic use/pharmacokinetics/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics ; *Free Radical Scavengers/pharmacology/therapeutic use/pharmacokinetics ; Cytoprotection/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.}, } @article {pmid41291238, year = {2025}, author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y}, title = {Chemical strategies for brain delivery of genomic therapy.}, journal = {Nature reviews. Chemistry}, volume = {9}, number = {12}, pages = {841-854}, pmid = {41291238}, issn = {2397-3358}, support = {P01 DA047233/DA/NIDA NIH HHS/United States ; R01 DA007359/DA/NIDA NIH HHS/United States ; R35 GM144117/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Genetic Therapy/methods ; *Brain/metabolism ; Animals ; Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Lipids/chemistry ; Polymers/chemistry ; Oligonucleotides/chemistry ; *Gene Transfer Techniques ; }, abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.}, } @article {pmid41294799, year = {2025}, author = {Medigovic, G and Rachamala, HK and Dutta, SK and Pal, K}, title = {Structural and Functional Perspectives of Optineurin in Autophagy, Immune Signaling, and Cancer.}, journal = {Cells}, volume = {14}, number = {22}, pages = {}, pmid = {41294799}, issn = {2073-4409}, support = {R56 HL160545/HL/NHLBI NIH HHS/United States ; W81XWH-21-1-0678//Department of Defense Congressionally Directed Medical Research Program/ ; R56HL160545//The National Heart, Lung, and Blood Institute/ ; }, mesh = {Humans ; *Autophagy ; *Neoplasms/immunology/metabolism/pathology ; *Membrane Transport Proteins/chemistry/metabolism ; *Signal Transduction ; *Cell Cycle Proteins/chemistry/metabolism ; Animals ; *Transcription Factor TFIIIA/metabolism/chemistry/genetics ; }, abstract = {Optineurin (OPTN) is a multifunctional adaptor protein that regulates diverse cellular processes, including inflammatory signaling, autophagy, vesicular trafficking, and immune responses. This multifaceted role of OPTN is made possible by the presence of a complex structure comprising multiple domains that interact with different proteins to exert various functions important for modulating key signaling processes. Mutations in OPTN are linked with several human pathologies including glaucoma, Paget's disease of bone, Crohn's disease, and neurodegenerative diseases such as amyotrophic lateral sclerosis, and dementia. Emerging evidence suggests that OPTN has a complex and context-dependent role in cancer biology as well. It is upregulated in pancreatic ductal adenocarcinoma and hepatocellular carcinoma but downregulated in lung and colorectal cancers, indicating its dual role as a potential oncogene or tumor suppressor depending on the cellular environment. Additionally, OPTN plays a critical role in preventing immune evasion in colorectal cancer by maintaining interferon-gamma receptor 1 (IFNGR1) expression and supporting dendritic cell-mediated T-cell priming, thereby enhancing antitumor immune responses. Despite its significance in oncogenic pathways and immune regulation, the therapeutic potential of targeting OPTN in cancer remains largely unexplored. This review aims to provide a comprehensive understanding of OPTN's pleiotropic functions, highlighting its role in autophagy, inflammation, immune surveillance, and cancer progression. By elucidating its diverse regulatory mechanisms, we seek to encourage further research into the therapeutic implications of OPTN in cancer treatment and immunotherapy.}, } @article {pmid41294911, year = {2025}, author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG}, title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {41294911}, issn = {2079-9721}, abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

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

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

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.}, } @article {pmid41296103, year = {2025}, author = {Ge, TQ and Ma, XY and Guan, PP and Wang, P}, title = {Aspirin Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Inhibiting the Activities of Microglia in a NF-κB-dependent Complement System-deactivating Mechanism.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {180}, pmid = {41296103}, issn = {1559-1182}, support = {JYTMS20230628//Liaoning Provincial Department of Education Funding/ ; D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; Animals ; *Aspirin/pharmacology/therapeutic use ; Mice ; *Complement System Proteins/metabolism ; Apoptosis/drug effects ; Cell Line ; Lipopolysaccharides/pharmacology ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which is pathologically characterized by impairing the motor neurons, leading to the disorders of motor function. Aspirin (ASP) has the ability to increase the survival time of SOD1[G93A] mice via concurrently reducing the activation of glial cells and restoring the number of neurons. Meanwhile, ASP treatment inhibited the activities of NF-κB pathway, which resulted in regulating the expression of complement system (CS), including C3, C1qb, and C4b in vivo. To reveal the inherent mechanisms, the in vitro experiments were carried out in SOD1[G93A] protein- and lipopolysaccharide (LPS)-treated BV2 cells. The results demonstrated that SOD1[G93A] protein or LPS induces the activation of NF-κB in BV2 cells, whose conditional medium induces the apoptosis of NSC34 cells. By blocking the activities of NF-κB by ASP, Bay 11-7082 or si NF-κB, the synthesis of CS molecules was suppressed, which results in alleviating the apoptosis of NSC34 cells. More importantly, Terminal complement complex (TCC) was identified to be the critical component of CS for mediating the effects of SOD1[G93A] protein or LPS on inducing the apoptosis of neurons, which was inhibited by the ASP or Bay 11-7082. On the basis of these observations, our findings novelly revealed that ASP delayed the progression of ALS via inhibiting the activities of microglia in a NF-κB-dependent CS-deactivating mechanisms.}, } @article {pmid41298223, year = {2026}, author = {Lin, CY and Lee, BC and Zhang, PH and Lu, SC and Chang, WZ and Wang, CC and Tsai, HJ}, title = {A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00806}, pmid = {41298223}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/genetics/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Mice ; Disease Progression ; Mice, Transgenic ; Disease Models, Animal ; *Nerve Degeneration/pathology/drug therapy ; Zebrafish ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Peptides/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Phosphoglycerate Kinase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.}, } @article {pmid41300346, year = {2025}, author = {Yeasmin, A and Torrente, MP}, title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.}, journal = {Biology}, volume = {14}, number = {11}, pages = {}, pmid = {41300346}, issn = {2079-7737}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; 1R15NS125394-01/NH/NIH HHS/United States ; }, abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.}, } @article {pmid41311831, year = {2025}, author = {Guan, S and Wang, S and Shi, Y and Leng, Y and Ming, Y and Hou, Z and Yu, Y and Wang, Z and Liu, J}, title = {Comparative safety analysis of Riluzole, Edaravone and Tofersen in ALS management: insights from FAERS database.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1687698}, pmid = {41311831}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Riluzole, Edaravone, and Tofersen, three promising treatments, have distinct profiles that merit comparative analysis to guide clinical decision-making.

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

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

CONCLUSION: This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of Riluzole, Edaravone, and Tofersen in clinical practice, providing valuable insights for personalized ALS management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events.}, } @article {pmid41312566, year = {2026}, author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M}, title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.}, journal = {Neurologia i neurochirurgia polska}, volume = {60}, number = {1}, pages = {15-25}, doi = {10.5603/pjnns.106498}, pmid = {41312566}, issn = {0028-3843}, mesh = {Humans ; *Aging/immunology ; *B-Lymphocytes/immunology ; Aged ; *T-Lymphocytes/immunology ; *Immunosenescence/immunology ; *Nervous System Diseases/immunology ; Alzheimer Disease/immunology ; Adaptive Immunity ; Parkinson Disease/immunology ; }, abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

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

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

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.}, } @article {pmid41314744, year = {2025}, author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S}, title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {1-52}, doi = {10.1016/bs.pbr.2025.08.006}, pmid = {41314744}, issn = {1875-7855}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; }, abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.}, } @article {pmid41314745, year = {2025}, author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ}, title = {Biomarkers: From early detection to treatment personalization.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {131-153}, doi = {10.1016/bs.pbr.2025.08.008}, pmid = {41314745}, issn = {1875-7855}, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; }, abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.}, } @article {pmid41319477, year = {2026}, author = {Benussi, A and Vucic, S}, title = {Emergent technologies and applications of TMS and TMS-EEG in clinical neurophysiology for early and differential diagnosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {182}, number = {}, pages = {2111459}, doi = {10.1016/j.clinph.2025.2111459}, pmid = {41319477}, issn = {1872-8952}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods/trends ; *Electroencephalography/methods/trends ; Diagnosis, Differential ; *Nervous System Diseases/physiopathology/diagnosis ; Early Diagnosis ; *Neurophysiology/methods ; }, abstract = {This chapter examines how emerging neurophysiological technologies are transforming the early and differential diagnosis of neurological disorders. While imaging and fluid biomarkers have greatly advanced the field, they remain limited by cost, invasiveness, and their inability to directly capture dynamic brain activity. Neurophysiological techniques, particularly transcranial magnetic stimulation (TMS) and TMS combined with EEG, offer a unique, non-invasive means of probing cortical excitability, connectivity, and plasticity with millisecond precision. Recent technological and analytical breakthroughs are moving these approaches from research laboratories into clinical practice. By detecting subtle network dysfunctions that precede structural degeneration, they open the possibility of identifying disease in its prodromal or even presymptomatic stages, when interventions may be most effective. This chapter outlines the principles of advanced TMS paradigms and TMS-EEG and explores their application across a range of conditions, including amyotrophic lateral sclerosis, dementias, and movement disorders. It also highlights how integrating neurophysiological measures with blood-based biomarkers and computational tools, such as machine learning, can enhance diagnostic accuracy and guide individualized treatment strategies. Together, these innovations establish neurophysiology as a cornerstone of precision neurology, linking mechanistic insights to clinical decision-making and enabling earlier diagnosis, improved patient stratification, and more targeted therapeutic interventions.}, } @article {pmid41323448, year = {2025}, author = {Tang, H and Jiang, P and Chen, J}, title = {Research Landscapes and Gaps in Neuropsychiatric Assessment for Neurodegenerative Diseases: A Bibliometric Study on Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {15}, number = {1}, pages = {174-191}, pmid = {41323448}, issn = {1664-5464}, abstract = {INTRODUCTION: The aim of the study was to provide a comprehensive overview of the current application of tools used for assessing neuropsychiatric symptoms (NPSs) in patients with Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA) through bibliometric analysis.

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

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

CONCLUSION: This study highlights the growing importance of NPSs in neurodegenerative diseases, particularly in HD, ALS, and MSA. We identify hotspots and deficiencies in the research field of validating NPS assessment tools, integrating NPSs into the diagnostic framework and elucidating neurobiological mechanisms. These findings will contribute to enhanced diagnostic and therapeutic approaches for neurodegenerative diseases.}, } @article {pmid41323796, year = {2025}, author = {Kang, M and Lin, WH and Li, Y and Xu, F and Zhou, X and Si, C and Dai, J and He, J and Schacht, I and Gan, Z and Huang, V and Li, LC}, title = {SCAD: A modular platform for efficient delivery of duplex RNA to the CNS and beyond.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {4}, pages = {102757}, pmid = {41323796}, issn = {2162-2531}, abstract = {Oligonucleotide therapeutics-including antisense oligonucleotides and duplex RNAs such as small interfering RNAs, small activating RNAs, and microRNAs-hold immense potential for treating both genetic and acquired diseases by modulating gene expression in a target-specific manner. However, effective delivery to extrahepatic tissues, particularly the central nervous system, remains a significant challenge. While N-Acetylgalactosamine conjugation has enabled liver-specific delivery of oligonucleotides leading to several approved siRNA drugs for hepatic indications, there remains a significant unmet need for effective treatment options in the CNS space. We have developed the smart chemistry-aided delivery platform that enables duplex RNA delivery by conjugating to an accessory oligonucleotide, which facilitates protein binding and promotes cellular uptake. Through extensive screening, we identified an optimal SCAD architecture that demonstrates enhanced cell-free protein binding and in vitro activity. In rodent models, local administration of SCAD-siRNA conjugates resulted in broad biodistribution throughout the CNS and sustained mRNA knockdown for over 5 months, with a favorable safety profile. The SCAD platform also exhibited efficient delivery to other extrahepatic tissues, including the eye, lung, and joint. The modular design of SCAD can be easily adapted to any duplex RNA, making it a powerful tool for advancing oligonucleotide therapeutics.}, } @article {pmid41327179, year = {2025}, author = {Eshak, D and Arumugam, M}, title = {Nanomaterials: an overview of current trends and future prospects in neurological disorder treatment.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1366}, pmid = {41327179}, issn = {1479-5876}, mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; Animals ; Blood-Brain Barrier ; }, abstract = {The World Health Organization (WHO) has identified neurological disorders (NDs) as one of the major health concerns worldwide, resulting in high mortality rates. NDs are conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, neuromuscular junctions, and muscles. These neurological diseases include Alzheimer's disease, Parkinson's disease, glioma/brain cancer, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuroinfections, ischemic stroke, trauma, hypoxia/anoxia, and depression. Unfortunately, these disorders remain difficult to treat due to the limited ability of conventional drugs to cross the blood-brain barrier (BBB) and achieve significant pharmacological effects in the brain. There is an urgent need to develop methods that can enhance drug efficacy and bypass the BBB. The application of various nanomaterials represents a promising approach to address these neurological disorders. Drugs incorporated with nanomaterials help improve therapeutic outcomes, reduce toxicity, provide better stability, enable targeted delivery, and enhance drug loading capacity. Numerous types and morphologies of inorganic and organic nanomaterials are increasingly employed for treating NDs, including quantum dots, dendrimers, metal nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, metal oxide nanoparticles, and micelles. Their exceptional properties such as sensitivity, selectivity, and potential to bypass the BBB make them suitable for both diagnosis and treatment of NDs. In this review article, we briefly summarize the etiology and pathophysiology of various NDs along with current literature highlighting the use of nanomaterials for treating neurological disorders.}, } @article {pmid41329282, year = {2025}, author = {Grigoryev, PN and Zefirov, AL and Mukhamedzyanov, RD and Salafutdinov, II and Islamov, RR and Mukhamedyarov, MA}, title = {Synaptic Vesicle Exocytosis and Endocytosis in Motor Nerve Endings of Transgenic Mice Modeling Amyotrophic Lateral Sclerosis upon Antioxidant Treatment and Gene-Cell Therapy.}, journal = {Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections}, volume = {525}, number = {1}, pages = {354-358}, pmid = {41329282}, issn = {1608-3105}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/metabolism/genetics/pathology ; *Exocytosis/drug effects ; *Endocytosis/drug effects ; Mice, Transgenic ; *Motor Neurons/metabolism/drug effects ; Mice ; *Synaptic Vesicles/metabolism/drug effects ; *Antioxidants/pharmacology ; Disease Models, Animal ; *Genetic Therapy ; Humans ; }, abstract = {Exocytosis and endocytosis of synaptic vesicles were studied in experiments with motor nerve endings of diaphragm neuromuscular preparations isolated from transgenic mice with a model of amyotrophic lateral sclerosis (ALS); treatment simulated antioxidant (edaravone) and gene-cell (umbilical cord blood mononuclear cells (UCB-MNCs) producing VEGF, GDNF, and NCAM) therapies. None of the treatments was found to significantly change the FM 1-43 fluorescent dye loading due to synaptic vesicle endocytosis. Gene-cell therapy increased the rate of dye unloading due to synaptic vesicle exocytosis, while antioxidant therapy did not change the FM 1-43 unloading rate. Based on the findings, gene-cell therapy was assumed to facilitate synaptic vesicle transport to release sites upon high-frequency stimulation in motor nerve endings of transgenic mice.}, } @article {pmid41341242, year = {2024}, author = {Gutman, B and Shmilovitch, AH and Aran, D and Shelly, S}, title = {Twenty-Five Years of AI in Neurology: The Journey of Predictive Medicine and Biological Breakthroughs.}, journal = {JMIR neurotechnology}, volume = {3}, number = {}, pages = {e59556}, pmid = {41341242}, issn = {2817-092X}, abstract = {Neurological disorders are the leading cause of physical and cognitive disability across the globe, currently affecting up to 15% of the world population, with the burden of chronic neurodegenerative diseases having doubled over the last 2 decades. Two decades ago, neurologists relying solely on clinical signs and basic imaging faced challenges in diagnosis and treatment. Today, the integration of artificial intelligence (AI) and bioinformatic methods is changing this landscape. This paper explores this transformative journey, emphasizing the critical role of AI in neurology, aiming to integrate a multitude of methods and thereby enhance the field of neurology. Over the past 25 years, integrating biomedical data science into medicine, particularly neurology, has fundamentally transformed how we understand, diagnose, and treat neurological diseases. Advances in genomics sequencing, the introduction of new imaging methods, the discovery of novel molecular biomarkers for nervous system function, a comprehensive understanding of immunology and neuroimmunology shaping disease subtypes, and the advent of advanced electrophysiological recording methods, alongside the digitalization of medical records and the rise of AI, all led to an unparalleled surge in data within neurology. In addition, telemedicine and web-based interactive health platforms, accelerated by the COVID-19 pandemic, have become integral to neurology practice. The real-world impact of these advancements is evident, with AI-driven analysis of imaging and genetic data leading to earlier and more accurate diagnoses of conditions such as multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease, and more. Neuroinformatics is the key component connecting all these advances. By harnessing the power of IT and computational methods to efficiently organize, analyze, and interpret vast datasets, we can extract meaningful insights from complex neurological data, contributing to a deeper understanding of the intricate workings of the brain. In this paper, we describe the large-scale datasets that have emerged in neurology over the last 25 years and showcase the major advancements made by integrating these datasets with advanced neuroinformatic approaches for the diagnosis and treatment of neurological disorders. We further discuss challenges in integrating AI into neurology, including ethical considerations in data use, the need for further personalization of treatment, and embracing new emerging technologies like quantum computing. These developments are shaping a future where neurological care is more precise, accessible, and tailored to individual patient needs. We believe further advancements in AI will bridge traditional medical disciplines and cutting-edge technology, navigating the complexities of neurological data and steering medicine toward a future of more precise, accessible, and patient-centric health care.}, } @article {pmid41341510, year = {2025}, author = {Yang, J and Yang, F and Chen, G and Liu, M and Yuan, S and Zhang, TE}, title = {Receptor-mediated mitophagy: a new target of neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1665315}, pmid = {41341510}, issn = {1664-2295}, abstract = {Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.}, } @article {pmid41345272, year = {2025}, author = {Duhayyim, MA}, title = {An efficient dimensionality reduction framework using metaheuristic optimization with deep learning models for amyotrophic lateral sclerosis disease progression prediction.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {1165}, pmid = {41345272}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/pathology/physiopathology ; Humans ; *Deep Learning ; Disease Progression ; Algorithms ; Dimensionality Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disastrous neuro-degenerative infection which affects motor neuron inhabitants of the spinal cord, brainstem, and cerebral cortex, resulting in progressive disorder and demise from respiratory difficulty. ALS is considerably assorted disorder comprising symptoms such as muscle weakness, difficulty in swallowing, speaking, breathing, and changes in mental and emotional health. Hence, this disease requires more beneficial medication and also, successful treatment is affected by heterogeneous disease development, resulting in issues with patient stratification. Recently, many researches have been published by using deep learning (DL) and machine learning (ML) methods and, more commonly, artificial intelligence (AI). This paper presents a Dimensionality Reduction Framework Using Metaheuristic Optimization with Deep Learning Models for the Amyotrophic Lateral Sclerosis Disease Progression Prediction (DRMODL-ALSDP) method. The aim is to provide an effectual model for the progression prediction of ALS disease using advanced techniques. Initially, the data pre-processing stage applies min-mx normalization to transform raw data into a suitable format. Furthermore, SMOTE is employed to address class imbalance by upsampling the minority classes in disease progression stages. Furthermore, the binary swordfish movement optimization algorithm (BSMOA) technique is used for feature selection. Moreover, the hybrid of a temporal convolutional network and long short-term memory with attention mechanism (TCN-LSTM-AM) technique is employed for the classification process. Finally, the marine predator's algorithm (MPA) technique optimally fine-tunes the hyperparameter values and improves classification performance. A widespread simulation is performed to verify the performance of the DRMODL-ALSDP model. The comparison study of the DRMODL-ALSDP model accentuated the superior accuracy output of 98.17% over existing methods.}, } @article {pmid41352634, year = {2026}, author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B}, title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.}, journal = {Brain, behavior, and immunity}, volume = {132}, number = {}, pages = {106201}, doi = {10.1016/j.bbi.2025.106201}, pmid = {41352634}, issn = {1090-2139}, mesh = {Humans ; *Endogenous Retroviruses/genetics/physiology ; *Neurodegenerative Diseases/virology/genetics ; Alzheimer Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Parkinson Disease/virology ; Frontotemporal Dementia/virology ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

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

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

CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.}, } @article {pmid41354105, year = {2026}, author = {Mendes Araújo, L and Chianca, T and Persaud, C and Hartung, P and Soares, Y and Almirón, G and João, R}, title = {Respiratory strength training for patients with amyotrophic lateral sclerosis: A meta-analysis of randomized controlled trials.}, journal = {Respiratory medicine}, volume = {251}, number = {}, pages = {108560}, doi = {10.1016/j.rmed.2025.108560}, pmid = {41354105}, issn = {1532-3064}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; Randomized Controlled Trials as Topic ; *Breathing Exercises/methods ; Male ; Middle Aged ; Respiratory Muscles/physiopathology ; *Resistance Training/methods ; Female ; Treatment Outcome ; Aged ; Maximal Respiratory Pressures ; }, abstract = {INTRODUCTION: Respiratory strength training (RST) has been considered as a possible add-on treatment for amyotrophic lateral sclerosis (ALS). However, the benefits of RST are still controversial. We performed a meta-analysis of randomized controlled trials (RCTs) on the efficacy of RST in patients with ALS.

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

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

CONCLUSION: In this meta-analysis of RCTs including patients with ALS, expiratory muscle training was associated with increased MEP compared with sham or minimal load. However, no statistically significant associations were found for overall RST in MIP, FVC, MEP, and ALSFRS-R.}, } @article {pmid41355735, year = {2025}, author = {Pal, P and Carrer, M and Weiss, L and Jaime, OG and Cheng, C and Shmara, A and Boock, V and Bosch, D and Youssef, M and Fazeli, Y and Afetian, M and Grossman, TR and Hicks, MR and Jafar-Nejad, P and Kimonis, V}, title = {Antisense oligonucleotides targeting valosin-containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.}, journal = {Clinical and translational medicine}, volume = {15}, number = {12}, pages = {e70530}, pmid = {41355735}, issn = {2001-1326}, support = {UM1 TR004927/TR/NCATS NIH HHS/United States ; //Cure VCP Disease Inc. Ionis Pharmaceuticals, Inc./ ; 1297770//Muscular Dystrophy Association/ ; }, mesh = {Animals ; *Valosin Containing Protein/genetics/metabolism/antagonists & inhibitors ; Mice ; *Oligonucleotides, Antisense/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; Muscle, Skeletal/pathology ; Muscular Dystrophies, Limb-Girdle/genetics ; Frontotemporal Dementia/genetics ; Myositis, Inclusion Body ; Osteitis Deformans/genetics ; }, abstract = {BACKGROUND: Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease presents with variable combinations of inclusion body myopathy, early-onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology.

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

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

KEY POINTS: VCP multisystem proteinopathy 1 is caused by gain-of-function pathogenic variants of the VCP gene. VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). The ASOs reduced VCP, TDP-43, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.}, } @article {pmid41364388, year = {2026}, author = {Levine, AA and Rucker, JA and Cockerham, A and Cartner, J and Chambers, JD}, title = {U.S. health plan coverage of Neuromuscular Disease Therapies: An assessment of policy availability and restrictions.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {3}, pages = {436-444}, pmid = {41364388}, issn = {2214-3602}, mesh = {Humans ; United States ; *Neuromuscular Diseases/therapy/economics ; *Insurance Coverage/statistics & numerical data ; *Health Policy ; *Medicaid/statistics & numerical data ; *Insurance, Health/statistics & numerical data ; }, abstract = {BACKGROUND: Health plan policies managing neuromuscular disease (NMD) therapies may impose burdensome requirements on patients and providers. While prior research has explored payer restrictions for rare NMD treatments, limited evidence exists on policies specifically governing therapy initiation and reauthorization.

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

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

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

CONCLUSIONS: Many plans lacked publicly accessible policies, and most covered therapies were subject to restrictive requirements. These barriers-such as step therapy, narrow prescriber criteria, and short approval periods-may delay treatment and disrupt care continuity. Findings underscore the need for greater transparency and reform in prior authorization and pharmacy benefit design to support timely access to NMD therapies.}, } @article {pmid41366746, year = {2025}, author = {Huang, J and Liu, Y and Li, M and He, R and Tang, Z and Lei, Y and Zha, Y and Wei, J}, title = {Safety and efficacy of botulinum toxin injection for sialorrhea in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {496}, pmid = {41366746}, issn = {1471-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; *Sialorrhea/drug therapy/etiology ; *Botulinum Toxins/therapeutic use/adverse effects/administration & dosage ; Treatment Outcome ; *Neuromuscular Agents/therapeutic use/administration & dosage/adverse effects ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, with 80% of ALS patients experiencing bulbar weakness at some stage of the disease. ALS patients with bulbar weakness often suffer from troublesome sialorrhea. Botulinum toxin injection, as a neuromuscular blocker, has been widely used in the treatment of sialorrhea. This paper evaluates the safety and efficacy of botulinum toxin injections for the treatment of sialorrhea in ALS patients through a systematic review and meta-analysis. METHODS: A systematic review and meta-analysis was conducted by searching eight databases, including PubMed, EMBASE, and CNKI, up to April 13, 2025. Eligible randomized controlled trials and quasi-experimental studies were analyzed using Review Manager 5.4 and Stata software. RESULTS: Thirteen studies (2 RCTs, 11 quasi-experimental studies) with 130 ALS patients were included. Botulinum toxin significantly reduced sialorrhea and improved quality of life (Z = 10.98, p < 0.00001; RD = 0.82, 95% CI: 0.67–0.97). The treatment effect was independent of toxin type (p = 0.48), injection site (p = 0.17), and ultrasound guidance use (p = 0.44). CONCLUSION: Botulinum toxin appears to be a safe and effective option for managing sialorrhea in ALS patients, regardless of injection technique. However, given that most included studies were observational, further validation through high-quality RCTs is warranted. TRIAL REGISTRATION: This meta-analysis has been registered with Prospero, and the registration number is CRD420251029441. The registration period is April 9, 2025.}, } @article {pmid41372737, year = {2025}, author = {Shah, A and Doshi, G}, title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41372737}, issn = {2240-2993}, abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.}, } @article {pmid41375620, year = {2025}, author = {Krysiak, D and Ćwiertnia, M and Wójcik, M and Babik, P and Suchanek, Ł and Jaskiewicz, F and Trojak-Piętka, J and Szlagor, M and Pollok-Waksmańska, W and Kawecki, M and Ilczak, T}, title = {Analysis of Medical Response Team Interventions and the Impact of Certified Training on the Treatment of Patients with Hypoglycaemia-A Simulation Study.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375620}, issn = {2077-0383}, abstract = {Background/objectives: The effectiveness of emergency medical procedures administered to a patient in a life-threatening condition depends, to a large degree, on the knowledge and skills of medical response team personnel. Their competencies can be developed through participation in training and then verified during emergency medicine championships. Methods: The research was conducted on the basis of one of the tasks carried out during the '16th International Winter Championships in Emergency Medicine'. The task was completed by 28 Polish emergency response teams from ambulance stations across the country. The teams carried out a simulated scenario related to procedures with a patient with hypoglycaemia. The teams' interventions were assessed in accordance with European Resuscitation Council (ERC) guidelines by judges selected from among academic lecturers and ERC instructors. Results: The research showed that 86% of the teams obtained the maximum number of points for adhering to safety procedures. Further, 61% of the teams obtained the maximum of 6 points for the initial assessment, with the average number of points obtained by the teams being 5.54. The average number of points for the physical examination was 21.04, with only one team obtaining the maximum result of 26 points. Additionally, 57% of the teams obtained the maximum number of 6 points for the medical consultation, with the average obtained by the teams being 5.43. The teams obtained, on average, 8.18 points for the correct treatment of hypoglycaemia, with 68% of the teams obtaining the maximum of 9 points. The research demonstrated a positive correlation between the quality of patient examination and the collection of medical data, and the effectiveness of hypoglycaemia treatment. It was also shown that if the team leader had completed an ALS course, they obtained higher scores for the treatment of hypoglycaemia, although this finding is specific to this scenario. Conclusions: The teams demonstrated generally high performance in a simulated hypoglycaemia scenario. More complete assessment and history-taking were associated with higher treatment scores. Correct treatment was achieved in 79% of ALS-led teams versus 44% of non-ALS teams, although this observation is specific to this simulation and should not be generalised.}, } @article {pmid41375893, year = {2025}, author = {Gratzer, A and Gdynia, N and Sasse, N and Beese, R and Winterholler, C and Bauer, Y and Schröter, C and Gdynia, HJ}, title = {Rehabilitation in Amyotrophic Lateral Sclerosis: Recommendations for Clinical Practice and Further Research.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375893}, issn = {2077-0383}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition characterized by the degeneration of upper and lower motor neurons. This degeneration leads to a gradual muscle weakness, dysarthria, dysphagia, respiratory insufficiency, and, in some patients, alterations in cognitive and behavioral performance. Regardless of advancements made in pharmacological and gene-targeted interventions, a definitive curative treatment remains elusive. Consequently, rehabilitation plays a pivotal role in preserving autonomy, participation, and overall quality of life. This review outlines the current evidence and clinical approaches related to multidisciplinary rehabilitation in ALS. It covers physical and occupational therapy, respiratory, speech and language, psychological, and palliative care domains. Evidence supports moderate tailored exercise programs, early respiratory therapy, and structured management of mobility deficits, spasticity, pain, dysphagia, and communication impairments as key elements of symptomatic treatment. Psychological and social support, which includes the involvement of caregivers and relatives, enhances emotional well-being and coping resilience. Even with progressive development of gene-targeted and disease-modifying therapies, rehabilitation will stay relevant for maintaining long-term motor function. This review highlights the need for standardized, evidence-based rehabilitation protocols and intensified neurorehabilitation research to strengthen clinical outcomes and quality of life as key therapeutic goals in ALS management.}, } @article {pmid41381004, year = {2026}, author = {Maas, D and Spindler, A and Zappi, I and Shapiro, J and Lo Sicco, KI}, title = {Response to Olsen et al's "Summation and recommendations for the safe and effective use of topical and oral minoxidil".}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {4}, pages = {e287-e288}, doi = {10.1016/j.jaad.2025.09.118}, pmid = {41381004}, issn = {1097-6787}, } @article {pmid41381656, year = {2025}, author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR}, title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {510}, pmid = {41381656}, issn = {2045-2322}, support = {LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Humans ; *Proteomics/methods ; Cell Line, Tumor ; Tandem Mass Spectrometry ; *Proteome ; *Dipeptides/toxicity ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; *Alanine/analogs & derivatives/toxicity ; }, abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.}, } @article {pmid41388206, year = {2025}, author = {Schmitt, P and Schumann, P and Koerbs, A and Lin, HJ and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Großkreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P and Meyer, T}, title = {Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis-results from a multicenter screening program.}, journal = {Journal of neurology}, volume = {273}, number = {1}, pages = {22}, pmid = {41388206}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/physiopathology/diagnosis ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; C9orf72 Protein/genetics ; Phenotype ; Aged ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Adult ; Disease Progression ; Cohort Studies ; DNA-Binding Proteins/genetics ; }, abstract = {OBJECTIVE: In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.

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

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

CONCLUSION: In C9orf72-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in SOD1-, FUS- and TARDBP-associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.}, } @article {pmid41389101, year = {2025}, author = {Li, Y and Zhou, Y and Yu, L and Bi, Y and Yi, L and Li, C and Liu, Y}, title = {Myeloid Irf5 Deficiency Enhances the Therapeutic Efficacy of IMD-0354 in a TDP-25-Induced Neurodegeneration Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {290}, pmid = {41389101}, issn = {1559-1182}, support = {H2024206009//the Hebei Natural Science Foundation/ ; 81901290//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Interferon Regulatory Factors/deficiency/metabolism ; *DNA-Binding Proteins/toxicity/metabolism ; Macrophages/metabolism/drug effects ; Mice, Knockout ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; Mitochondria/metabolism/drug effects ; Cell Line ; Amyotrophic Lateral Sclerosis/drug therapy ; Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Nerve Degeneration/drug therapy/pathology/metabolism ; *Myeloid Cells/metabolism/drug effects ; }, abstract = {Neuroinflammation is recognized as a key contributor to the pathogenesis and progression of amyotrophic lateral sclerosis (ALS), with dysregulated innate immune activation implicated in exacerbating neuronal injury. However, the molecular mechanisms by which macrophages contribute to neurodegeneration in motor neurons harboring TAR DNA-binding protein 43 (TDP-43) mutations are not fully understood. M1 macrophages were generated from the bone marrow of Irf5 knockout or wild-type mice and co-cultured with the NSC34 motor neuron-like cell line overexpressing the C-terminal fragment of TDP-43 (TDP-25) using a Transwell system. Mitochondrial alterations, and apoptosis were evaluated through Western blotting, flow cytometry, and transmission electron microscopy. IMD-0354 mitigated mitochondrial dysfunction and apoptosis induced by TDP-25 exposure. This neuroprotective effect was attenuated in the presence of pro-inflammatory macrophages. Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation.}, } @article {pmid41389988, year = {2026}, author = {Gomez-Almeria, M and Martinez-Gonzalez, L and Matos, AT and Rodriguez-Cueto, C and Vaz, AR and Martín-Baquero, R and Pérez de la Lastra, C and Infantes, R and Fernández-Ruiz, J and Palomo, V and Gil, C and Brites, D and Martinez, A and de Lago, E}, title = {Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy.}, journal = {Neuropharmacology}, volume = {285}, number = {}, pages = {110804}, doi = {10.1016/j.neuropharm.2025.110804}, pmid = {41389988}, issn = {1873-7064}, mesh = {*Riluzole/administration & dosage/pharmacology/therapeutic use ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/administration & dosage ; Drug Therapy, Combination ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; *TDP-43 Proteinopathies/drug therapy ; *Protein Kinase Inhibitors/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Male ; Dose-Response Relationship, Drug ; DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3-18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.}, } @article {pmid41392158, year = {2025}, author = {Le Friec, J and Mourier, H and Couly, S and Cubedo, N and Dubois, K and Meunier, J and Delprat, B and De Zordo-Banliat, A and Ayad, T and Virieux, D and Su, TP and Lasbleiz, C and Maurice, T and Liévens, JC}, title = {Positive modulation of sigma-1 receptor: a new weapon to mitigate disease progression in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {68}, pmid = {41392158}, issn = {2047-9158}, support = {grant 23667//AFM-Téléthon/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; *Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; Zebrafish ; Disease Progression ; Mice ; Humans ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Disease Models, Animal ; C9orf72 Protein/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of motor neurons, leading to muscle weakness and progressive paralysis. Currently, no treatment is available to halt or reverse the progression of the disease. Oxidative stress, mitochondrial dysfunction, accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS. A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death. Targeting sigma-1 receptor (S1R) could meet this objective, as this chaperone protein modulates many cell survival mechanisms. So far, the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2% of patients. In the present study, the impact of two different S1R activators, the reference agonist PRE-084 and the positive modulator OZP002, was compared on two key ALS genes: TDP43 and C9orf72.

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

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

CONCLUSIONS: We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology. Additionally, we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.}, } @article {pmid41394670, year = {2025}, author = {O'Connor, JT and Loo, HQ and Guo, C and Pickles, S and Sundali, S and Jawahar, VM and Dickson, DW and Bloom, AJ and Petrucelli, L and Gitler, AD and Milbrandt, J and DiAntonio, A}, title = {TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394670}, issn = {2692-8205}, support = {R01 NS133348/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; R01 NS065053/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; F32 AG086044/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, abstract = {Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.}, } @article {pmid41396180, year = {2026}, author = {Xu, X and Zhou, Q and Zhang, X and Li, T and Niu, L and Xu, G and Chen, S and Shao, Y and Le, W}, title = {Untargeted metabolomics based on LC-MS and GC-MS reveal metabolic reprogramming and putative biomarkers in amyotrophic lateral sclerosis.}, journal = {Chinese medical journal}, volume = {139}, number = {4}, pages = {610-619}, pmid = {41396180}, issn = {2542-5641}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Metabolomics/methods ; *Biomarkers/metabolism/blood ; Male ; Female ; Middle Aged ; *Gas Chromatography-Mass Spectrometry/methods ; Chromatography, Liquid/methods ; Adult ; Aged ; ROC Curve ; Metabolic Reprogramming ; Liquid Chromatography-Mass Spectrometry ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unknown etiology. The absence of reliable biochemical and imaging markers often delays diagnosis and limits treatment effectiveness. As metabolic reprogramming is increasingly recognized as a hallmark of ALS, a comprehensive untargeted metabolomics analysis was employed to identify critical metabolic perturbations in ALS and explore novel candidate biomarkers with potential utility in clinical diagnosis.

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

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

CONCLUSION: The disturbed pathways and biomarker candidates identified in this study may provide novel insights into ALS pathogenesis and improve diagnostic strategies.}, } @article {pmid41399419, year = {2025}, author = {Chen, HW}, title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e99153}, pmid = {41399419}, issn = {2168-8184}, abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.}, } @article {pmid41399798, year = {2025}, author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S}, title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.}, journal = {Chinese herbal medicines}, volume = {17}, number = {4}, pages = {643-672}, pmid = {41399798}, issn = {2589-3610}, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.}, } @article {pmid41400569, year = {2026}, author = {Vacchiano, V and Cherici, A and Criante, MS and Mengoli, E and Fonti, C and Bonan, L and de Pasqua, S and Donadio, V and Giannoccaro, MP and Rizzo, G and Quarta, CC and Marzocchi, E and Taggi, F and Liguori, R and , }, title = {Cognitive and behavioral impairment may influence shared care planning and treatment decisions in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {622-631}, doi = {10.1080/21678421.2025.2597937}, pmid = {41400569}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Female ; Male ; Middle Aged ; Aged ; *Cognitive Dysfunction/psychology/etiology/therapy ; Neuropsychological Tests ; *Decision Making, Shared ; Decision Making ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, often accompanied by cognitive and/or behavioral impairments. Shared Care Planning (SCP) involves a collaborative decision-making process, playing a key role in aligning medical treatments with patient values. This study aimed to investigate potential associations between neuropsychological impairment and treatment decisions in ALS patients. Methods: We included 118 ALS patients who had completed at least the cognitive section of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). As part of routine clinical practice, patients were invited to participate in Shared Care Planning (SCP) discussions regarding key medical interventions, namely noninvasive ventilation (NIV), artificial nutrition via PEG/RIG, and tracheostomy. Results: SCP discussions were initiated with 78% of patients. NIV was accepted by 96% of patients, PEG/RIG by 63.9% and tracheostomy by 17.8%. Patients who accepted PEG/RIG were more frequently female (p = 0.047) and had significantly lower adjusted scores on the total ECAS (p = 0.027), ALS-specific domains (p = 0.020), verbal fluency (p = 0.012), and semantic fluency (p = 0.042), compared to those who refused PEG/RIG. Acceptance of tracheostomy was more common among younger patients (p < 0.001) and those with cognitive or behavioral impairments (p = 0.014). Binary logistic regression analysis, using tracheostomy acceptance as the dependent variable and age, sex, and Strong's diagnostic categories as independent variables, revealed a significant association with age (p = 0.002) and with certain Strong's categories, particularly ALS with combined cognitive and behavioral impairment (ALS-CBI) (p = 0.031). Conclusions: Cognitive and behavioral impairment appeared to increase the likelihood of consenting to invasive treatments in ALS patients.}, } @article {pmid41400574, year = {2025}, author = {Huang, S and Li, A and Ling, Y and Yang, X and Wang, J and Yuan, J and Qin, D and Yao, X}, title = {Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1224}, pmid = {41400574}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1[G93A], TDP43[A315T], and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1[G93A] transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1[G93A] transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.}, } @article {pmid41401652, year = {2026}, author = {Braverman, A and Frenkel, A and Schwarzfuchs, D and Jaffe, E and Bitan, Y}, title = {Verbal and visual information exchange in EMS-to-ED patient handovers: An observational and attitudinal study.}, journal = {International emergency nursing}, volume = {84}, number = {}, pages = {101735}, doi = {10.1016/j.ienj.2025.101735}, pmid = {41401652}, issn = {1878-013X}, mesh = {Humans ; *Patient Handoff/standards/statistics & numerical data ; Male ; Female ; Israel ; Adult ; Emergency Service, Hospital/organization & administration/statistics & numerical data ; *Emergency Medical Services/methods/standards/statistics & numerical data ; Middle Aged ; Surveys and Questionnaires ; *Attitude of Health Personnel ; Communication ; }, abstract = {BACKGROUND: Although effective information exchange during emergency medical services (EMS)-to-emergency department (ED) patient handovers is critical for care continuity and patient safety, handover communication patterns and information gaps remain poorly characterized.

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

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

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

CONCLUSIONS: Because EMS-to-ED handovers rely almost exclusively on brief verbal communication, they are vulnerable to information loss. Critical safety-relevant information (allergies, medications) is frequently omitted, with BLS teams showing greater gaps than ALS teams. Structured handover protocols may improve information completeness and continuity of care by incorporating digital tools to complement verbal communication.}, } @article {pmid41404692, year = {2025}, author = {Żur-Wyrozumska, K}, title = {A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.}, journal = {Folia medica Cracoviensia}, volume = {65}, number = {3}, pages = {173-183}, doi = {10.24425/fmc.2025.156692}, pmid = {41404692}, issn = {2957-0557}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Sequestosome-1 Protein/genetics ; Middle Aged ; Female ; NF-E2-Related Factor 2/genetics/metabolism ; Autophagy/genetics ; NF-kappa B/genetics ; Mutation ; Signal Transduction ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.

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

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

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

CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.}, } @article {pmid41406304, year = {2026}, author = {Geva, M and Goldberg, YP and Leitner, ML and Cruz-Herranz, A and Hand, R and Chen, K and Gershoni Emek, N and Tan, AM and Paganoni, S and Berry, JD and Macklin, EA and Shefner, JM and Cudkowicz, ME and Hayden, MR}, title = {Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {432-444}, doi = {10.1080/21678421.2025.2597935}, pmid = {41406304}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Male ; Female ; Double-Blind Method ; Middle Aged ; *Piperidines/therapeutic use ; Aged ; Treatment Outcome ; Adult ; Receptors, sigma/agonists ; Disease Progression ; Sigma-1 Receptor ; }, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.}, } @article {pmid41417044, year = {2026}, author = {Rott, N and Reinsch, L and Dirks, B and Böttiger, BW}, title = {[The new European Resuscitation Council (ERC) guidelines 2025-Overview of the most important changes; the first 3-5 min are decisive].}, journal = {Die Anaesthesiologie}, volume = {75}, number = {1}, pages = {44-50}, pmid = {41417044}, issn = {2731-6866}, mesh = {Adult ; Humans ; Advanced Cardiac Life Support/standards ; *Cardiopulmonary Resuscitation/standards/methods ; Epinephrine/administration & dosage ; Europe ; Heart Arrest/therapy ; *Practice Guidelines as Topic ; *Resuscitation/standards/methods ; Time Factors ; }, abstract = {In October 2025 the new resuscitation guidelines of the European Resuscitation Council (ERC) were published. In the chapter on advanced life support (ALS) for adults the update emphasizes topics such as efficient ventilation with adequate chest compressions, early defibrillation, identification and treatment of reversible causes as rapidly as possible and the administration of epinephrine in cases of non-defibrillatable cardiac arrest. The aim of the guidelines is to sustainably improve survival rates after cardiac arrest through structured and evidence-based care systems.}, } @article {pmid41417753, year = {2026}, author = {Lam, P and Zygmunt, DA and Bennett, M and Ashbrook, A and Hefty, J and Martin, PT}, title = {Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.}, journal = {Journal of neuromuscular diseases}, volume = {13}, number = {3}, pages = {474-492}, pmid = {41417753}, issn = {2214-3602}, support = {P50 HD117373/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Thrombocytopenia/genetics ; *Anemia/genetics ; *Hemorrhage/genetics ; *Multienzyme Complexes/genetics ; Gene Deletion ; Disease Models, Animal ; Muscle, Skeletal/pathology/metabolism ; *Muscular Diseases/genetics ; Mice, Transgenic ; }, abstract = {The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne[lox/lox] gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER[T2]/Rosa-CreER[T2]Gne[lox/lox] mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER[T2/+]Gne[lox/lox] mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne[lox/lox] mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.}, } @article {pmid41428860, year = {2026}, author = {Curtis, SE and Tatlock, S and O'Hara, L and Seçinti, E and Mehdiyoun, NF and Ayala-Nunes, L and Flynn, J and Fernelius, K and Hodson, N and Delbecque, L}, title = {Patient experience and clinical outcome assessment validity in amyotrophic lateral sclerosis: a targeted literature review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {285-300}, doi = {10.1080/21678421.2025.2604233}, pmid = {41428860}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/diagnosis ; *Quality of Life/psychology ; *Outcome Assessment, Health Care/methods ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials.

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

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

CONCLUSIONS: This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.}, } @article {pmid41428942, year = {2025}, author = {Sannes, A and Rognli, EW and Hanssen-Bauer, K and Torp, NC and Storfossen, SK and Høstaker, MN and Aalberg, M}, title = {Barriers to and Facilitators of Implementation of Internet-Delivered Therapist-Guided Therapy in Child and Adolescent Mental Health Services: Systematic Review and Bayesian Meta-Analysis.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e83543}, pmid = {41428942}, issn = {1438-8871}, mesh = {Adolescent ; Child ; Humans ; *Adolescent Health Services ; Bayes Theorem ; *Child Health Services ; *Internet ; *Mental Health Services ; *Psychotherapy/methods ; }, abstract = {BACKGROUND: Internet-delivered therapist-guided therapy (e-therapy) represents a promising approach for enhancing accessibility, treatment fidelity, and scalability within child and adolescent mental health services (CAMHS).

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

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

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

CONCLUSIONS: This review provided the first integrated synthesis of pooled benchmarks for implementation outcomes of e-therapy in CAMHS and modifiable determinants to inform future service planning and scale-up. These findings highlighted service-level enablers, such as leadership anchoring, targeted use, technical stability, structured patient flow, and therapist training, that organizations could prioritize to strengthen sustainable e-therapy implementation in CAMHS.}, } @article {pmid41430470, year = {2026}, author = {Piol, D and Khalil, B and Robberechts, T and Killian, T and Georgopoulou, M and Partel, G and Wouters, D and Hecker, N and Tziortzouda, P and Verresen, Y and Corthout, N and Kint, S and Vandereyken, K and Van Damme, P and Voet, T and Davie, K and Poovathingal, S and Van Den Bosch, L and Aerts, S and Sifrim, A and Da Cruz, S}, title = {Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.}, journal = {Nature neuroscience}, volume = {29}, number = {1}, pages = {53-66}, pmid = {41430470}, issn = {1546-1726}, support = {962700//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 1060285//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; Eukaryotic Translation Initiation Factor 5A ; *Axons/metabolism ; *Peptide Initiation Factors/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Motor Neurons/metabolism ; *Protein Biosynthesis/physiology ; Drosophila ; Mutation/genetics ; Mice, Transgenic ; }, abstract = {Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.}, } @article {pmid41432316, year = {2026}, author = {Genge, A and Rothstein, J and De Silva, S and Zinman, L and Chum, M and Chiò, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Hirai, M and Sasson, N and Takahashi, F and Cecić, M and Wamil, A and Apple, S}, title = {Phase 3b Extension Study MT-1186-A04 to Evaluate the Continued Efficacy and Safety of Edaravone Oral Suspension for Up to an Additional 48 Weeks in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {534-543}, pmid = {41432316}, issn = {1097-4598}, support = {//Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/administration & dosage/therapeutic use ; Male ; Middle Aged ; Double-Blind Method ; Female ; Aged ; Treatment Outcome ; Administration, Oral ; *Free Radical Scavengers/administration & dosage/therapeutic use/adverse effects ; Adult ; Suspensions ; *Antipyrine/analogs & derivatives/administration & dosage/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is currently approved in the US for treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed that IV edaravone slows physical functional decline. Study MT-1186-A04 continued to examine the efficacy and safety of investigational once daily and approved on/off dosing of edaravone oral suspension in patients with ALS.

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

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

DISCUSSION: Similar to Study MT-1186-A02, once daily edaravone oral suspension in extension Study MT-1186-A04 did not show superiority in terms of the primary efficacy endpoint, but had equivalent efficacy, safety, and tolerability, compared with the approved On/Off regimen. The results reinforce the appropriateness of the approved dosing regimen.}, } @article {pmid41438688, year = {2026}, author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H}, title = {In vitro 3D models of neuron-astrocyte interactions.}, journal = {Biochemistry and biophysics reports}, volume = {45}, number = {}, pages = {102400}, pmid = {41438688}, issn = {2405-5808}, abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.}, } @article {pmid41440030, year = {2025}, author = {Su, J and Alaiz Noya, J and Lingappa, AF and Solas, D and Tong, J and Daughrity, L and Castanedes-Casey, M and Kurti, A and Dickson, DW and Lingappa, VR and Petrucelli, L and Zhang, Y}, title = {Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD.}, journal = {Cells}, volume = {14}, number = {24}, pages = {}, pmid = {41440030}, issn = {2073-4409}, support = {ADSF-24-1284327-C//Alzheimer's Disease Strategic Fund grant/ ; NA//Robert Packard Center for ALS Research at Johns Hopkins/ ; NA//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; NA//BrightFocus Foundation/ ; NA//Target ALS Foundation/ ; U19 AG063911/AG/NIA NIH HHS/United States ; NA//Cure Alzheimer's Fund/ ; NA//Kissick Family Foundation/ ; U54NS123743, R35 NS137447, P01NS084974, R01NS132330 and R01NS117461//National Institutes of Health/National Institute of Neurological Disorders and Stroke/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; NA//Association for Frontotemporal Degeneration Biomarkers Initiative/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; 5P30AG0062677, ALLFTD U19AG063911, R01AG089380 and R01AG085307//National Institutes of Health/National Institute on Aging/ ; R01 AG085307/AG/NIA NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; Disease Models, Animal ; *Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism ; Mice ; Humans ; Male ; Mice, Transgenic ; Drug Evaluation, Preclinical ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.}, } @article {pmid41454086, year = {2025}, author = {Mi, X and Shan, K and Ye, X and Cheng, R}, title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3371}, pmid = {41454086}, issn = {2045-2322}, support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; }, mesh = {*Spinal Cord Injuries/drug therapy/metabolism/pathology/physiopathology ; Animals ; *Hydrogen Peroxide/metabolism ; *Astrocytes/drug effects/metabolism ; *Nerve Regeneration/drug effects ; Cell Proliferation/drug effects ; Mice ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Disease Models, Animal ; Cells, Cultured ; }, abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.}, } @article {pmid41455134, year = {2026}, author = {Du, O and Wu, YJ and Li, MY and Du, JR}, title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.}, journal = {Cytokine}, volume = {198}, number = {}, pages = {157099}, doi = {10.1016/j.cyto.2025.157099}, pmid = {41455134}, issn = {1096-0023}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Central Nervous System Diseases/metabolism/therapy/pathology ; Animals ; Biomarkers/metabolism ; }, abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.}, } @article {pmid41458376, year = {2025}, author = {Qian, G and Ding, L and Tan, C and Wang, L and Long, C}, title = {Mucosal immune response modulated by secreted and membrane-bound hydrolases of Candida albicans in vulvovaginal candidiasis.}, journal = {Frontiers in fungal biology}, volume = {6}, number = {}, pages = {1692795}, pmid = {41458376}, issn = {2673-6128}, abstract = {Vulvovaginal candidiasis (VVC) affects the physical and mental health of millions of women worldwide. The leading cause of VVC, Candida albicans, can induce a strong mucosal inflammatory reaction during the VVC infection, where secreted and membrane-bound adhesion and hydrolases seem to be the key virulent factors to promote the mucosal antifungal immunity and immunopathology. Several hydrolases, such as Saps, Als, candidalysin, lipases, and phospholipases, have been identified in vaginal secretions isolated from VVC patients; however, the immune impacts of some hydrolases have not been well documented. In this review, we focus on the literature that addresses the immunopathogenic roles of the Als adhesin family or proteinase, such as Sap and candidalysin, in VVC. Our goal is to expand our knowledge of VVC pathogenesis in order to provide new strategies for VVC treatment.}, } @article {pmid41462890, year = {2025}, author = {Fajkić, A and Belančić, A and Lam, YW and Rački, V and Pilipović, K and Janković, T and Mežnarić, S and Mršić-Pelčić, J and Vitezić, D}, title = {Novel Translational Concept: Axon-to-Muscle Exosomal Signaling as an Emerging Therapeutic Target in Spinal Muscular Atrophy.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462890}, issn = {2227-9059}, abstract = {Spinal muscular atrophy (SMA) has transitioned from a uniformly fatal disease to a treatable condition, yet incomplete neuromuscular recovery underscores the limits of current SMN-restorative therapies. Emerging data implicate disrupted axon-to-muscle exosomal signaling as an important, overlooked driver of residual dysfunction. Exosomes, nanovesicles mediating bidirectional neuronal-muscular communication, carry synaptic organizers, trophic factors, and microRNAs essential for neuromuscular junction integrity. SMN deficiency alters exosomal biogenesis and cargo, leading to loss of agrin-MuSK signaling, impaired β-actin transport, and muscle atrophy. Comparative insights from amyotrophic lateral sclerosis and muscular dystrophy reveal that stem-cell-derived or engineered exosomes restore synaptic stability, enhance regeneration, and cross biological barriers safely. Thus, we speculate herein on a translational model integrating exosome-based therapies with existing genetic interventions to achieve durable, systems-level recovery in SMA. Exosomal profiling may further yield minimally invasive biomarkers for disease monitoring and treatment optimization, establishing vesicle-mediated communication as a novel therapeutic axis in neuromuscular medicine.}, } @article {pmid41463070, year = {2025}, author = {Goyal, NA and Andrews, JA and Oskarsson, BE and Wiedau, MH and Kasarskis, EJ and Forrest, BD and Zhang, R and Bracci, PM and Davis, MW and Azhir, A and McGrath, MS}, title = {Quantitative Measures of Time to Loss of 15% Vital Capacity and Survival Extension in Slowly Progressive Amyotrophic Lateral Sclerosis (ALS) Patients Treated with the Immune Regulator NP001 Suggests an Immunopathogenic Subset of ALS.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463070}, issn = {2227-9059}, support = {Neuvivo - NP001//Ari Azhir/ ; }, abstract = {Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.}, } @article {pmid41464612, year = {2025}, author = {Klumb, S and Haley, L and Hathaway, C and Irby, J and Cheng, J and Rumley, J}, title = {Degenerative Cervical Myelopathy Diagnosis and Its Differentiation from Neurological Mimics, MS and ALS: A Literature Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {24}, pages = {}, pmid = {41464612}, issn = {2077-0383}, abstract = {Multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and degenerative cervical myelopathy (DCM) share features that may confound diagnosis. DCM is caused by degenerative changes in the cervical spine leading to spinal cord compression and injury, resulting in significant disability. Misdiagnosis of DCM for a similar neurological condition can lead to further spinal cord damage from delayed surgical treatment. Here we review the diagnostic criteria, clinical signs and symptoms, and imaging typical for DCM, and two of its clinical mimics, MS and ALS. Shared motor symptoms of all three conditions can make diagnosis difficult, especially early in disease course. Noteworthy differences include neck and shoulder pain in DCM, visual disturbances in MS, and bulbar symptoms and the absence of sensory deficits in ALS. In DCM and MS, MRI is used to support the diagnosis, with specific findings on MRI that differentiate DCM versus MS. In ALS, MRI is used to rule out differential diagnoses. Applying the diagnostic criteria for MS and ALS, as well as understanding the typical presentation and MRI findings of DCM, is crucial. Through discussion of these conditions, this review aims to help limit misdiagnosis rates, allowing for early management, which can improve long-term patient outcomes.}, } @article {pmid41467438, year = {2026}, author = {Zhao, J and Wang, J and Guo, X}, title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4734-4744}, pmid = {41467438}, issn = {1673-5374}, abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.}, } @article {pmid41468784, year = {2026}, author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D}, title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.}, journal = {Neuropeptides}, volume = {115}, number = {}, pages = {102583}, doi = {10.1016/j.npep.2025.102583}, pmid = {41468784}, issn = {1532-2785}, mesh = {Humans ; *Neuropeptide Y/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; Signal Transduction/physiology ; Oxidative Stress/physiology ; Receptors, Neuropeptide Y/metabolism ; }, abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.}, } @article {pmid41471389, year = {2025}, author = {Gershoni Emek, N and Tan, AM and Geva, M and Fekete, A and Abate, C and Hayden, MR}, title = {Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {12}, pages = {}, pmid = {41471389}, issn = {1424-8247}, abstract = {Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca[2+] homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine's mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine's S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.}, } @article {pmid41477139, year = {2025}, author = {Syamal, M}, title = {Treatment of Neurogenic Voice Disorders.}, journal = {World journal of otorhinolaryngology - head and neck surgery}, volume = {11}, number = {4}, pages = {541-547}, pmid = {41477139}, issn = {2589-1081}, abstract = {This overview serves as a foundational resource for clinicians caring for neurologically complex patients presenting with voice complaints. Neurogenic voice disorders are diverse in their clinical presentations and therapeutic approaches. A thorough medical history, including family history, detailed laryngeal examination, voice assessments, and neuroimaging, are imperative, as well as a multidisciplinary, collaborative approach with neurologists, speech language pathologists, and patient caregivers. Disorders such as amyotrophic lateral sclerosis (ALS), cerebrovascular accidents (strokes), Huntington's disease, myasthenia gravis (MG), Parkinson's disease (PD), and voice tremor should be understood by otolaryngologists. Each condition presents unique challenges and requires tailored treatment strategies ranging from supportive therapies and pharmacological interventions to surgery. Voice management techniques, including the use of botulinum toxin for hyperkinetic disorders and deep brain stimulation for refractory cases, are highlighted as promising interventions.}, } @article {pmid41478512, year = {2026}, author = {Strohmer, B and Grosh, K and Montañana-Rosell, R and Mora, S and Ausborn, J and Allodi, I}, title = {Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study.}, journal = {Neurobiology of disease}, volume = {219}, number = {}, pages = {107253}, pmid = {41478512}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/pathology ; *Motor Neurons/physiology ; Animals ; *Spinal Cord/physiopathology ; Computer Simulation ; Interneurons/physiology ; Mice ; Humans ; *Models, Neurological ; *Nerve Net/physiopathology ; Disease Models, Animal ; *Neural Networks, Computer ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1-motoneuron connections improved motor function and saved motoneurons in the SOD1[G93A] ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor-extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1[G93A] ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.}, } @article {pmid41479929, year = {2025}, author = {Bagrodia, A and Vaithiyam, V and Laguduva Mohan, S}, title = {Large colorectal lesions: Expanding the boundaries of endoscopic management.}, journal = {World journal of gastrointestinal endoscopy}, volume = {17}, number = {12}, pages = {115008}, pmid = {41479929}, issn = {1948-5190}, abstract = {Large colorectal lesions (≥ 3 cm) present a significant therapeutic challenge due to their potential for malignancy and the technical difficulties they encounter. Endoscopic resection techniques, including endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection, have revolutionized the management of these lesions by offering organ-preserving alternatives to surgery with favorable outcomes. We read with great interest and commended Zhu et al for their valuable study on the endoscopic treatment of large colorectal lesions. Zhu et al's study provides crucial real-world evidence regarding the safety and effectiveness of advanced endoscopic resection techniques in this challenging patient group. These findings support the possibility of achieving high rates of complete resection with acceptable adverse event profiles, reinforcing the role of endoscopic mucosal resection and submucosal dissection in routine practice. This editorial also offers a comprehensive review of the current literature, discusses its clinical implications, explores future directions, and compares endoscopic resection methods with surgical options. Zhu et al's study findings not only validate the efficacy of advanced endoscopic resection but also signify a paradigm shift from surgical to organ-preserving strategies in colorectal oncology, a transformation that requires deliberate system-wide training and capacity building.}, } @article {pmid41480618, year = {2025}, author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE}, title = {Extracellular vesicle-based therapies for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {4}, pages = {377-390}, pmid = {41480618}, issn = {2750-6665}, support = {R01 MH121402/MH/NIMH NIH HHS/United States ; R01 NS034239/NS/NINDS NIH HHS/United States ; }, abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.}, } @article {pmid41488323, year = {2025}, author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R}, title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1733659}, pmid = {41488323}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.}, } @article {pmid41490238, year = {2026}, author = {Ni, S and Chen, K and Wang, H and Chen, S and Qiu, Y and Wang, T and Mo, F and Wang, S and Li, B and Bai, Y and Zhao, J and Zhai, X and Li, Z}, title = {A new paradigm of bidirectional regulation of the gut-spinal cord axis.}, journal = {Neural regeneration research}, volume = {21}, number = {9}, pages = {4100-4111}, pmid = {41490238}, issn = {1673-5374}, abstract = {The bidirectional interactions of spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis with the gut operate through a distinct gut-spinal cord axis, rather than being fully explained by the conventional gut-brain axis. The spinal cord, with its unique anatomical and physiological features, serves as a central hub of communication. The gut and spinal cord communicate through various pathways, including the immune system and the autonomic and enteric nervous systems. This review summarizes existing clinical and basic research on the relationship between gut homeostasis and spinal cord diseases. First, we present findings from epidemiological studies showing that patients with spinal cord disorders often exhibit altered gut function, which may be influenced by antibiotic exposure and environmental factors. Second, we review the key physiological and anatomical structures of the gut-spinal cord axis, including the intestinal barrier, gut microbiota, and enteric nervous system, all of which are involved in maintaining gut health, as well as sensory neurons, motor neurons, and interneurons in spinal nerve regulation. Third, we describe the roles of the three axes (microbial, immune, and neural) in bidirectional regulation and their pathological mechanisms. Moreover, vicious cycles involving these axes can exacerbate spinal cord disorders. Fourth, we outline potential biomarkers in the gut-spinal cord axis, such as uridine, hypoxanthine, and 5-methoxytryptophan. Fifth, we propose several treatment strategies with potential clinical applications, including fecal microbiota transplantation and the use of probiotics and prebiotics. Finally, this review emphasizes the gut-spinal cord axis as a promising therapeutic target, highlighting the need for multi-omics integration, longitudinal cohort studies, and individualized interventions to resolve existing debates. Overall, the recognition of the gut-spinal cord axis provides a conceptual shift that extends beyond the gut-brain framework.}, } @article {pmid41493797, year = {2026}, author = {Esteve, D and Bresque, M and Okhuevbie, D and Ramachandran, S and Pehar, M and Vargas, MR}, title = {Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes.}, journal = {Glia}, volume = {74}, number = {3}, pages = {e70136}, pmid = {41493797}, issn = {1098-1136}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS122973/NS/NINDS NIH HHS/United States ; R01NS089640/NS/NINDS NIH HHS/United States ; R01NS122973/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Astrocytes/drug effects/metabolism/pathology/enzymology ; Humans ; *Fatty Acids/toxicity ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; *L-Lactate Dehydrogenase/antagonists & inhibitors/metabolism/genetics ; Mice, Transgenic ; Mice ; Cells, Cultured ; Motor Neurons/drug effects/metabolism/pathology ; Coculture Techniques ; Phenotype ; Spinal Cord/pathology ; Mice, Inbred C57BL ; Disease Models, Animal ; Lipid Metabolism/drug effects ; Lipid Droplets/metabolism/drug effects ; Male ; }, abstract = {Astrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid-binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co-culture model, we examined the effect of FA overload and its impact on astrocyte-motor neuron interaction. LD accumulation was tightly coupled with an NF-κB-driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS-linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte-neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.}, } @article {pmid41495620, year = {2026}, author = {Li, Y and Feng, Y and Liu, X and Yuan, R and Chen, S and Wang, J and Pan, C and Li, G and Tang, Z}, title = {Functional near-infrared spectroscopy: Systematic mapping of abnormal brain function features in neurological disorders.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {4506-4522}, pmid = {41495620}, issn = {1673-5374}, abstract = {Functional near-infrared spectroscopy quantifies cerebral hemodynamic signals by capturing oxygenation-dependent changes in hemoglobin in a noninvasive, portable, and ecologically valid manner, providing a unique insight into neurovascular coupling. However, functional imaging biomarkers with high ecological validity for neurological disorders such as stroke, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, spinal cord injury, and traumatic brain injury are lacking, limiting the mechanistic understanding, treatment evaluations, and individualized interventions. The aim of this review is to systematically summarize evidence from the past decade on the use of functional near-infrared spectroscopy under the aforementioned conditions, synthesize its value for revealing neural mechanisms and assessing therapeutic responses, and identify current technical bottlenecks and future directions for advancement. Collectively, the findings demonstrate that functional near-infrared spectroscopy possesses substantial and far-reaching potential for uncovering the neural mechanisms underlying disease and for evaluating treatment-induced changes in brain function. Equipped with wearable probes, functional near-infrared spectroscopy can continuously and noninvasively monitor brain activity in naturalistic environments for extended periods, thereby overcoming the limitations of conventional imaging modalities that can only acquire data under restricted settings. This capability can furnish unprecedented objective neuroimaging evidence for neuroregenerative therapy research. Moreover, the portability of functional near-infrared spectroscopy allows it to be integrated into neurofeedback training systems: hemoglobin signals can be fed back to participants within milliseconds, enabling targeted, individualized, closed-loop modulation of brain function and considerably expanding the scope of hemodynamics-based neurofeedback. When combined with other brain function assays (such as electroencephalography) and intervention techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation), functional near-infrared spectroscopy also supplies high-temporal-resolution hemodynamic information, laying a critical foundation for the construction of high-precision noninvasive brain-computer interfaces, real-time cognitive-state decoding, and adaptive neuromodulation. Admittedly, almost all existing functional near-infrared spectroscopy studies are still observational and have small sample sizes, short follow-ups, and insufficient controls-shortcomings that together produce low-grade evidence. Therefore, there is still a significant gap before clinical translation can be achieved. Technically, the limited penetration depth of functional near-infrared spectroscopy restricts sampling to the superficial cortex, leaving deep nuclei largely unreachable. In addition, no consensus exists across devices regarding optode layout, light-source choice, motion-artifact correction, or analytical pipelines, creating pronounced heterogeneity that undermines reproducibility. With artificial intelligence and big data analytics advancing rapidly, functional near-infrared spectroscopy embedded within multimodal fusion frameworks is now poised to systematically map aberrant brain function signatures of neurological disorders, identify pathological regions suitable for targeted intervention, and provide real-time assessments of functional changes produced by neuroregenerative therapies.}, } @article {pmid41498587, year = {2026}, author = {Maskell, KG and Cook, AL and King, AE and Dickson, TC and Blizzard, CA}, title = {Modeling amyotrophic lateral sclerosis (ALS) in vitro: from mechanistic studies to translatable drug discovery.}, journal = {Lab on a chip}, volume = {26}, number = {5}, pages = {1108-1122}, doi = {10.1039/d5lc00577a}, pmid = {41498587}, issn = {1473-0189}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Humans ; *Drug Discovery ; Animals ; *Models, Biological ; }, abstract = {Amyotrophic lateral sclerosis is a rapidly progressing, fatal neurodegenerative disease that causes selective degeneration of the corticomotor system. Currently, ALS remains incurable, and the available treatment options offer little in the way of extending life or improving quality of life. This is due, at least in part, to a lack of representative disease models. In vitro modeling offers rapid, experimentally accessible platforms for mechanistic discovery research and drug screening, but modeling the complexity of ALS - a multicellular, multisystem disease - in a dish, is not without its challenges. Here, we review the current landscape of in vitro pre-clinical ALS research, with emphasis on the development of compartmentalised culture and the promise this holds for translatable modeling of ALS.}, } @article {pmid41504056, year = {2025}, author = {Lymperopoulos, A and M'Sadoques, AJ and Stoicovy, RA and Altsman, VL}, title = {Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β2-Adrenergic Receptor Activation.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {12}, pages = {47927}, doi = {10.31083/FBL47927}, pmid = {41504056}, issn = {2768-6698}, support = {R01 #HL155718-01//National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant/ ; #333609-2025//American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship/ ; }, mesh = {*Epinephrine/therapeutic use/pharmacology ; Humans ; *Heart Arrest/drug therapy ; *Receptors, Adrenergic, beta-2/metabolism ; *Vasoconstrictor Agents/therapeutic use/pharmacology ; Cardiopulmonary Resuscitation/methods ; Animals ; }, abstract = {Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β2-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β2AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β2AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.}, } @article {pmid41510529, year = {2026}, author = {Reedy, MB and Abdul Azeem, M and Subramaniam, T and Salamat, S and Rowley, H and Beinlich, B}, title = {Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report.}, journal = {Case reports in neurological medicine}, volume = {2026}, number = {}, pages = {5565739}, pmid = {41510529}, issn = {2090-6668}, abstract = {West Nile virus (WNV) is the most common mosquito-borne infection in North America; while most cases are asymptomatic, fewer than 1% develop neuroinvasive disease with significant morbidity and mortality. We report a 57-year-old man from rural Wisconsin who presented with a 10-week history of progressive asymmetric quadriparesis and severe intractable pain, preceded by fatigue, shoulder pain, and paresthesias. Neurologic examination demonstrated mild encephalopathy, bulbar involvement, and mixed upper and lower motor neuron signs. MRI showed patchy thoracic cord T2 hyperintensities and diffuse lumbar ventral root enhancement. Electrodiagnostic studies revealed diffuse active denervation and reduced compound muscle action potentials, initially raising concern for amyotrophic lateral sclerosis. Elevated WNV IgM and IgG titers in serum and cerebrospinal fluid confirmed neuroinvasive WNV infection. Despite treatment with corticosteroids and intravenous immunoglobulin, the patient deteriorated and was transitioned to hospice care. Autopsy demonstrated T-cell-mediated meningoencephalitis with widespread lymphocytic inflammation involving motor neurons, spinal cord, ventral rootlets, and peripheral nerves, consistent with diffuse axonopathy. This case underscores that neuroinvasive WNV may closely mimic motor neuron disease and emphasizes the importance of serologic testing for accurate diagnosis. Management remains supportive, and outcomes can be severe due to extensive central and peripheral nervous system involvement.}, } @article {pmid41510716, year = {2026}, author = {Bano, A and Khan, AA and Kushwaha, SP and Aleena, and Zaidi, SMH and Misbahul Hasan, S and Fatima, A}, title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure- Activity Relationships and Drug-Receptor Interactions.}, journal = {Mini reviews in medicinal chemistry}, volume = {26}, number = {13}, pages = {1046-1069}, pmid = {41510716}, issn = {1875-5607}, mesh = {Humans ; *Indoles/chemistry/chemical synthesis/pharmacology/therapeutic use ; Structure-Activity Relationship ; *Nervous System Diseases/drug therapy ; Animals ; *Neuroprotective Agents/chemical synthesis/chemistry/pharmacology/therapeutic use ; Molecular Structure ; }, abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

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

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

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

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.}, } @article {pmid41510728, year = {2026}, author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M}, title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249397580251117044621}, pmid = {41510728}, issn = {1875-6166}, abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.}, } @article {pmid41518572, year = {2026}, author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P}, title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {1}, pages = {11}, pmid = {41518572}, issn = {1573-675X}, support = {82171363//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Stress, Physiological ; *Chromosomal Proteins, Non-Histone/metabolism/genetics ; Tumor Suppressor Protein p53/metabolism/genetics ; Animals ; *Neoplasms/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; }, abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.}, } @article {pmid41527739, year = {2026}, author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W}, title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {110}, number = {1}, pages = {5-25}, doi = {10.1177/13872877251411546}, pmid = {41527739}, issn = {1875-8908}, mesh = {Humans ; *Phosphoproteins/metabolism ; *Proteomics/methods ; Biomarkers/metabolism ; *Brain Diseases/metabolism/diagnosis ; Animals ; Phosphorylation ; }, abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.}, } @article {pmid41530082, year = {2026}, author = {Cooper, P and Lu, M and Chan, M and Wilman, A and Kalra, S and Ghavanini, AA}, title = {Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-6}, doi = {10.1017/cjn.2026.10527}, pmid = {41530082}, issn = {0317-1671}, abstract = {OBJECTIVES: Early diagnosis of amyotrophic lateral sclerosis (ALS) is essential for treatment initiation and symptom management, yet it remains challenging due to nonspecific symptoms and the lack of reliable diagnostic biomarkers. Although conventional MRI sequences such as T2* weighted and fluid-attenuated inversion recovery (FLAIR) have shown potential in identifying upper motor neuron abnormalities, their diagnostic utility in ALS is not well established. This study aimed to evaluate the sensitivity and specificity of brain T2* weighted and FLAIR MRI sequences in diagnosing ALS using prospectively collected data and to assess associations with disease severity.

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

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

CONCLUSION: While T2* weighted and FLAIR MRI sequences may have some specificity for ALS, our study suggests they are not sufficiently sensitive to be used as reliable diagnostic tools for ALS.}, } @article {pmid41536515, year = {2026}, author = {Voldřich, R and Svoboda, N and Kachlířová, Z and Bartáková, L and Charvát, F and Netuka, D}, title = {Urodynamic outcomes and prognostic determinants following endovascular treatment of spinal dural arteriovenous fistulas.}, journal = {Brain & spine}, volume = {6}, number = {}, pages = {105913}, pmid = {41536515}, issn = {2772-5294}, abstract = {INTRODUCTION: The prognosis of untreated spinal dural arteriovenous fistulas (SDAVFs) is unfavorable. Current outcome scales used to assess the effect of surgery or endovascular treatment (EVT) rely largely on patient-reported symptoms and may underestimate actual impairment. Moreover, prognostic factors remain debated and conclusions in the literature are inconsistent.

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

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

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

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

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

ETHICS AND DISSEMINATION: This study was approved by the French ethics committee CPP Nord-Ouest I (no. 23.02378.000201). Participant data are anonymised and securely stored in the laboratory's database, accessible only to the research team. Results will be disseminated through peer-reviewed journals and conferences.NCT06199284.}, } @article {pmid41546910, year = {2026}, author = {Elyasi, L and Wężyk, M}, title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {119001}, doi = {10.1016/j.biopha.2026.119001}, pmid = {41546910}, issn = {1950-6007}, mesh = {Humans ; *Exosomes/metabolism/genetics ; *Neurodegenerative Diseases/therapy/genetics/metabolism ; *Tooth, Deciduous/cytology/metabolism ; *MicroRNAs/genetics/metabolism ; Animals ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; Tooth Exfoliation ; }, abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.}, } @article {pmid41549027, year = {2026}, author = {Shenouda, M and Shenouda, S and Kartono, B and Eid, S and Cheng, C and Robertson, J}, title = {Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {1}, pages = {e00834}, pmid = {41549027}, issn = {1878-7479}, mesh = {Animals ; Humans ; *beta Karyopherins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Molecular Chaperones/metabolism ; Mice ; Neurons/drug effects/metabolism ; *TDP-43 Proteinopathies/metabolism/drug therapy/pathology ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.}, } @article {pmid41553108, year = {2026}, author = {Rudnicki, SA and Giacomelli, E and Herder, K and Ingre, C and Kupfer, S and Malik, FI and Meng, L and Paganoni, S and Schellenberg, K and Scirocco, E and Simkins, T and Wei, J and Shefner, JM and , }, title = {The Use of Durable Medical Equipment in COURAGE-ALS, a Phase 3, Multicentre, Randomized Clinical Trial for ALS.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {608-614}, doi = {10.1002/mus.70150}, pmid = {41553108}, issn = {1097-4598}, support = {//Cytokinetics, Incorporated/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Double-Blind Method ; Female ; Male ; Aged ; Middle Aged ; *Durable Medical Equipment/statistics & numerical data ; *Noninvasive Ventilation/instrumentation ; *Wheelchairs ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Durable medical equipment (DME)-wheelchairs, non-invasive ventilation, gastrostomy tubes, and communication devices-provides vital support for individuals with amyotrophic lateral sclerosis (ALS). Here, we describe DME use in COURAGE-ALS evaluating reldesemtiv's efficacy and safety in ALS, to evaluate if DME use can be considered an endpoint of interest in ALS trials.

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

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

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

TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT04944784).}, } @article {pmid41556400, year = {2026}, author = {Howard, I and Lyerly, M and Reimer, R and Patwa, H and Darling, L}, title = {Symptom Burden and Care Satisfaction in US Military Veterans With ALS: Results of a National Survey.}, journal = {Muscle & nerve}, volume = {73}, number = {4}, pages = {623-629}, doi = {10.1002/mus.70147}, pmid = {41556400}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology/diagnosis ; *Veterans/psychology ; United States/epidemiology ; *Patient Satisfaction ; Middle Aged ; Male ; Female ; Symptom Burden ; Surveys and Questionnaires ; Aged ; United States Department of Veterans Affairs ; Adult ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) affects military veterans at a higher rate than the general civilian population. The aim of the present study is to assess symptom burden and satisfaction with care among persons with ALS care enrolled in the US Veterans Health Administration (VA).

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

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

DISCUSSION: This survey indicates that, overall, veterans with ALS receive comprehensive symptom-based care within the nationalized VA care system and report high levels of satisfaction. Furthermore, this study provides baseline data and findings that may be used for quality improvement efforts across a large healthcare system and may serve as a model for similar efforts in other health systems.}, } @article {pmid41557593, year = {2026}, author = {Meyer, T and Maier, A and Grehl, T and Weyen, U and Rödiger, A and Smesny, U and Steinbach, R and Grosskreutz, J and Göricke, B and Bernsen, S and Weydt, P and Fabian, R and Petri, S and Lumi, R and Bjelica, B and Boentert, M and Lingor, P and Kettemann, D and Norden, J and Walter, B and Riitano, A and Schumann, P and Münch, C and Spittel, S}, title = {Minimum important slowing of disease progression as determined by the ALS functional rating scale - a survey of patient expectations toward disease-modifying drugs in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {457-468}, doi = {10.1080/21678421.2026.2615117}, pmid = {41557593}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/psychology/diagnosis ; *Disease Progression ; Female ; Male ; Middle Aged ; Aged ; Surveys and Questionnaires ; Severity of Illness Index ; Adult ; }, abstract = {Objective: To define the minimum important slowing (MIS) of ALS progression that patients would expect from disease-modifying drug treatment in ALS. Methods: In a survey of ALS patients, the MIS in ALS progression (change in the ALS Functional Rating Scale-Revised, ALSFRS-R) was assessed by asking: "At what point of slowing of ALS, as determined by the ALSFRS-R, do you consider a drug to be important?" Data were collected during clinic visits or remotely via the ALS App. Participants were differentiated in the prognostic groups of slower (<0.5), intermediate (≥0.5 and ≤1.0), or faster (>1.0) ALS progression (ALSPR; ALSFRS-R/month). Results: Of 522 participants (ALS App, n = 397; clinic, n = 125), 395 (75.7%) completed the survey, while 127 (24.3%) selected the option "cannot estimate". The distribution of MIS was as follows: modest slowing of ALS progression (5% and 10% slowing, n = 146 patients, 36.9%), moderate slowing (20%, 30%, and 40% slowing, n = 135, 34.2%), and major slowing (≥50% slowing, n = 114, 28.9%). Median MIS was 20% (IQR 10-50%). Patients with faster ALSPR more frequently assessed a major slowing as the MIS (n = 18, 36.0%) compared to those with slower ALSPR (n = 54, 25.2%). Conclusion: A considerable number of participants viewed a modest slowing in ALS progression as the MIS, followed closely by preferences for moderate and major slowing. Expectations varied according to patients' individual ALS progression. These insights may inform the design of future clinical trials in ALS. Study limitations include potential selection and response biases, as well as the predominantly remote digital assessment.}, } @article {pmid41560764, year = {2026}, author = {Ge, Y and Zhu, J and Ren, Y and Wu, X and Zhou, B and Wu, Y and Ge, Y}, title = {Trans-Generational Morphological Trait Plasticity in Parthenogenetic Offspring of Two Brachionus dorcas Morphotypes Induced by Asplanchna Kairomones.}, journal = {Ecology and evolution}, volume = {16}, number = {1}, pages = {e72956}, pmid = {41560764}, issn = {2045-7758}, abstract = {We compared trans-generational (F0-F12) morphological trait plasticity induced by Asplanchna kairomones between two Brachionus dorcas morphotypes (long-posterior spines, LS; short-posterior spines, SS) along with life-table parameters of the non-induced morphotypes. Under control conditions, SS rotifers tended to show higher fertility and smaller body size than LS rotifers. Low kairomone concentrations (50 and 200 ind./L) tended to increase body size in SS offspring, while exposure to 50, 200, and 800 ind./L kairomones induced spine elongation in both morphotypes, with posterolateral spine (PS) length increasing with kairomone concentration. Compared to the F0 generation, offspring of both morphotypes in unexposed controls showed generational fluctuations in body size; LS offspring exhibited shortening or no change in anteromedian spine (AMS) and anterolateral spine (ALS) lengths, while SS offspring showed elongation or no change in these spine lengths and PS length. Across all kairomone treatments, significant elongation of AMS and ALS in LS offspring was typically observed only in later generations, whereas SS offspring exhibited significant elongation from F1 through F12; LS offspring showed significant PS elongation from F2 through F12, with maximum lengths in the later generations (F5-F12), while SS offspring showed significant PS elongation from F1 through F12, peaking in early generations (F2-F4). Notably, the multi-generational mean PS length in SS offspring remained significantly shorter than that in LS offspring under each kairomone treatment. Overall, SS offspring appeared to employ a synergistic defense combining increased body size and spine elongation favoring a "rapid and moderate response," whereas LS offspring exhibited a "slow and extreme defense" strategy. These divergent strategies may result from evolutionary trade-offs involving resource allocation, environmental predictability, and genetic constraints.}, } @article {pmid41562880, year = {2026}, author = {Fiorella, ML and Ballini, L and Lavermicocca, V and Ragno, MS and Restivo, DA and Marchese-Ragona, R}, title = {Dysphagia and Dysarthria in Neurodegenerative Diseases: A Multisystem Network Approach to Assessment and Management.}, journal = {Audiology research}, volume = {16}, number = {1}, pages = {}, pmid = {41562880}, issn = {2039-4330}, abstract = {Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024), focusing on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included "dysphagia", "dysarthria", "neurodegenerative diseases", "neural networks", "swallowing control" and "speech production." Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life.}, } @article {pmid41569095, year = {2026}, author = {Charbonnel, T and Richard, E and Dupuis, A and Palla, M and Vourc'h, P and Corcia, P and Al Ojaimi, Y and Blasco, H}, title = {The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt?.}, journal = {Expert opinion on drug discovery}, volume = {21}, number = {2}, pages = {147-160}, doi = {10.1080/17460441.2026.2619067}, pmid = {41569095}, issn = {1746-045X}, mesh = {*Edaravone/pharmacology/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Drug Discovery/methods ; Neuroprotective Agents/pharmacology/administration & dosage ; Drug Development/methods ; Mice, Transgenic ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/administration & dosage ; Oxidative Stress/drug effects ; Mice ; Blood-Brain Barrier/metabolism ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with limited therapeutic options. Among the few approved drugs, edaravone, a free radical scavenger developed originally for ischemic stroke, has attracted particular attention for its ability to counteract oxidative stress, a key driver of neurodegeneration. Its amphipathic structure and ability to cross the blood-brain barrier support its potential neuroprotective action.

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

EXPERT OPINION: Clinically, edaravone provides modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges in ALS drug discovery, including limited model predictivity, methodological variability, and lack of patient stratification. The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS.}, } @article {pmid41575675, year = {2026}, author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M}, title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.}, journal = {Biogerontology}, volume = {27}, number = {1}, pages = {42}, pmid = {41575675}, issn = {1573-6768}, mesh = {Humans ; *Dysbiosis/microbiology/therapy ; *Aging/physiology ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use ; Animals ; *Nervous System Diseases/microbiology/therapy ; Fecal Microbiota Transplantation ; }, abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.}, } @article {pmid41579929, year = {2026}, author = {Murakami, K and Sudou, N and Kurata, A and Kawaguchi-Niida, M}, title = {An ALS-associated mutant SOD1 protein can be eliminated in microglia culture by selective autophagy.}, journal = {Neuroscience}, volume = {598}, number = {}, pages = {47-58}, doi = {10.1016/j.neuroscience.2026.01.017}, pmid = {41579929}, issn = {1873-7544}, mesh = {Animals ; *Microglia/metabolism/pathology ; *Autophagy/physiology ; Superoxide Dismutase-1/metabolism ; *Superoxide Dismutase/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Mutation ; Spinal Cord/pathology/metabolism ; Mice, Transgenic ; Mice ; Cell Line ; Humans ; Cells, Cultured ; }, abstract = {The acquired toxicity of the familial amyotrophic lateral sclerosis (ALS)-associated mutant Zn-superoxide dismutase 1 (SOD1) protein has been implicated in motoneuron death, and cytosolic aggregates or inclusions have been observed in the cytoplasm of motoneurons, astrocytes, and neuronal axons but not in that of microglia. This study elucidates the mechanisms by which mutant SOD1 does not aggregate in and is cleared by microglia. We generated pcDNA3-Venus-tagged SOD1 constructs: wild-type SOD1 and mutant SOD1 were used as controls, and the A4V, D90A, and G93A SOD1 mutants were used as disease-related constructs; these plasmids were introduced into the Ra2 microglia line for subsequent evaluation. In spinal cords collected from postsymptomatic G93A mice, very little aggregation of the mutant SOD1 protein was detected in microglia, consistent with previous reports. Our new findings, which were based on immunohistochemical, Western blot, and enzyme immunoassay analyses, revealed that the protein expression of mutant SOD1 in microglia is significantly lower than that of wild-type SOD1. Furthermore, we observed the recovery of mutant SOD1 protein levels in autophagy suppression experiments and its colocalization with WDFY3, a selective autophagy-related protein. These in vitro results demonstrate that only the mutant SOD1 protein (i.e., not wild-type SOD1) is degraded by selective autophagy. Furthermore, we found that both wild-type and mutant SOD1 are secreted directly from microglia. These findings provide an opportunity to elucidate the precise mechanism through which microglia manage mutant SOD1 proteins during the pathological process of ALS and are likely to lead to improvements in ALS treatment strategies.}, } @article {pmid41582437, year = {2026}, author = {Chen, X and Cao, Z and Liang, X and Zhao, T and Wang, Y}, title = {TRIM9 and TRIM26 Interact with UBQLN2[P497H] to Modulate Its Proteasomal Degradation.}, journal = {ACS chemical biology}, volume = {21}, number = {2}, pages = {230-234}, pmid = {41582437}, issn = {1554-8937}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Ubiquitin-Protein Ligases/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Tripartite Motif Proteins/metabolism ; *Cell Cycle Proteins/metabolism/genetics ; Proteolysis ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; HEK293 Cells ; Mutation ; Protein Binding ; Autophagy-Related Proteins ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. ALS-linked mutations in UBQLN2 promote protein aggregation and disrupt proteostasis, yet the mutation-specific protein interactomes and their functional relevance remain poorly defined. We employed APEX2 proximity labeling, together with affinity enrichment of biotinylated peptides and LC-MS/MS analysis, to profile the interactomes of wild-type UBQLN2 and two ALS-linked variants, UBQLN2[P497H] and UBQLN2[P497S]. We identified 785 unique biotinylated proteins, many of which exhibit augmented enrichment in the proximity proteomes of the two mutants over wild-type UBQLN2. Notably, the E3 ubiquitin ligases TRIM9 and TRIM26 were selectively enriched in the proximity proteome of UBQLN2[P497H], which we validated by coimmunoprecipitation followed by Western blot analysis. Fractionation analysis revealed coaccumulation of TRIM9 and TRIM26 with UBQLN2[P497H] in the insoluble fraction, consistent with its heightened aggregation propensity. Treatment of UBQLN2[P497H]-expressing cells with a proteasomal inhibitor led to elevated accumulation of a C-terminal UBQLN2 fragment that is absent in cells expressing wild-type UBQLN2 or its P497S mutant. Individual knockdown of TRIM9 and TRIM26 significantly increased the abundance of the fragment, establishing UBQLN2[P497H] as a substrate for TRIM9- and TRIM26-mediated ubiquitinylation and subsequent proteasomal degradation. These findings nominate TRIM9 and TRIM26 as specific interactors of UBQLN2[P497H] and as regulators of a previously underexplored C-terminal UBQLN2 fragment, suggesting that impaired clearance of this species may contribute to ALS pathogenesis.}, } @article {pmid41583971, year = {2018}, author = {Lawson, V and Robbins, NM}, title = {The Potential Misdiagnosis of Multifocal Motor Neuropathy as Amyotrophic Lateral Sclerosis-A Case Series.}, journal = {US neurology}, volume = {14}, number = {2}, pages = {102-107}, pmid = {41583971}, issn = {1758-4000}, support = {K23 NS042713/NS/NINDS NIH HHS/United States ; }, abstract = {Multifocal motor neuropathy (MMN) is a rare neuropathy that is often treatable with immunomodulatory therapy if diagnosed early. However, accurate diagnosis is difficult due to a significant overlap of symptoms with other neurological conditions, such as amyotrophic lateral sclerosis (ALS). Evidence of immunoglobulin M (IgM) anti-ganglioside GM1 antibodies and electrodiagnostic findings of conduction block are useful diagnostic criteria for MMN but are not universal findings. This review explores the differential diagnosis of MMN and ALS and discusses three cases of MMN initially diagnosed as ALS, in which the correct diagnosis allowed effective treatment. These cases highlight the need for greater awareness of MMN among physicians.}, } @article {pmid41585268, year = {2025}, author = {Srivastav, J and Sharma, S}, title = {Viral and non-viral cellular therapies for neurodegeneration.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1718669}, pmid = {41585268}, issn = {2296-858X}, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.}, } @article {pmid41586107, year = {2025}, author = {Berthiaume, AA and Kleist, KN and Reda, SM and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Church, KJ}, title = {ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1582765}, pmid = {41586107}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration, muscle atrophy, and paralysis. The complexity of ALS pathology, driven by factors such as TDP-43 pathology, excitotoxicity, and neuroinflammation, has hindered therapeutic development. While riluzole (an anti-excitotoxic agent) is the current standard treatment, additional therapeutics are needed to address the broad spectrum of ALS-related pathology. ATH-1105, a small-molecule positive modulator of hepatocyte growth factor (HGF) signaling, has shown promise in preclinical models of ALS. Given the multifactorial nature of ALS and the growing recognition that combination approaches may represent the best treatment options, we investigated the therapeutic potential of ATH-1105 in a TDP-43-driven mouse model of ALS, by comparing and combining it with the known efficacious treatment of riluzole. Additionally, we characterize the mechanism by which ATH-1105 induces neuroprotective effects, emphasizing its effects on TDP-43 pathology.

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

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

DISCUSSION: Our study underscores the therapeutic potential of ATH-1105 in treating ALS, both as a standalone treatment and in combination with riluzole. ATH-1105 demonstrates neuroprotective effects that slow neuromuscular deterioration in a relevant mouse model, aligning with the need to counteract the neurodegeneration central to ALS.}, } @article {pmid41588889, year = {2026}, author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R}, title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.}, journal = {Current Alzheimer research}, volume = {23}, number = {4}, pages = {245-269}, pmid = {41588889}, issn = {1875-5828}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *RNA, Untranslated/therapeutic use/genetics ; Animals ; MicroRNAs ; *Genetic Therapy/methods ; Drug Delivery Systems ; }, abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.}, } @article {pmid41592787, year = {2026}, author = {Mammone, RM and Willis, E and Ruivo, P and Finesso, GE and Cox, A and Assenmacher, CA and Radaelli, E and Piersigilli, A and Miranda, IC}, title = {Pathology associated with human CAR T cell administration in NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice: A retrospective analysis.}, journal = {Veterinary pathology}, volume = {63}, number = {3}, pages = {462-477}, pmid = {41592787}, issn = {1544-2217}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice, Inbred NOD ; Retrospective Studies ; Mice ; Humans ; *Receptors, Chimeric Antigen/immunology ; Graft vs Host Disease/pathology ; *Immunotherapy, Adoptive/adverse effects/veterinary ; Female ; *T-Lymphocytes/immunology ; Mice, SCID ; Disease Models, Animal ; }, abstract = {Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for neoplasia and autoimmune diseases. Immunocompromised mice are a common model to test the efficacy and safety of CAR T cells of human origin. Preclinical toxicity associated with human CAR T-cell products encompasses a spectrum of morphologic changes, with currently limited documentation in the scientific literature. The purpose of this retrospective study was to characterize the histopathologic features associated with human CAR T-cell administration in immunodeficient NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice (n = 392) submitted to 3 different academic institutions in the United States between 2017 and 2024. Lesions were categorized into xenogeneic graft-versus-host disease (xGvHD) (n = 287), aberrant proliferation of human T cells (n = 188), vascular pathologies (n = 66), on-target/off-tumor (OTOT) toxicity (n = 44), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) in mice previously humanized with human CD34+ hematopoietic stem cells (HSCs) (n = 21), and acute lysis syndrome (ALS) (n = 5). This study provides veterinary pathologists with descriptive guidance on the pathology associated with human CAR T-cell therapy in immunodeficient mice. Additional molecular data and detailed information related to each construct are necessary to further investigate the translatability of such liabilities to the clinical setting.}, } @article {pmid41593242, year = {2026}, author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.}, journal = {Nature immunology}, volume = {27}, number = {2}, pages = {323-335}, pmid = {41593242}, issn = {1529-2916}, support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; P30 AG066462/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; RF1 NS142171/NS/NINDS NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; *Meninges/immunology/pathology ; Brain/immunology/pathology ; Microglia/immunology/metabolism ; *Alzheimer Disease/immunology/pathology ; Female ; Receptors, Antigen, T-Cell/genetics ; *Neurodegenerative Diseases/immunology ; *Parkinson Disease/immunology ; Aged ; *Amyotrophic Lateral Sclerosis/immunology ; Male ; Memory T Cells/immunology ; Animals ; }, abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.}, } @article {pmid41594924, year = {2026}, author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C}, title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.}, journal = {Biology}, volume = {15}, number = {2}, pages = {}, pmid = {41594924}, issn = {2079-7737}, abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.}, } @article {pmid41596266, year = {2026}, author = {Ryu, IS and Ha, DI and Jung, YJ and Lee, HJ and Kim, I and Lim, YN and Min, HS and Kim, SH and Yoon, I and Cho, HJ and Ryu, JH}, title = {Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis.}, journal = {International journal of molecular sciences}, volume = {27}, number = {2}, pages = {}, pmid = {41596266}, issn = {1422-0067}, support = {RS-2023-00283779//Ministry of SMEs and Startups/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; *MicroRNAs/genetics/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Nanoparticles/chemistry ; Mice ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/pathology ; Humans ; *Oligonucleotides, Antisense/administration & dosage/pharmacology ; Disease Models, Animal ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1[G93A]-expressing HMC3 microglial cells and in the spinal cords of SOD1[G93A] transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1[G93A] transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease.}, } @article {pmid41599185, year = {2026}, author = {Benech, H and Flament, V and Lhotellier, C and Roucairol, C and Joudinaud, T}, title = {New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599185}, issn = {1999-4923}, abstract = {Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.}, } @article {pmid41599225, year = {2026}, author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K}, title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.}, journal = {Pharmaceutics}, volume = {18}, number = {1}, pages = {}, pmid = {41599225}, issn = {1999-4923}, support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; }, abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.}, } @article {pmid41603250, year = {2026}, author = {Naumann, M and Wierschin, TM and Kretschmer, S and Dash, BP and Held, A and Salzinger, A and Peikert, K and Karlek, A and Glaß, H and Großmann, D and Günther, R and Petri, S and Rödiger, A and Brenner, D and Pan-Montojo, F and Aronica, E and Kipp, M and Zimyanin, V and Sterneckert, J and Grehl, T and Seebacher, ND and Böckers, TM and Catanese, A and Wainger, BJ and Oeckl, P and Lee-Kirsch, MA and Hermann, A}, title = {RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New Biomarker-Driven Individualized Treatment Options for (FUS-)ALS.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {18}, pages = {e17135}, pmid = {41603250}, issn = {2198-3844}, support = {CRC237 369799452/B21//German Research Foundation (DFG)/ ; CRC237 369799452/A11//German Research Foundation (DFG)/ ; CRC369 501752319/C06//German Research Foundation (DFG)/ ; 01GM2206C (GAIN)//German Federal Ministry of Education and Research (BMBF)/ ; 01GL2405H (DZKJ)//German Federal Ministry of Education and Research (BMBF)/ ; na//Stichting ALS Nederland/ ; na//Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; //Clinician Scientist program of the Medical Faculty of the University of Rostock (RAS)/ ; //Stichting ALS Nederland/ ; //Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; }, mesh = {Humans ; *Receptors, Immunologic/metabolism ; Signal Transduction/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Biomarkers/metabolism ; *DEAD Box Protein 58/metabolism/genetics ; *Motor Neurons/metabolism ; *Interferon Type I/metabolism/genetics ; cGAS-STING Signaling Pathway ; Immunity, Innate/genetics ; }, abstract = {Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUS[mut] iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUS[mut] sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUS[wt] sMNs phenocopied the axonal degeneration of FUS[mut] sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.}, } @article {pmid41605460, year = {2026}, author = {Martínez-Alesón, P and Benito-Casado, C and Fernández-Martos, CM and Polanco Mora, MJ}, title = {Pleiotrophin/Midkine Pathway Is Dysregulated in a TDP-43[A315T] Mouse Model of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {46}, number = {1}, pages = {e70044}, pmid = {41605460}, issn = {1440-1789}, support = {FUSPBS-PPC03/2018//University San Pablo CEU-Santander precompetitive grants/ ; SBPLY/17/180501/000303//Junta de Comunidades de Castilla-la Mancha/ ; PIPF-2023/SAL-GL-29613//Consejería de Educación, Ciencia y Universidades Comunidad de Madrid/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Midkine/metabolism ; *Cytokines/metabolism ; *Carrier Proteins/metabolism ; Mice ; Disease Models, Animal ; Signal Transduction/physiology ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; DNA-Binding Proteins/genetics ; Humans ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by progressive degeneration of both upper and lower motor neurons, along with skeletal muscles innervated by them. The identification of key molecules involved in disease pathology remains crucial for ALS, as no curative treatment is currently available. Pleiotrophin (PTN) and midkine (MK) are closely related, heparin-binding cytokines with overlapping effects. These molecules have been shown to be neuroprotective by modulating neuroinflammation, supporting neuronal survival, growth, and differentiation, and enhancing synaptic strength and plasticity. Despite their reported neuroprotective properties, the involvement of PTN and MK signaling in ALS has not been previously investigated. In this study, we characterized the expression of the PTN/MK pathway in the lumbar spinal cords (SCs) of TDP-43[A315T] mice across different disease stages. We report a significant upregulation of Ptn, Mdk, and its receptor protein tyrosine phosphatase zeta (Ptprz1) mRNA levels at end-stage of disease in the lumbar SC of TDP-43[A315T] mice compared with age-matched wild-type littermates. Protein levels of PTN and MK were also upregulated at end-stage of disease. By immunofluorescence analysis, we also observed an upregulation of the immunostaining of both cytokines in neurons, astrocytes, microglia, and pericytes-like structures at end-stage of disease in the SC of TDP-43[A315T] mice. These findings open a new avenue to further study the potential role of the PTN/MK signaling axis in the pathogenesis of ALS. Trial Registration: Animal Ethics Committee of the Hospital Nacional de Parapléjicos in Toledo (Spain): Approval No. 26/OH 2018.}, } @article {pmid41607656, year = {2025}, author = {Ha, LL and Mitra, S and Ho, DT and Fillingham, B and Berry, JD and Swoboda, KJ and Alves, CRR}, title = {Circulating Tau Profiles in Pediatric and Adult Patients with Spinal Muscular Atrophy.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41607656}, support = {K01 NS134784/NS/NINDS NIH HHS/United States ; R01 HD054599/HD/NICHD NIH HHS/United States ; R21 NS108015/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: To determine alterations in circulating Tau and phosphorylated Tau (pTau) profiles in pediatric and adult patients with spinal muscular atrophy (SMA).

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

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

CONCLUSIONS: Circulating Tau, particularly pTau-262, may serve as a disease-relevant biomarker in adult SMA, while pediatric profiles appear more heterogeneous. Transient Tau elevations after gene therapy may reflect acute neuronal vulnerability and warrant further investigation.}, } @article {pmid41609131, year = {2026}, author = {García Estévez, DA}, title = {Effectiveness of Risdiplam Treatment in Adult Patients With Spinal Muscular Atrophy Type IIb-III.}, journal = {Revista de neurologia}, volume = {81}, number = {1}, pages = {44408}, pmid = {41609131}, issn = {1576-6578}, support = {SP240424010//Roche/ ; }, mesh = {Humans ; Female ; Adult ; Male ; *Spinal Muscular Atrophies of Childhood/drug therapy/blood/physiopathology ; Middle Aged ; Treatment Outcome ; Aged ; *Pyrimidines/therapeutic use ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Azo Compounds ; }, abstract = {INTRODUCTION: Risdiplam is a pharmacological agent developed for the treatment of spinal muscular atrophy (SMA) associated with 5q deletion, with the therapeutic objective of increasing the concentration of the survival motor neuron 2 protein. Most clinical trials and real-world studies have focused on pediatric and young adult populations. Our aim was to assess the effectiveness of risdiplam treatment in adult patients with SMA type IIb and III.

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

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

CONCLUSIONS: In our series, treatment with risdiplam may stabilize adult patients with type IIb-III SMA.}, } @article {pmid41616079, year = {2026}, author = {Steenkjaer, CH and Storgaard, JH and Levison, L and Blicher, JU}, title = {A national survey of pseudobulbar affect and symptomatic treatment in Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {565-571}, doi = {10.1080/21678421.2026.2620448}, pmid = {41616079}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/diagnosis ; Female ; Cross-Sectional Studies ; *Pseudobulbar Affect/epidemiology/diagnosis/etiology/drug therapy/therapy ; Male ; Middle Aged ; Aged ; Denmark/epidemiology ; Prevalence ; Antidepressive Agents/therapeutic use ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: We aimed to determine diagnostic prevalence and symptom burden of pseudobulbar affect (PBA) in patients with Amyotrophic Lateral Sclerosis (ALS) in Denmark and differences in ongoing symptomatic treatment.

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

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

CONCLUSIONS: The proportion of diagnosed PBA among the study population was low compared to previous studies; however, the proportion of patients with symptoms of possible PBA was markedly higher. Patients with known PBA were more likely to receive recommended symptomatic treatment compared to patients not diagnosed with PBA, despite symptoms indicative of PBA. These findings highlight the potential underrecognition of PBA in ALS and concurrent absence of symptomatic treatment.}, } @article {pmid41618386, year = {2026}, author = {Omranikhoo, H and Rezaee, M and Verdizadeh, A and Goudarzi, Z and Jafari, M and Gholami, A and Poursadeghfard, M and Keshavarz, K}, title = {Cost-utility analysis of Edaravone compared to Riluzole in patients with amyotrophic lateral sclerosis (ALS) in Iran.}, journal = {Cost effectiveness and resource allocation : C/E}, volume = {24}, number = {1}, pages = {}, pmid = {41618386}, issn = {1478-7547}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating disease that damages motor neurons. Currently, two drugs, Riluzole and Edaravone, have been shown to slow the progression of this condition. This study aimed to evaluate the cost-utility of Edaravone compared to Riluzole in ALS patients.

METHODS: This is an economic evaluation and cost-utility analysis from Iran’s health system perspective using a 10-year and 20-year Markov model. Cost data were collected from medical records and expert interviews, while clinical outcomes and transition probabilities were obtained from a clinical trial study. The robustness of the findings was tested through both deterministic and probabilistic sensitivity analysis. Data was analyzed using Excel 2019 and TreeAge Pro 2020 software.

RESULTS: The findings of this study indicated that the cost of treatment and QALYs obtained from Edaravone (58,077 PPP$ and 1.66) compared to Riluzole (53,216 PPP$ and 1.37) were estimated to be higher in Iran. The calculated ICUR was equal to 16,704 PPP$ which is considered to be a cost-effective option in terms of the cost-effectiveness threshold to treat the patients with ALS. Furthermore, a one-way sensitivity analysis showed that the model is most affected by the cost discount rate and the price of Edaravone. Edaravone was identified as the best treatment strategy in 66% of simulations, making it the preferred option across different willingness to pay scenarios.

CONCLUSION: The findings of the study indicated that the Edaravone may be a more cost-effective and affordable option compared to the Riluzole. Consequently, the availability of this drug in the country is likely to improve the quality of life and increase the survival rates of patients.}, } @article {pmid41626035, year = {2025}, author = {Jackson, MC and Azarraga, RB and Fraix, MP and Agrawal, DK}, title = {Stage-Based Communication Rehabilitation in Amyotrophic Lateral Sclerosis (ALS): A Review of Strategies for Enhancing Quality of Life.}, journal = {Archives of internal medicine research}, volume = {8}, number = {4}, pages = {359-371}, pmid = {41626035}, issn = {2688-5654}, support = {R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable progressive degenerative neuromuscular disease. One way ALS affects patients is through dysarthria significantly impacting a patient's quality of life by affecting their ability to communicate. This makes maintaining relationships, identity and autonomy difficult, all of which affect psychological wellbeing - a determinant of the quality of life. Dysarthria makes communication difficult, and because the regions affected by ALS first are different for each patient, creating strategies for rehabilitating communication can be challenging. In this review we explore the different communication rehabilitation options available and organize them based on if they are usable based on the onset of intelligibility and locked in state. Interventions before the onset of intelligibility in the early stage are proactive measures such as voice banking and education which empower patient autonomy and a sense of control. Interventions between onset of intelligibility and the locked-in state in the middle stage are alternative and augmentative communication strategies varied in accessibility and usability in patients based on their preferences and functional ability. Late-stage interventions which work after a patient with ALS has entered a locked-in state, are the most technologically advanced alternative and augmentative communication devices and rehabilitate function inaccessible by other methods in this disease stage. While assessing patient values and recommending interventions which meet patient needs is most important in rehabilitation of communication in patient with ALS, using a stage-based approach to evaluate and recommend the treatment of dysarthria and communication rehabilitation will optimize quality of life throughout the progression of disease.}, } @article {pmid41626491, year = {2026}, author = {Akimoto, Y and Miyamae, Y and Shigemori, H}, title = {Effects of Cyanidin Derivatives for the Aggregation of Cu/Zn Superoxide Dismutase 1.}, journal = {ACS omega}, volume = {11}, number = {3}, pages = {3849-3865}, pmid = {41626491}, issn = {2470-1343}, abstract = {Cu/Zn superoxide dismutase 1 (SOD1), whose aggregation is considered cytotoxic, is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Therefore, inhibiting SOD1 aggregation may represent a promising strategy for the treatment and prevention of this disease. We first screened seven polyphenols using an optimized thioflavin T (Th-T) assay and found that cyanidin exhibited the strongest inhibitory activity among the seven polyphenols. We then compared cyanidin with its derivatives(?)delphinidin, petunidin, malvidin, and cyanidin-3-glucoside (C3G). In this study, we concluded that delphinidin had the strongest antifibrillation activity among the five cyanidin derivatives. Turbidity, transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), circular dichroism (CD) spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy indicated that the inhibitory activity was influenced by the number of phenolic hydroxyl groups on the B-ring of the cyanidin derivatives. Based on the LDH assay, delphinidin was the most effective compound in preventing the formation of cytotoxic SOD1 aggregates in the cells. Furthermore, we found that the compounds also interfered with the SOD1 cross-linking. Finally, we transfected GFP-SOD1A4 V into Neuro2a cells and observed that the compounds' inhibitory activity on intracellular aggregation was limited.}, } @article {pmid41628987, year = {2026}, author = {Xue, X and Cui, H and Hu, S and Ma, H and Wei, S and Huang, H and Li, X and Huang, Z}, title = {Both target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Silene conoidea L.}, journal = {Pesticide biochemistry and physiology}, volume = {218}, number = {}, pages = {106905}, doi = {10.1016/j.pestbp.2025.106905}, pmid = {41628987}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Molecular Docking Simulation ; Mutation ; }, abstract = {Silene conoidea L., a common weed in wheat fields, is mainly controlled by acetolactate synthase (ALS)-inhibiting herbicides such as mesosulfuron-methyl. In this study, we investigated a mesosulfuron-methyl resistant population to elucidate the resistance mechanisms. The resistant (R) population displayed a high level of resistance to mesosulfuron-methyl, with the resistance index (RI) of 18.87. It also exhibited cross-resistance to halosulfuron-methyl, florasulam, flumetsulam, and flucarbazone‑sodium. In vitro ALS enzyme activity in the R population was 22.85-fold higher than in the susceptible (S) population. A W574L mutation (leucine replaced tryptophan) was identified in the ALS gene of the R population. Through molecular docking, this substitution of amino acid weakened the π-π stacking interaction between mesosulfuron-methyl molecule and the non-mutated ALS enzyme. The R population also showed significantly higher ALS expression than the S population, while the ALS gene copy number did not differ between the two populations. Pretreatment with malathion (cytochrome P450 inhibitor) and NBD-Cl (glutathione S-transferases inhibitor) reduced mesosulfuron-methyl resistance by 43.92 % and 29.20 %, respectively. Indicating that CYP450s and GSTs are involved in resistance. Transcriptome and qPCR analyses identified significant upregulation of three ABC transporter genes, three CYP450 genes, and one GST gene in the R population. Meanwhile, KEGG pathway analysis indicated that the photosynthetic pathways were significantly affected after mesosulfuron-methyl treatment. This is the first report of mesosulfuron-methyl resistance in S. conoidea, involves both target site resistance and non-target site resistance mechanisms.}, } @article {pmid41640104, year = {2026}, author = {Karros, M and DiFulco, M and Nogid, A}, title = {Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {60}, number = {8}, pages = {795-804}, doi = {10.1177/10600280251408862}, pmid = {41640104}, issn = {1542-6270}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Superoxide Dismutase-1/genetics/cerebrospinal fluid ; *Oligonucleotides, Antisense/administration & dosage/therapeutic use/adverse effects ; Animals ; }, abstract = {OBJECTIVE: This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).

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

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

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

CONCLUSION: Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.}, } @article {pmid41641779, year = {2026}, author = {Varderidou-Minasian, S and Jakobs, CE and Pasteuning-Vuhman, S and Gal, L and Timmers, A and Altelaar, M and Lorenowicz, MJ and Pasterkamp, RJ}, title = {Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.}, journal = {Neural regeneration research}, volume = {21}, number = {10}, pages = {5035-5043}, pmid = {41641779}, issn = {1673-5374}, abstract = {Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell–derived motor neurons carrying amyotrophic lateral sclerosis–associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell–derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell–derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell–derived extracellular vesicles as a versatile therapeutic approach.}, } @article {pmid41642483, year = {2026}, author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS}, title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.}, journal = {Cellular and molecular neurobiology}, volume = {46}, number = {1}, pages = {43}, pmid = {41642483}, issn = {1573-6830}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Neuroglia/metabolism/pathology ; *Gonadal Steroid Hormones/metabolism ; }, abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.}, } @article {pmid41649614, year = {2026}, author = {Mukherjee, R and Mehan, S and Choudhary, D and Rana, R and Das Gupta, G and Samant, R and Tongra, M}, title = {Sulforaphane-Mediated Multitarget Therapeutic Effects in Methylmercury-Induced ALS-Like Pathology: Comparative Analysis and Multifaceted Approach to Neuroprotection and Systemic Recovery.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {422}, pmid = {41649614}, issn = {1559-1182}, mesh = {Animals ; Sulfoxides/pharmacology/therapeutic use ; *Isothiocyanates/pharmacology/therapeutic use ; Female ; Methylmercury Compounds/toxicity ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/chemically induced/physiopathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Recovery of Function/drug effects ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Rats ; Antioxidants/metabolism ; Signal Transduction/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss driven by oxidative stress, neuroinflammation, and dysregulated survival signaling. The objective of this study was to evaluate the neuroprotective efficacy and safety of sulforaphane (SUFP) in a methylmercury (MMHg[+])-induced preclinical rat model of ALS, with comparison to omaveloxolone (OVX) and dimethyl fumarate (DIMT). SUFP treatment, particularly at 4 mg/kg, significantly restored antioxidant defense mechanisms through upregulation of Nrf2, HO-1, and SIRT1 while suppressing pro-inflammatory cytokines (IL-1β, TNF-α), apoptotic markers (Bax, caspase-3), and stress-related signaling pathways including p75NTR, PI3K/Akt, and MAPKs. These molecular effects translated into meaningful functional recovery, as evidenced by improvements in grip strength, locomotor performance, spatial memory, and depressive-like behavior. Histopathological evaluation demonstrated attenuation of demyelination and preservation of neuronal architecture in cortical, hippocampal, and cerebellar regions. Beyond central neuroprotection, SUFP exerted systemic benefits by normalizing hepatic enzymes, improving skeletal muscle integrity, restoring redox balance, stabilizing neurofilament and myelin-associated proteins, and correcting hematological alterations. Comparative analysis revealed that SUFP conferred superior neuroprotection with a favorable safety profile relative to OVX and, although slightly less efficacious than DIMT, exhibited reduced systemic toxicity. Molecular docking further supported SUFP's interaction with Nrf2-Keap1 targets, reinforcing its antioxidant and anti-inflammatory mechanisms. Collectively, these findings identify SUFP as a multifaceted and well-tolerated therapeutic candidate for ALS, supporting its further translational and clinical evaluation.}, } @article {pmid41651385, year = {2026}, author = {Raina, GS and Mehan, S and Das Gupta, G}, title = {Neuroprotection via IGF-1 neuronal signaling activation by melatonin and edaravone synergy in methylmercury-induced ALS-like neurotoxicity: Comprehensive analysis of brain regions, spinal cord, CSF, and blood plasma.}, journal = {Neurotoxicology}, volume = {113}, number = {}, pages = {103398}, doi = {10.1016/j.neuro.2026.103398}, pmid = {41651385}, issn = {1872-9711}, mesh = {Animals ; *Methylmercury Compounds/toxicity ; Rats ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Melatonin/pharmacology/administration & dosage ; *Brain/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/chemically induced/metabolism/drug therapy ; Signal Transduction/drug effects ; *Edaravone/pharmacology/administration & dosage ; *Insulin-Like Growth Factor I/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Male ; Drug Synergism ; Oxidative Stress/drug effects ; Neurons/drug effects/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5 mg/kg (MLT5) and 10 mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.}, } @article {pmid41652348, year = {2026}, author = {Johansen, H and Nakken, O and Holmøy, T and Fredheim, OMS}, title = {Disease trajectories and end of life care in a Norwegian ALS cohort.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {41652348}, issn = {1471-2377}, mesh = {Humans ; *Terminal Care/methods/statistics & numerical data ; Norway/epidemiology ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; *Palliative Care ; Female ; Male ; Aged ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; }, abstract = {OBJECTIVE: This retrospective cohort study aims to provide comprehensive data on the disease trajectory and end-of-life care in patients dying from ALS.

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

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

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

TRIAL REGISTRATION: Retrospectively registered.}, } @article {pmid41653003, year = {2026}, author = {Brooks, BR and Shefner, J and Apple, S}, title = {Study 19 (MCI186-19) Post Hoc Analyses.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S19-S22}, pmid = {41653003}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; Treatment Outcome ; Disease Progression ; Female ; Male ; *Free Radical Scavengers/therapeutic use ; }, abstract = {While randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of therapies in amyotrophic lateral sclerosis (ALS), post hoc analyses can provide critical insights into clinical effectiveness, treatment durability, and subpopulation responses. Several post hoc analyses of Study MCI186-19 (Study 19), the pivotal phase 3 RCT that supported the United States Food and Drug Administration approval of intravenous edaravone, have been performed to explore the broader clinical impact of this therapy. These analyses assessed the long-term treatment efficacy, changes in individual ALS Functional Rating Scale-Revised item scores, survival and additional milestone events, and the impact of edaravone in patient subgroups defined by disease progression trajectories using latent class analysis. Collectively, these findings reinforce the long-term clinical benefit of edaravone and demonstrate that edaravone may offer benefits across a spectrum of ALS disease trajectories, beyond those defined in the original study criteria. These studies help address questions not captured in the original RCT and may inform future trial design and treatment decisions.}, } @article {pmid41653004, year = {2026}, author = {Brooks, BR and Berry, JD and Ciepielewska, M}, title = {Survival of Intravenous Edaravone-Treated Patients With ALS: Evidence From Administrative Claims Analyses.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S23-S25}, pmid = {41653004}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Edaravone/administration & dosage/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Female ; Retrospective Studies ; Male ; Aged ; Middle Aged ; *Free Radical Scavengers/administration & dosage/therapeutic use ; Administration, Intravenous ; United States/epidemiology ; Treatment Outcome ; }, abstract = {Randomized controlled trials remain the cornerstone of evidence generation in amyotrophic lateral sclerosis (ALS), yet their inherent challenges, including disease rarity, heterogeneity, and limited validated biomarkers, highlight the need for complementary clinical evidence. This exploratory, retrospective study assessed overall survival in patients with ALS treated with intravenous (IV) edaravone using data from a large United States administrative claims database of patients enrolled from August 2017 to March 2020. Patients receiving IV edaravone (n = 318) were propensity score matched 1:1 with controls not treated with IV edaravone (n = 318), adjusting for 11 covariates. Median overall survival was 29.5 versus 23.5 months for the edaravone-treated group compared to controls, with a 27% reduced risk of death observed in the treated cohort (p = 0.005). These findings, together with existing data from the pivotal phase 3 Study MCI186-19 of IV edaravone, contribute to the growing body of literature suggesting a dual benefit of edaravone on both function and survival in ALS, offering critical insights for clinicians, patients, and payers navigating ALS treatment decisions.}, } @article {pmid41653005, year = {2026}, author = {Genge, A and Apple, S}, title = {Safety of Intravenous Edaravone in Clinical Practice.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S13-S15}, pmid = {41653005}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; Edaravone ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Antipyrine/analogs & derivatives/adverse effects/administration & dosage/therapeutic use ; *Free Radical Scavengers/adverse effects/administration & dosage ; Administration, Intravenous ; Female ; Pharmacovigilance ; Male ; Middle Aged ; Aged ; }, abstract = {This article summarizes the post-marketing pharmacovigilance safety data of intravenous (IV) edaravone during the 1- and 3-year periods following its launch for amyotrophic lateral sclerosis (ALS) in the United States. The most frequently reported adverse events (AEs) and serious AEs (SAEs) included those consistent with ALS disease progression, such as fatigue and muscular weakness, and were not qualitatively different from those reported in previous ALS trials. There were AEs and SAEs associated with IV administration, such as administration site reactions, and five non-fatal anaphylaxis SAEs were reported. No new safety signals were identified, and IV edaravone continues to demonstrate a favorable safety profile. These insights are especially useful as treatment transitions to edaravone oral suspension, which avoids IV-related complications. These findings underscore the importance of ongoing clinical safety assessments in informing ALS treatment decisions.}, } @article {pmid41653006, year = {2026}, author = {Gwathmey, KG and Apple, S}, title = {Introduction to the Supplement.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S3-S6}, pmid = {41653006}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with marked phenotypic and clinical heterogeneity. Three active pharmaceutical agents are currently approved by the United States Food and Drug Administration (FDA) for ALS: riluzole, edaravone (including intravenous [IV] and oral suspension formulations), and tofersen. Study MCI186-19 (Study 19) was a pivotal, phase 3 randomized controlled trial that demonstrated a significant reduction in physical functional decline vs. placebo in Japanese patients with ALS and contributed to FDA approval of IV edaravone in 2017. Edaravone oral suspension was FDA-approved in May 2022 following the results of Study MT-1186-A01, which showed it was well tolerated with a safety profile consistent with IV edaravone. Following Study 19, the clinical benefit of edaravone has remained an active area of investigation. This supplement presents data from clinical trials, post hoc analyses, and clinical studies that expand understanding of the use of edaravone in broader ALS populations. Topics include safety in clinical practice, generalizability of efficacy, clinical treatment outcomes, and health economics and outcomes research studies. Together, these findings aim to inform clinicians, researchers, and stakeholders regarding the evolving evidence base for edaravone in the management of ALS.}, } @article {pmid41653008, year = {2026}, author = {Brooks, BR and Ennist, DL and Beaulieu, D and Apple, S}, title = {Generalizability of Edaravone Efficacy.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S16-S18}, pmid = {41653008}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Female ; Male ; Treatment Outcome ; *Free Radical Scavengers/therapeutic use ; Middle Aged ; Aged ; Disease Progression ; Vital Capacity/drug effects ; Retrospective Studies ; }, abstract = {The pivotal phase 3 trial MCI186-19 (Study 19) demonstrated the efficacy of intravenous edaravone in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS), leading to United States Food and Drug Administration approval. Study 19 utilized a targeted enrollment enrichment strategy based on post hoc analyses from earlier trials, selecting patients with higher baseline function, more rapid disease progression, and better respiratory status. To evaluate the generalizability of Study 19 results, subsequent post hoc analyses assessed the efficacy of edaravone in broader ALS populations. One machine learning-based analysis retrospectively applied a validated model to Study 16 data, stratifying patients by predicted risk of respiratory decline. This detectable effect cluster analysis suggested that up to 70% of Study 16 participants may have benefited from edaravone. A second analysis investigated edaravone efficacy in patients from Study 19 with forced vital capacity (FVC) < 80% predicted (%p) at the start of treatment, since FVC ≥ 80%p was one of the Study 19 inclusion criteria. Both high- and low-FVC subgroups demonstrated reduced ALS functional rating scale-revised decline at 48 weeks when treated continuously with edaravone. These findings support the potential benefit of edaravone in a wider range of patients with ALS than those enrolled in Study 19, providing important insights into how clinical trial enrichment strategies may influence perceived efficacy, and underscoring the need for future prospective studies in more diverse ALS populations.}, } @article {pmid41653010, year = {2026}, author = {Abrahao, A and Zinman, L and Apple, S}, title = {Current and Ongoing Clinical Studies.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S26-S28}, pmid = {41653010}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/therapeutic use ; *Clinical Trials as Topic ; *Free Radical Scavengers/therapeutic use/administration & dosage ; *Antipyrine/analogs & derivatives/therapeutic use/administration & dosage ; }, abstract = {This article provides a comprehensive overview of current and ongoing studies evaluating intravenous (IV) edaravone and edaravone oral suspension in the treatment of amyotrophic lateral sclerosis (ALS). In addition to data from clinical practice and post hoc analyses, multiple observational and interventional studies are underway to better understand the efficacy, safety, and biological impact of edaravone in clinical settings. Key studies include SUNRISE Japan, a long-term postmarketing surveillance study of IV edaravone in Japanese patients with ALS; the ALS/Motor Neuron Disease Natural History Study, a longitudinal registry designed to inform clinical trial design and track ALS progression; and the REFINE-ALS study, which is actively collecting biomarker data to elucidate the pathophysiologic mechanisms influenced by edaravone. For edaravone oral suspension, United States Food and Drug Administration approval was supported by Study MT-1186-A01, a phase 3 trial assessing safety and tolerability over 48 weeks, with extension Study MT-1186-A03. Study MT-1186-A02, conducted as an FDA postmarketing commitment, and its extension, Study MT-1186-A04, evaluated whether investigational once daily dosing showed superior efficacy vs. the approved on/off dosing regimen. Collectively, these studies contribute to a growing body of evidence supporting the use of edaravone as a therapeutic option for ALS. They also underscore the importance of continued data collection from both clinical trials and clinical settings to inform optimal treatment strategies and combination therapy approaches as more agents become available in an evolving ALS treatment landscape.}, } @article {pmid41653014, year = {2026}, author = {Abrahao, A and Ciepielewska, M and Zinman, L}, title = {Value of Clinical Evidence and Health Economics and Outcomes Research (HEOR) Studies.}, journal = {Muscle & nerve}, volume = {73 Suppl 1}, number = {Suppl 1}, pages = {S7-S12}, pmid = {41653014}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America, Inc./ ; }, mesh = {Humans ; *Outcome Assessment, Health Care ; Amyotrophic Lateral Sclerosis/economics/therapy ; Randomized Controlled Trials as Topic ; *Evidence-Based Medicine ; *Economics, Medical ; }, abstract = {Randomized controlled trials (RCTs) remain the gold standard for establishing the efficacy and safety of new treatments. However, clinical evidence derived from the systematic analysis of real-world data generated through routine clinical practice can complement RCT data by offering insights into treatment performance in broader, more heterogeneous patient populations and clinical care settings. The integration of high-quality clinical evidence into health economics and outcomes research (HEOR) is increasingly important, as it supports healthcare decision-making across multiple stakeholders, including regulatory agencies, payers, clinicians, and patients. Multiple study designs, such as pragmatic trials, hybrid RCTs, external control arms, and observational studies, can provide valuable clinical evidence beyond the controlled trial setting. These data can enhance understanding of comparative effectiveness, patient-reported outcomes, treatment safety, and healthcare utilization and costs. The field of amyotrophic lateral sclerosis offers a compelling example of how clinical evidence derived from global registries and clinical studies has advanced understanding of disease epidemiology, treatment patterns, and the effectiveness of therapies, including riluzole and edaravone. Consequently, this review and the associated supplementary articles are meant to serve as a primer to inform clinicians of the potential contribution of clinical evidence to HEOR studies.}, } @article {pmid41656808, year = {2025}, author = {Yu, C and Zeng, W and Meekrathok, P and Bu, Y and Wang, J and Qiu, J}, title = {[Heterogeneity in the regulation of cellular stress responses by FUS gene mutations associated with amyotrophic lateral sclerosis].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {50}, number = {10}, pages = {1755-1770}, pmid = {41656808}, issn = {1672-7347}, support = {2019RS1010//the Project of Department of Science and Technology of Hunan Province/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mutation ; Nuclear Localization Signals/genetics ; *Stress, Physiological/genetics ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective death of motor neurons, exhibiting marked clinical heterogeneity and lacking effective treatment. The etiology and pathogenic mechanisms remain incompletely understood. The FUS (fused in sarcoma) gene is one of the key causative genes in ALS. Pathogenic mutations in the encoded protein are predominantly clustered in the C-terminal nuclear localization signal (NLS) region, and distinct NLS mutation sites show considerable differences in pathogenic potency, clinical phenotypes, and molecular mechanisms. This study focuses on 2 representative pathogenic NLS mutations of FUS (FUS[R514S] and FUS[P525L]) to investigate their differential regulation of cellular stress responses and explore the underlying mechanisms.

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

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

CONCLUSIONS: Distinct pathogenic NLS mutations of FUS differentially regulate cellular stress responses through different mechanisms, contributing to ALS initiation and progression. Among these, FUS[P525L] promotes the formation of larger stress granules, whereas FUS[R514S] more readily activates the cellular ISR.}, } @article {pmid41657419, year = {2026}, author = {Wang, Z and Huang, J and Yun, D}, title = {Current and emerging therapeutic strategies for amyotrophic lateral sclerosis: from pharmacological approaches to gene and stem cell therapies.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1729302}, pmid = {41657419}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that involves upper and lower motor neurons, severely impairing patients' quality of life. The complex interaction of genetic and environmental factors in ALS pathophysiology complicates therapeutic development. Currently available disease-modifying pharmacological therapies for ALS offer limited efficacy, only slowing disease progression to a modest degree. The recent market withdrawal of a previously approved therapy (AMX0035) further underscores the challenges in this field. Biological targets for ALS and related neurodegenerative diseases offer a unique avenue for therapeutic intervention. With the advancement of genetic engineering technology, innovative therapies such as Stem cell therapy and gene therapy are also discussed, offering a promising horizon for ALS treatment. In addition, the management of ALS symptoms plays a key role in improving the daily lives of people with the disease. In this review, we summarize various strategies for treating ALS, providing an overview of the disease.}, } @article {pmid41661214, year = {2026}, author = {Miller, TM and Cudkowicz, ME and Shaw, PJ and Genge, A and Sobue, G and Bucelli, RC and Chiò, A and Van Damme, P and Ludolph, AC and Glass, JD and Andrews, JA and Babu, S and Benatar, M and McDermott, CJ and Salachas, F and Bruneteau, G and Al-Chalabi, A and Amorin, M and Nestorov, I and Graham, D and Lin, L and Sun, P and McNeill, M and Malek, S and Inra, J and Garafalo, S and Fradette, S and , }, title = {Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {83}, number = {2}, pages = {115-125}, pmid = {41661214}, issn = {2168-6157}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *Oligonucleotides/therapeutic use/administration & dosage ; *Oligonucleotides, Antisense/therapeutic use ; *Superoxide Dismutase-1/genetics ; Treatment Outcome ; }, abstract = {IMPORTANCE: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.

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

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

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

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

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

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

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.}, } @article {pmid41663779, year = {2026}, author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S}, title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41663779}, issn = {2240-2993}, abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.}, } @article {pmid41665706, year = {2026}, author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É}, title = {Eye tracking as a digital biomarker in neurodegenerative diseases.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {133}, pmid = {41665706}, issn = {1432-1459}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; Biomarkers ; *Eye-Tracking Technology ; }, abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.}, } @article {pmid41670738, year = {2026}, author = {Thorarinsson, BL and Sveinsson, OA and Hilmarsson, A and Sigurthorsdottir, TB and Andersen, PM}, title = {Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.}, journal = {Journal of neurology}, volume = {273}, number = {2}, pages = {140}, pmid = {41670738}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Female ; Male ; Middle Aged ; Iceland ; Neurofilament Proteins/cerebrospinal fluid ; Aged ; Mutation ; *Oligonucleotides, Antisense/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. We describe four patients with hereditary ALS caused by the p.Gly94Ser SOD1 mutation who were treated monthly with the intrathecal antisense oligonucleotide tofersen in a clinical setting at Landspitali University Hospital of Iceland. After initiating treatment 15-26 months ago, no significant clinical deterioration was observed, and three patients showed signs of clinical improvement, with some recovery of motor function. All four patients currently present with chronic nonprogressive ALS, a phenotype not previously observed or documented. Concomitantly, the concentration of neurofilament light chain (Nf-L) in the cerebrospinal fluid decreased to the normal range. This clinical benefit and decrease in Nf-L levels were detected regardless of the patient's initial ALSFRS-R score. No serious adverse events were observed. Notably, we observed a clinically meaningful effect in two patients who had been ill for several years before treatment was instituted, raising questions about who should receive treatment and the biology of paresis and motor neuron cell loss in patients with ALS. Although only a minority of ALS patients carry a SOD1 mutation, the advent of this new precision medicine has profound implications for ALS management.}, } @article {pmid41672113, year = {2026}, author = {Prova, NS and Elsayyid, MW and Tanis, JE}, title = {Superoxide dismutase impacts extracellular vesicle shedding and uptake.}, journal = {Free radical biology & medicine}, volume = {247}, number = {}, pages = {540-550}, pmid = {41672113}, issn = {1873-4596}, support = {P20 GM103446/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; S10 OD030321/OD/NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Extracellular Vesicles/metabolism/genetics ; Reactive Oxygen Species/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Superoxide Dismutase/genetics/metabolism ; Cilia/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Caenorhabditis elegans Proteins/genetics/metabolism ; Humans ; Mutation ; Neuroglia/metabolism ; Sensory Receptor Cells/metabolism ; }, abstract = {Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play a critical role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and on the potential for EVs as diagnostic biomarkers, while the effects of pathogenic factors on EV release are poorly understood. Using a functional endogenous reporter, we showed that the key antioxidant enzyme superoxide dismutase 1 (SOD-1) is expressed in C. elegans EV-releasing neurons, localizes to the cytoplasm, and reduces levels of reactive oxygen species (ROS). We then defined how sod-1 mutations affect EV shedding from sensory neuron primary cilia into the environment, ciliary enrichment of proteins packaged into EVs, and glial uptake of EVs in vivo, by imaging C. elegans expressing fluorescent protein-tagged EV cargoes. Deletion of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different EV subpopulation that is shed from the ciliary base, without affecting release into the environment. These results demonstrate that SOD-1 has a subtype-specific effect on the release of EVs with distinct signaling potentials. Intriguingly, we discovered that exposure to paraquat, which increases mitochondrial ROS, reduced the shedding of both distal tip and ciliary base-derived EVs. These opposing effects of the sod-1 mutations and paraquat treatment on EV release suggest that ROS in distinct subcellular compartments may differentially impact ciliary EV shedding.}, } @article {pmid41672134, year = {2026}, author = {Maneu, V and García, AG}, title = {P2X7 receptors as targets for neuroprotection.}, journal = {Neuropharmacology}, volume = {289}, number = {}, pages = {110877}, doi = {10.1016/j.neuropharm.2026.110877}, pmid = {41672134}, issn = {1873-7064}, mesh = {Humans ; *Receptors, Purinergic P2X7/metabolism ; Animals ; *Purinergic P2X Receptor Antagonists/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroinflammatory Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects/physiology ; }, abstract = {In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.}, } @article {pmid41673790, year = {2026}, author = {Zheng, W and Xu, L and Cai, J and Hou, J and Chen, L and Zhang, N and Zhan, S and Fan, D and He, J}, title = {Comprehensive clinical and genetic architecture of familial amyotrophic lateral sclerosis in China: A 15-year cohort study with 302 families.}, journal = {Neural regeneration research}, volume = {21}, number = {6}, pages = {2573-2579}, pmid = {41673790}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202606000-00072/figure1/v/2026-02-11T151048Z/r/image-tiff The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident. However, there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population. This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland. Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023. A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis, as well as patients with sporadic amyotrophic lateral sclerosis (matched at a 1:4 ratio, with replacement). DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1, FUS, TDP43, and C9ORF72, of which 146 were also subjected to genome-wide next-generation sequencing. Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort. We found that rapid dynamic disease progression was associated with an older age at onset, shorter diagnostic delay, lower body mass index, bulbar onset, and ≥ 1 affected first-degree relative. Certain attributes, such as age at onset and time from onset to diagnosis, had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis. Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis. Among the patients with familial amyotrophic lateral sclerosis, 17.8% possessed ≥ 2 pathogenic/likely pathogenic variants. Sequencing kernel association test analysis showed that the SOD1 rare variant burden (P = 1.3e-15) was associated with a significant risk of familial amyotrophic lateral sclerosis. Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China, contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis. This comprehensive evaluation of specific clinical characteristics, clinical prognosis, and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.}, } @article {pmid41675725, year = {2026}, author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N}, title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.}, journal = {Annals of medicine and surgery (2012)}, volume = {88}, number = {2}, pages = {1441-1453}, pmid = {41675725}, issn = {2049-0801}, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

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

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

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

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.}, } @article {pmid41677019, year = {2026}, author = {Bjørnstadjordet, M and Kvernmo, HB and Bråthen, G and Simpson, MR and Sando, SB and Hagen, K and Devik, K and Wergeland, T}, title = {Four decades of ALS care: a retrospective study of epidemiology, clinical course and changes in management.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {3-4}, pages = {422-431}, doi = {10.1080/21678421.2026.2627903}, pmid = {41677019}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis ; Female ; Retrospective Studies ; Male ; Aged ; Norway/epidemiology ; Middle Aged ; Riluzole/therapeutic use ; Aged, 80 and over ; Noninvasive Ventilation ; *Disease Management ; Incidence ; Disease Progression ; }, abstract = {BACKGROUND: Several interventions have been introduced for amyotrophic lateral sclerosis (ALS) in recent decades, and population-level studies investigating their use and impact are needed. This study describes the epidemiology, disease trajectory, and changes in clinical management of ALS in a county of Norway over a 38-year period.

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

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

CONCLUSION: This comprehensive regional study reveals a rising incidence of ALS in Trøndelag, with increased adoption of supportive interventions over time.}, } @article {pmid41705073, year = {2026}, author = {Sotgia, S and Zinellu, A and Zoroddu, S and Pateri, MI and Loi, E and Pisano, A and Sabalic, A and Tutedde, D and Vega-Benedetti, AF and Floris, F and Puligheddu, M and Valera, P and Zavattari, P and Borghero, G and Madeddu, R}, title = {Elevated serum trimethylamine N-oxide (TMAO) and trimethyllysine in patients with amyotrophic lateral sclerosis (ALS): An exploratory case-control study.}, journal = {IBRO neuroscience reports}, volume = {20}, number = {}, pages = {227-231}, pmid = {41705073}, issn = {2667-2421}, abstract = {Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite implicated in protein homeostasis, inflammation, and chronic disease, but its relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. In this exploratory pilot study, we quantified circulating TMAO and related trimethylammonium-containing compounds in a Sardinian ALS cohort using targeted LC-MS/MS. Serum samples were collected under fasting conditions from 12 ALS patients and 8 age- and sex-matched healthy controls. Median serum TMAO levels were markedly higher in ALS patients than in controls (27.9 vs. 4.0 µmol/L, P < 0.05), with substantial inter-individual variability in the ALS group (range 2.4-125.0 µmol/L). Trimethyllysine (TML) concentrations were also significantly elevated in ALS (0.43 vs. 0.34 µmol/L, P < 0.05), whereas choline, carnitine, betaine, ergothioneine, and γ-butyrobetaine levels did not differ between groups. Most ALS patients were receiving acetyl-L-carnitine (ALCAR) supplementation, suggesting that ALCAR intake may contribute to the observed metabolite profiles. Overall, these findings indicate alterations in trimethylammonium-containing compound metabolism in ALS and underscore the need for larger, well-controlled studies to determine whether such changes reflect disease-related mechanisms, treatment effects, or their interaction.}, } @article {pmid41707703, year = {2026}, author = {Xu, B and Wu, J}, title = {Response to He et al's "Comments on 'Optimized combination: Isotretinoin in conjunction with oral tranexamic acid for the treatment of moderate to severe acne vulgaris-A randomized, double-blind, placebo-controlled trial'".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e55}, doi = {10.1016/j.jaad.2026.01.092}, pmid = {41707703}, issn = {1097-6787}, } @article {pmid41707709, year = {2026}, author = {He, K and Wang, H and Cao, Y}, title = {Response to Bingyang Xu et al's "Optimized combination: Isotretinoin in conjunction with oral tranexamic acid for the treatment of moderate to severe acne vulgaris-A randomized, double-blind, placebo-controlled trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e57-e58}, doi = {10.1016/j.jaad.2025.12.117}, pmid = {41707709}, issn = {1097-6787}, } @article {pmid41708347, year = {2026}, author = {Gontier, G and Kim, G and Wang, C and Zhu, K and Gau, R and Zhang, N and Naphade, S and Stewart, A and Schmidt, MJ and Galemmo, R and Shook, B and Tarachandani, A and Choi, I and Raines, S and Scannevin, RH and Grievink, HW and Smits, LMG and Kremer, PHC and Cadavid, D}, title = {Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB): A Translational Pharmacodynamic Biomarker for PIKfyve Inhibition With VRG50635.}, journal = {Clinical and translational science}, volume = {19}, number = {2}, pages = {e70489}, pmid = {41708347}, issn = {1752-8062}, support = {//Verge Genomics/ ; }, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; *Membrane Glycoproteins/metabolism/blood ; Male ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/pharmacokinetics ; Phosphatidylinositol 3-Kinases/metabolism ; Biomarkers/metabolism/blood ; Leukocytes, Mononuclear/drug effects/metabolism ; Adult ; Female ; }, abstract = {Glycoprotein non-metastatic melanoma protein B (GPNMB) was investigated as a pharmacodynamic (PD) biomarker for PIKfyve inhibition across translational studies ex vivo, in vitro, in animals, and in the clinic, demonstrating significant response to VRG50468 in cells, in vivo in the central nervous system (CNS) and in peripheral fluids and tissues. VRG50468 is the active metabolite of VRG50635, a small molecule PIKfyve inhibitor pro-drug in development for treating amyotrophic lateral sclerosis (ALS). Peripheral pharmacology was evaluated in peripheral blood mononuclear cells (PBMCs) from healthy volunteers ex vivo and in vitro and in PBMCs from mice given oral VRG50635. Central pharmacology was evaluated in vitro using C9orf72 ALS patient-derived induced pluripotent stem cell motor neurons and mouse primary neurons, and in vivo in brains of mice given oral VRG50635. Two clinical studies in healthy adults examined plasma, PBMCs, and cerebrospinal fluid following oral VRG50635 for peripheral and central pharmacologic activity via GPNMB induction. PD GPNMB upregulation with VRG50468 was demonstrated across preclinical translational and clinical studies. A PD response to VRG50468 was observed ex vivo in rodent and human PBMCs and in primary rodent neurons and motor neurons induced from stem cells of people with ALS. Repeated administration of VRG50635 to rodents and healthy human volunteers robustly induced GPNMB peripherally and in the CNS, which was concentration and time dependent in vitro and dose and treatment duration dependent in vivo, peripherally, and in CNS. GPNMB is a robust translatable PD biomarker for clinical trials with the PIKfyve inhibitor VRG50635. TRIAL REGISTRATION: Clinical trial number: VGCS-50635-001 and VGCS-50635-003; identifier: NL81735.056.22 and NCT06286475.}, } @article {pmid41710977, year = {2026}, author = {Liu, Q and Zhang, X and Wang, L and Chen, H and Wang, G and Sun, Y and He, B and Gao, J and Qiu, W and Ma, C and Sun, M and Cui, L and Zhang, X}, title = {BTK inhibition suppresses neuroinflammation and neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag070}, pmid = {41710977}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis(ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regulators that integrate multiple inflammatory cascades remain poorly understood. Here, we investigated whether Bruton's tyrosine kinase (BTK), which integrates DNA-sensing and Toll-like receptor signals upstream of the cGAS-STING-NF-κB cascade, serves as a key regulatory node in ALS pathogenesis. Public RNA-seq datasets of motor neurons and post-mortem tissues from ALS patients were utilized to identify BTK expression patterns. SOD1-mutant human induced pluripotent stem cells (hiPSC) were differentiated into motor neurons (hiPSC-MNs) and microglia (hiPSC-MGs). NF-κB dysregulation was profiled by scRNA-seq (hiPSC-MGs) and bulk RNA-seq (hiPSC-MNs). DNA damage (γH2AX), inflammatory signalling (western blot/ELISA) and phagocytosis (pH-rodo uptake) were quantified, and MG-conditioned medium was tested for MN toxicity. Monocultures and MN-MG co-cultures received zanubrutinib (3 µM, 12 h). SOD1-G93A mice were administered zanubrutinib (30 mg/kg, daily) from 2.5 months; motor performance, survival, spinal histology and PI3K-AKT-mTOR activity were assessed after 2 months of treatment. ALS spinal cord and cortex tissues of patients, as well as SOD1-mutant hiPSC-MGs and hiPSC-MNs, demonstrated elevated BTK phosphorylation with increased p-STING, p-TBK1, and nuclear NF-κB accumulation. ALS hiPSC-MGs exhibited inflammatory activation, NLRP3 induction, and impaired phagocytosis, while ALS hiPSC-MNs showed DNA damage and caspase-3-mediated apoptosis. Conditioned medium from inflammatory microglia amplified neuronal STING-NF-κB activity and apoptosis, demonstrating non-cell-autonomous toxicity. The STING inhibitor H-151 reduced neuronal p-STING/p-TBK1/NF-κB and apoptosis, confirming pathway causality. Pharmacological BTK inhibition reduced DNA damage in ALS hiPSC-MNs by 61.4% (p<0.05), restored phagocytosis in ALS hiPSC-MGs to 87.2% of control levels (p<0.01), and prevented neuronal apoptosis induced by microglial conditioned medium. In SOD1-G93A mice, BTK blockade extended median survival from 158 to 173 days (p<0.01, log-rank test), improved motor function, and attenuated neuroinflammation while moderately rebalancing PI3K-AKT-mTOR signaling without impairing autophagy-lysosome dynamics. We identify BTK as a critical upstream regulator of the dysregulated cGAS-STING-NF-κB signalling axis characteristic of ALS pathogenesis. BTK orchestrates both cell-autonomous dysfunction in motor neurons and non-cell-autonomous toxicity through microglial activation, representing a convergent regulatory node that integrates multiple pathogenic pathways. These mechanistic insights provide a molecular framework for understanding ALS neuroinflammation and establish a rational basis for BTK-targeted therapeutic intervention in neurodegeneration.}, } @article {pmid41714394, year = {2026}, author = {Warmann, S}, title = {[Motor neuron diseases from a radiological perspective : Focus on amyotrophic lateral sclerosis].}, journal = {Radiologie (Heidelberg, Germany)}, volume = {66}, number = {4}, pages = {272-277}, pmid = {41714394}, issn = {2731-7056}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; *Magnetic Resonance Imaging ; Electromyography ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Diagnosis, Differential ; Muscular Atrophy, Spinal/diagnostic imaging ; }, abstract = {BACKGROUND: Motor neuron diseases (MND) affect the upper and/or lower motor neurons. Radiological diagnostics primarily serve to systematically exclude treatable mimics and support the clinical and electrophysiological diagnosis. The focus is on amyotrophic lateral sclerosis (ALS); supplementary progressive muscular atrophy (PMA, purely lower motor neuron, LMN disease) and spinal muscular atrophy (SMA).

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

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

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

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

DISCUSSION: The diagnosis remains primarily clinical; EMG and MRI are supportive. The radiological priority is the exclusion of mimics. The UMN markers increase diagnostic certainty in the context of clinical/EMG findings but do not replace them. Clear findings facilitate classification according to Gold Coast. The PMA and SMA require careful differential diagnostics; characteristic MRI patterns support progression and treatment planning.}, } @article {pmid41718290, year = {2026}, author = {Messina, C}, title = {Silent Damage, Delayed Symptoms: A Case of Breast Cancer Radiation-Induced Lumbosacral Plexopathy.}, journal = {Reports (MDPI)}, volume = {9}, number = {1}, pages = {}, pmid = {41718290}, issn = {2571-841X}, abstract = {Background and Clinical Significance: Radiation-induced lumbosacral plexopathy (RILP) is a rare but potentially debilitating complication of radiotherapy, typically affecting patients treated for pelvic malignancies. We report the first documented case of asymmetric RILP following radiotherapy for breast cancer. Case Presentation: A 64-year-old woman developed progressive left lower limb weakness, foot drop, and sensory disturbances four years after receiving locoregional radiotherapy extending to the left thoracoabdominal and lumbar areas. Electrophysiological studies revealed an asymmetric sensorimotor axonal neuropathy predominantly involving the left lower limb, without conduction block and sparing the upper limbs, whereas needle electromyography of the lower limbs showed fibrillation potentials, positive sharp waves, and fasciculations in the vastus lateralis, tibialis anterior, and medial gastrocnemius muscles on the left. Magnetic resonance imaging demonstrated edema and contrast enhancement of bilateral L2-L4 nerve roots with paraspinal muscle atrophy. Cerebrospinal fluid analysis showed albuminocytologic dissociation and elevated neurofilament levels. After exclusion of alternative diagnoses, including amyotrophic lateral sclerosis and inflammatory neuropathies, a diagnosis of radiation-induced peripheral neuropathy and RILP was made. The patient's condition stabilized with physiotherapy and symptomatic treatment. Conclusions: This case highlights the need for heightened awareness of RILP as a late complication of breast cancer radiotherapy, underscoring the importance of accurate diagnosis to avoid misclassification and unnecessary treatments. Clinicians should carefully integrate all clinical elements-including a thorough remote medical history-since radiation-related neurological damage may manifest many years after the initial insult.}, } @article {pmid41723979, year = {2026}, author = {Gao, Y and Lu, Y and Zhao, S and Chen, R and Liu, J and Zhang, S and Bai, X and Zhang, J}, title = {Allicin improves motor neuron survival in amyotrophic lateral sclerosis by reducing neuroinflammation and modulating gut microbiota.}, journal = {Biochemical and biophysical research communications}, volume = {809}, number = {}, pages = {153503}, doi = {10.1016/j.bbrc.2026.153503}, pmid = {41723979}, issn = {1090-2104}, mesh = {Animals ; *Sulfinic Acids/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Gastrointestinal Microbiome/drug effects ; *Motor Neurons/drug effects/pathology ; Disulfides ; Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/pathology ; Mice ; Cell Survival/drug effects ; Disease Models, Animal ; Male ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MNs). Allicin, a defensive molecule in garlic with anti-inflammatory and gut microbiota-modulating properties, has shown therapeutic potential in animal models of various diseases including Alzheimer's disease (AD). However, its possible therapeutic role in ALS remains unclear. The purpose of this study is to investigate the therapeutic effect of allicin in ALS transgenic SOD1[G93A] mice. Starting at 60 days of age, SOD1[G93A] mice received oral gavage of allicin (10 mg/kg) on alternate days, while the control group received an equal volume of normal saline (NS) on the same schedule. Twelve mice per group were used for monitoring disease onset and survival. Nissl staining and choline acetyltransferase (ChAT) immunofluorescence were used to quantify MNs in the anterior horn. Microglial activation was analyzed by immunofluorescence staining for Iba1, ARG1, and CD86. The mRNA expression levels of IL-10, TGF-β, IL-1β, and TNF-α were examined using qPCR. Additionally, fecal samples were collected for 16S rDNA sequencing to evaluate changes in gut microbiota composition. We observed that allicin treatment failed to prolong the onset time and survival period of SOD1[G93A] mice, but it extended the disease duration. Nissl staining analysis revealed that allicin treatment delayed the loss of spinal MNs, a finding corroborated by ChAT immunofluorescence. Furthermore, allicin treatment significantly reduced neuroinflammation and improved gut microbiota. Taken together, although allicin may prolong disease duration in ALS, it did not improve overall survival or delay disease onset. Therefore, its potential disease-modifying effects require further validation.}, } @article {pmid41740899, year = {2026}, author = {Al Tawil, A and Lauseker, M and Mansmann, U}, title = {Estimating causal effects on quality of life under treatment discontinuation: the ALTA-1L trial.}, journal = {Journal of clinical epidemiology}, volume = {193}, number = {}, pages = {112189}, doi = {10.1016/j.jclinepi.2026.112189}, pmid = {41740899}, issn = {1878-5921}, mesh = {Humans ; *Quality of Life ; *Lung Neoplasms/drug therapy ; Treatment Interruption ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; *Crizotinib/therapeutic use ; *Pyrimidines/therapeutic use ; }, abstract = {BACKGROUND AND OBJECTIVES: Time to worsening in health-related quality of life (HRQoL) is increasingly used in oncology trials. Treatment discontinuation poses a challenge: once discontinued, patients cease HRQoL assessments, precluding outcome observation. Standard survival analyses censor at discontinuation, assuming noninformative censoring-an assumption often violated when discontinuation relates to disease progression or toxicity. Bridging the ICH E9(R1) estimand framework with causal inference methods clarifies how to define and estimate treatment effects in such settings. We reanalyze time to worsening in global health status from the ALTA-1L trial (brigatinib vs crizotinib in ALK + non-small-cell lung cancer), integrating both frameworks.

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

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

CONCLUSION: This study bridges the ICH E9(R1) estimand framework with causal inference methods for time-to-event HRQoL analysis when discontinuation precludes observation. By quantifying bias from standard approaches, we provide methodological clarity for applied researchers. To facilitate practical implementation, we translate these insights into a decision flowchart for estimand specification and method selection when intercurrent events (ICEs) act as competing events. Future trials should prespecify ICE-handling strategies and consider data collection beyond ICEs to support treatment policy estimation.}, } @article {pmid41743427, year = {2026}, author = {Luo, Y and Liu, X and Yang, M}, title = {Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.}, journal = {Frontiers in rehabilitation sciences}, volume = {7}, number = {}, pages = {1666530}, pmid = {41743427}, issn = {2673-6861}, abstract = {Neurological disorders represent a significant category of diseases that profoundly affect human health, accounting for the second leading cause of global mortality. This group of conditions includes stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, Parkinson's disease, and cerebral palsy, among others. These disorders are highly susceptible to sequelae and profoundly impact individuals' daily lives. In this context, Brain-Computer Interface (BCI) technology has demonstrated considerable potential in the domain of neurorehabilitation, although numerous challenges remain. The manuscript provides a comprehensive review of recent advancements in research and clinical applications, highlighting current limitations and outlining future directions. It elucidates the applicability and constraints of Brain-Computer Interface (BCI) technology across various diseases and patient populations. To facilitate insights across different conditions, comparative tables are presented, aligning BCI strategies with therapeutic targets, outcomes, advantages, limitations, and existing evidence gaps. The scope extends beyond motor restoration to include under-explored domains, such as neuropathic pain, with a focus on real-world translation, including home and community feasibility and the distinction between assistive and rehabilitative applications. The review distills overarching limitations within the field, such as small sample sizes, protocol heterogeneity, and limited longitudinal evidence, while synthesizing the most recent studies. An actionable research and development roadmap is proposed to guide next-generation BCI rehabilitation, incorporating individualized cortical-network simulators, self-architecting decoders, adaptive therapy approaches akin to game seasons, and proprioceptive "write-back" mechanisms via peripheral interfaces. Moreover, the review reveals significant research focal points and critical issues that warrant further investigation in the context of neurological rehabilitation utilizing BCI technology.}, } @article {pmid41744019, year = {2026}, author = {Shi, Y and Xiao, S and He, D}, title = {Visualization analysis of the use of traditional Chinese medicine in the diagnosis and treatment of rare diseases in mainland China based on CiteSpace.}, journal = {Intractable & rare diseases research}, volume = {15}, number = {1}, pages = {71-84}, pmid = {41744019}, issn = {2186-3644}, abstract = {This study used CiteSpace (version 6.4.R1) to perform a visualization analysis of 3,058 articles on traditional Chinese medicine (TCM) diagnosis and treatment of rare diseases retrieved from the China National Knowledge Infrastructure (CNKI) database, the VIP Chinese Science and Technology Periodical Database (VIP), the Wanfang database (Wanfang), and the Chaoxing database (Chaoxing). The goal was to ascertain the current status of research, hotspots in research, and trends in the development of TCM for rare disease diagnosis and treatment in mainland China, providing insights for future TCM research in this field. Visual maps of annual publication volume, authors, institutions, keywords, and other content have revealed that TCM demonstrates prominent advantages in 5 out of 207 defined rare diseases: idiopathic pulmonary fibrosis, hepatolenticular degeneration (Wilson's disease), osteosarcoma, retinitis pigmentosa, and multiple sclerosis. Potential advantages are identified in treating melanoma, amyotrophic lateral sclerosis, homocysteinemia, primary biliary cholangitis, and lymphangioleiomyomatosis. TCM research on rare diseases focuses on etiology, pathogenesis, and syndrome differentiation-based treatment. Case-control studies and mechanism investigations have been initiated for some conditions, while clinical research is gradually incorporating integrated TCM-Western medicine approaches. However, enhanced team and institutional collaboration, development of multicenter networks, exploration of multidisciplinary research, and clinical studies yielding high-level evidence are still needed to provide quality evidence-based support for clinical decision-making in the TCM treatment of rare diseases.}, } @article {pmid41744126, year = {2026}, author = {Yang, Q and Wu, H and Huang, X and Xie, M and Shan, Y and Dou, Z and Li, Y and Wen, H and Li, C}, title = {Prevalence and Risk Factors of Dysphagia in Amyotrophic Lateral Sclerosis: A Retrospective Study Using the Nationwide Inpatient Sample Database.}, journal = {Muscle & nerve}, volume = {73}, number = {5}, pages = {875-881}, doi = {10.1002/mus.70188}, pmid = {41744126}, issn = {1097-4598}, support = {2024FYQ001//Affiliated Hospital of Shandong Second Medical University/ ; 2023B110003//Guangdong Provincial Clinical Research Center for Rehabilitation Medicine/ ; }, mesh = {Humans ; *Deglutition Disorders/epidemiology/etiology/economics ; Female ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Retrospective Studies ; Prevalence ; Risk Factors ; Male ; Aged ; Middle Aged ; Databases, Factual ; Inpatients ; United States/epidemiology ; Length of Stay ; Aged, 80 and over ; Hospitalization ; Adult ; }, abstract = {INTRODUCTION/AIMS: Dysphagia is a common but under-characterized complication in Amyotrophic lateral sclerosis (ALS), contributing to morbidity and healthcare burden. This study aimed to investigate the prevalence, pinpoint risk factors, and assess the adverse clinical outcomes linked to dysphagia in hospitalized patients with ALS.

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

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

DISCUSSION: Dysphagia affected approximately one-third of hospitalized ALS patients in this study, contributing to extended hospital stays and increased healthcare costs. Timely screening and tailored interventions are crucial for minimizing complications and maximizing the efficient use of resources.}, } @article {pmid41744255, year = {2026}, author = {Labeit, B and Bach, J and Harborth, E and Dziewas, R and Meuth, SG and Grefkes, C and Willems, L and Lapa, S}, title = {Impact of a Neurogenic Dysphagia Outpatient Clinic on Diagnosis, Treatment, and Nutrition.}, journal = {European journal of neurology}, volume = {33}, number = {3}, pages = {e70544}, pmid = {41744255}, issn = {1468-1331}, support = {529859742//Deutsche Forschungsgemeinschaft/ ; }, abstract = {BACKGROUND: The aim was to evaluate the diagnostic, therapeutic, nutritional, and complication-related impact of a university-led neurogenic dysphagia outpatient clinic.

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

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

CONCLUSION: A dedicated outpatient dysphagia clinic enhances diagnostic precision, optimizes therapy, and supports individualized nutritional and airway management. FEES-based phenotyping strengthens differential diagnostics and enables the identification of previously unrecognized neurological syndromes. Silent aspiration and frailty identify patients at the highest pneumonia risk. Dysphagia should be regarded as an independent therapeutic target within disease-specific neurological treatment, and dysphagia outpatient clinics should be integrated into standard neurological care pathways.}, } @article {pmid41744765, year = {2026}, author = {Dellazizzo Toth, T and Bond, S and Saxena, S}, title = {The Calcium Connection: Explaining Motor Neuron Vulnerability in ALS.}, journal = {Cells}, volume = {15}, number = {4}, pages = {}, pmid = {41744765}, issn = {2073-4409}, abstract = {ALS is a severe neuromuscular disease classically characterized by the progressive loss of motor neurons, leading to incremental muscle weakness and eventually death. Current treatment options for ALS have proven to have limited effect, merely delaying the progression of symptoms and prolonging patient survival. This motor neuron subtype-related differential vulnerability has been linked to neuron excitability, metabolism, and protein aggregation. Calcium dysregulation, which serves as an important second messenger in neural signaling pathways, has been implicated in each of these mechanisms and represents a potential target for therapeutic intervention. Armed with cutting-edge tools for visualizing and recording calcium transients in vivo, ALS researchers have delved deeper into the role of calcium dysregulation in disease in recent years. Vulnerable motor neuron populations display an excess of calcium-permeable ion channels together with reduced expression of calcium-binding proteins, generating a cellular environment primed for excitotoxic stress. Loss of inhibitory synaptic input further heightens susceptibility to calcium overload. Paradoxically, some evidence suggests that elevated neuronal activity can exert neuroprotective effects, highlighting the complexity of activity-dependent calcium signaling in ALS. Additionally, ALS-related toxic protein accumulation disrupts calcium homeostasis, contributing to endoplasmic reticulum stress and mitochondrial dysfunction. Emerging data indicate that calcium dysregulation impairs neuron-glia communication, amplifying neuroinflammation and accelerating disease progression. This review aims to synthesize current evidence on how calcium imbalance contributes to motor neuron vulnerability and degeneration in ALS. By exploring the cellular, synaptic, and network-level mechanisms of calcium dysregulation in ALS, the review examines its interplay with mitochondrial and ER stress and explores its impact on neuron-glia interactions with the aim of synthesizing key mechanistic insights into the disease pathogenesis and therapeutic targets.}, } @article {pmid41745965, year = {2026}, author = {Haroun, M and Tratrat, C and Mathew, RT and Munir, M and Sattar, MN and Shawky, M and Kochkar, H and Aldakhilallah, ON and Ghafoor, A and Turk, KGB and Geronikaki, A and Ghazzawy, HS}, title = {Avian Candidiasis: A Comprehensive Review of Pathogenesis, Diagnosis, and Control.}, journal = {Veterinary sciences}, volume = {13}, number = {2}, pages = {}, pmid = {41745965}, issn = {2306-7381}, support = {Grant number: KFU260519//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia/ ; }, abstract = {This review is a comprehensive investigation of avian candidiasis, mainly caused by Candida albicans, although the prevalence of non-albicans Candida species has increased in domestic and wild birds. Avian candidiasis causes significant economic losses in poultry production through increased mortality, cost of treatments, and reduced growth rates, particularly in young birds and intensive farming operations. The pathogenesis section provides a description of the molecular virulence factors such as adhesin-mediated attachment (ALS, Agglutinin-Like Sequence family; HWP1, Hyphal Wall Protein 1), yeast-to-hypha morphogenesis, tissue damage by Candidalysin, biofilm formation on mucosal and abiotic surfaces, and secreted hydrolytic enzymes including secreted aspartyl proteinases (SAPs) and phospholipases. The identified predisposing factors include immunosuppression, malnutrition, abuse of antibiotics, bad husbandry, and crop stasis. The diagnostic methods discussed encompass cytological analysis and fungal culture on selective media to more sophisticated methods of molecular analysis (PCR, MALDI-TOF MS, and NGS). Antifungal susceptibility investigations indicate that nystatin and amphotericin B are still very effective against most avian isolates and that resistance to the azoles is on the rise, especially with respect to the non-albicans Candida species. Nystatin is still the first-line treatment of localized infections; azoles are still used for resistant or systemic infections despite their hepatotoxicity. Sanitation, proper nutrition, and proper use of antimicrobials are essential to prevent diseases. The knowledge gaps comprise the absence of avian-specific pharmacokinetic information, poor knowledge of species-species virulence phenotypes, and the lack of point-of-care diagnostics. The need to have integrated One Health surveillance systems is emphasized by the zoonotic potential of the avian Candida reservoirs.}, } @article {pmid41746412, year = {2026}, author = {Tarazona-Santabalbina, FJ and Belenguer-Varea, A and Borrás-Blasco, J and García-Tercero, E and Martin, ML and Prior, NP and Mariscal, G and Valcuende-Rosique, A}, title = {Safety profile of tofersen 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 = {47}, number = {3}, pages = {}, pmid = {41746412}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To evaluate the safety profile of tofersen in patients with SOD1-associated amyotrophic lateral sclerosis (ALS) through a systematic review and meta-analysis of randomized controlled trials and observational cohorts. METHODS: A comprehensive search was conducted up to August 2025. Eligible studies included adults with SOD1-associated ALS treated with intrathecal tofersen. Outcomes were treatment-emergent adverse events (AEs), serious adverse events (SAEs), cerebrospinal fluid (CSF) abnormalities, and procedure-related complications. Pooled incidence rates with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models depending on heterogeneity. Risk of bias was assessed with MINORS, and certainty of evidence was graded using GRADE. RESULTS: Six studies (2 RCTs, 4 cohorts) comprising 179 patients receiving tofersen and 48 placebo controls were included. The pooled incidence of any AE was 98.0% (95% CI: 95.6–100), while SAEs occurred in 10.0% (95% CI: 0–22.1). Common adverse events included procedural pain (56.2%), headache (54.1%), back pain (38.4%), and extremity pain (35.9%). CSF pleocytosis was reported in 44.1% of patients, with high heterogeneity across studies. Gastrointestinal and constitutional events such as nausea (17.0%) and fatigue (21.6%) were usually mild. Respiratory failure occurred in 9.2% of cases. Most adverse events were manageable, though rare severe complications (e.g., meningitis, myelitis, intracranial hypertension) were described in individual reports. CONCLUSION: Tofersen is associated with frequent adverse events, predominantly mild to moderate, while serious complications are less common but clinically relevant. The overall safety profile supports its continued clinical use in SOD1-associated ALS, although long-term surveillance is warranted to better characterize rare outcomes.}, } @article {pmid41751793, year = {2026}, author = {Ptáček, O and Musil, Z and Guarnieri, G and Vrbacká, A and Moudrá, P and Zlámalová, A and Röszlerová, P and Tonhajzer, M and Musil, V and Morelli, A and Zach, P}, title = {Amyotrophic Lateral Sclerosis: The State of the Art on Treatments and the Therapeutic Role of the Intestinal Microbiome in Human Studies.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41751793}, issn = {1422-0067}, support = {Cooperatio 39 - Oncology and Haematology//Charles University/ ; Cooperatio 33-Intensive Care Medicine//Charles University/ ; Cooperatio 36-Medical Diagnostics and Basic Medical Sciences//Charles University/ ; #NEXTGENERATIONEU//European Commission/ ; MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease (DR. 1553 11.10.2022)//Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; *Fecal Microbiota Transplantation/methods ; *Gastrointestinal Microbiome ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder; to date, there is no long-term effective treatment. Recently, a relationship has been discovered between the human intestinal microbiome and the pathogenesis of ALS, on which basis faecal microbiota transplantation (FMT) has been proposed as a potential treatment for ALS. In this review, we compare three existing case studies examining the effect of FMT on the course of ALS, highlighting differences in methodology and results. In two of the studies, a halt in the progression of ALS symptoms was observed following FMT, accompanied by improvement in patient health. However, in the third and largest study, no significant effect of FMT was observed. The possible explanation for this discrepancy may be the intentional depletion of intestinal microorganisms using antibiotics prior to FMT in the third study. Future studies and/or completion of the ongoing clinical studies will help clarify the therapeutic effectiveness of FMT in ALS patients.}, } @article {pmid41751955, year = {2026}, author = {Luong, DT and Niu, C and Kim, E and Tanji, N and Duong, I and Galero, B and Zhang, YJ and Bennett, CL and La Spada, AR}, title = {PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41751955}, issn = {1422-0067}, support = {W81XWH-20-1-0154//United States Department of Defense/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *PPAR delta/agonists ; *C9orf72 Protein/genetics/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *DNA-Binding Proteins/genetics/metabolism ; Phenotype ; Humans ; Male ; Neurofilament Proteins/blood ; }, abstract = {Peroxisome-proliferator-activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43[Q331K] transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9-10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43[Q331K] mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement-particularly for T3D-959-neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.}, } @article {pmid41752118, year = {2026}, author = {Kurdi, MA and Alotaibi, H and Alkhuraymi, AT and Aldahery, LN and Alhawaj, AF and Aldali, HJ}, title = {Amyotrophic Lateral Sclerosis (ALS) Genetics and Microbiota: A Comprehensive Review.}, journal = {International journal of molecular sciences}, volume = {27}, number = {4}, pages = {}, pmid = {41752118}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/therapy ; Animals ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; RNA-Binding Protein FUS/genetics ; Genetic Therapy/methods ; Mutation ; *Microbiota ; *Gastrointestinal Microbiome ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe, progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons, affecting 0.5 to 2.6 per 100,000 people, with a median survival of 2 to 5 years. It is increasingly seen as a multisystem disorder, sharing essential clinicopathological features with Frontotemporal Dementia (FTD). This convergence arises from overlapping molecular processes, including severe oxidative stress, glutamate-mediated excitotoxicity, mitochondrial dysfunction, and widespread aggregated TDP-43 proteinopathy in both sporadic and familial cases. Several key genetic factors have been identified, particularly mutations in C9orf72, SOD1, TARDBP, and FUS, which serve as important targets for novel treatments, such as Tofersen, a recently approved SOD1-specific antisense oligonucleotide (ASO) gene therapy. Additionally, there is increasing evidence of the gut-brain connection. Dysbiosis, involving species such as Akkermansia muciniphila, and lower levels of neuroprotective metabolites, such as nicotinamide, may affect the course of the disease. As a result, treatment strategies are shifting toward a personalized approach. This includes using gene therapy, ranging from ASOs and RNA interference (RNAi) to new CRISPR-based genome editing. It also involves exploring microbiome-modulating treatments, such as specific probiotics and Fecal Microbiota Transplantation (FMT). While microbiome and gene therapies remain largely experimental, their potential is promising, as highlighted by the recent approval of Tofersen. These novel approaches could be further enhanced and guided by more robust diagnostic criteria and by investigating early multimodal treatment strategies to slow the progression of this complex disease.}, } @article {pmid41756461, year = {2026}, author = {Petriti, B and Subramanian, S and Williams, PA and Chau, KJ and Licznerski, P and Lascaratos, G and Aguilar-Munoa, S and Kamal, D and Bae, H and Alavian, KN and Garway-Heath, DF and Jonas, EA}, title = {Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41756461}, issn = {2693-5015}, support = {R01 NS123405/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.}, } @article {pmid41756852, year = {2026}, author = {Malik, T and Jones, S and Ma, O and Mohan, S and Burger, RM and Babcock, DT}, title = {Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.02.19.706635}, pmid = {41756852}, issn = {2692-8205}, support = {R01 NS110727/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.}, } @article {pmid41760732, year = {2026}, author = {Sinderewicz, E and Dąbkowska, M and Sarnowska, A and Staszkiewicz-Chodor, J and Mystkowska, D and Holak, P and Drozd, I and Chodkowska-Michalowska, M and Rytel, M and Paczkowska, E and Mycko, MP and Machalinski, B and Jezierska-Wozniak, K}, title = {Safety and biodistribution of intrathecal administration of mesenchymal stem cells (MSCs) and neurotrophin-releasing nanoparticles in a porcine CSF-guided delivery model for amyotrophic lateral sclerosis (ALS) drug discovery.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41760732}, issn = {2045-2322}, support = {No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Nanoparticles/administration & dosage/chemistry ; *Mesenchymal Stem Cell Transplantation/methods/adverse effects ; *Mesenchymal Stem Cells/cytology/metabolism ; Male ; *Nerve Growth Factors/administration & dosage/pharmacokinetics ; Swine ; Tissue Distribution ; Injections, Spinal ; Disease Models, Animal ; Drug Delivery Systems ; Humans ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS.}, } @article {pmid41762049, year = {2026}, author = {Zhang, Y and Chen, B and Lin, Y and Kang, D and Zhao, T}, title = {Advances and Challenges in the Use of Spinal Cord Organoids in ALS.}, journal = {Journal of integrative neuroscience}, volume = {25}, number = {2}, pages = {44709}, doi = {10.31083/JIN44709}, pmid = {41762049}, issn = {0219-6352}, support = {82301543//National Natural Science Foundation of China/ ; 2021QNA025//Youth Scientific Research Project of Fujian Provincial Health Commission/ ; 2021Y2001//Technology Platform Construction Project of Fujian Province/ ; 2020Y2003//Technology Platform Construction Project of Fujian Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Humans ; *Organoids/pathology ; *Spinal Cord/pathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease. No effective treatments have yet been found for ALS, primarily because the molecular mechanisms that underlie its pathogenesis are unknown. Although animal models are suitable for ALS research, species differences between these models and human spinal cord organs make it difficult to accurately predict the progression of disease in humans. Therefore, the development of more suitable models is urgently needed. Human stem cells have unlimited development potential and can be used to make three-dimensional organoid structures that mimic the architecture and function of actual organs. Organoid models can be used to overcome some of the species differences and accelerate experimental research, leading to the development of practical applications for the treatment of ALS. This article discusses the pathological mechanisms and cell types involved in ALS, as well as the genes associated with this disease. We also discuss the possible applications of spinal cord organoids (SCOs) in ALS research, such as the modeling of disease characteristics, study of pathological mechanisms, and drug screening. Finally, the prospects for SCOs in ALS treatment are highlighted, while acknowledging the need for further development of relevant technologies.}, } @article {pmid41763422, year = {2026}, author = {Li, Y and Liu, S and Cao, L and Zhu, M and Lin, S and Wang, X and Qiu, Z and Teng, Y}, title = {Ginsenoside compound K inhibited the gelation of GGGGCC repeats and regulated co-aggregation with arginine-rich poly-dipeptides in C9orf72-related ALS.}, journal = {International journal of biological macromolecules}, volume = {351}, number = {}, pages = {151138}, doi = {10.1016/j.ijbiomac.2026.151138}, pmid = {41763422}, issn = {1879-0003}, mesh = {*Ginsenosides/pharmacology/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; *C9orf72 Protein/genetics ; Humans ; Animals ; *DNA Repeat Expansion/drug effects ; G-Quadruplexes/drug effects ; Arginine/chemistry ; *Peptides/chemistry ; }, abstract = {GGGGCC repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It produces toxic RNA repeats and poly-dipeptides, leading to abnormal phase separation and deposition in nerve cells. In particular, repeat RNAs form gels that induce cellular toxicity. Thus, they are potential therapeutic targets. Ginsenoside compound K (CK) is the major metabolite of Panax ginseng, a traditional Chinese medicine commonly used for the treatment of neurodegenerative diseases. In this study, CK significantly inhibited the gelation of GGGGCC repeats both in vitro and in vivo. Moreover, it reduced the co-aggregation of RNA and arginine-rich poly-dipeptides via electrostatic interactions. Further investigation suggested that CK preferentially interacts with G-quadruplex monomers formed by GGGGCC repeats rather than with complex multimers, thereby inhibiting the formation of toxic RNA foci. These results elucidate the mechanism of action of CK in C9orf72-related ALS/FTD. Thus, this study provides new avenues for the potential application of ginsenoside in the treatment of neurodegeneration.}, } @article {pmid41763443, year = {2026}, author = {Zafarjonovna, AZ and Aysulu, E and Matlyuba, S and Rashid, H and Azamatovich, JB and Ahmadjon, A and Barno, A and Kurbanovna, AM and Ugli, MRM and Shaxodat, I and Rustam, T and Jumaniyazovna, MG and Ishankulov, A}, title = {Small extracellular vesicles as emerging biomarkers and therapeutic targets in neurodegenerative diseases.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {587}, number = {}, pages = {120932}, doi = {10.1016/j.cca.2026.120932}, pmid = {41763443}, issn = {1873-3492}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; Biomarkers/metabolism/analysis ; *Neurodegenerative Diseases/diagnosis/metabolism/therapy/drug therapy ; Animals ; }, abstract = {Small extracellular vesicles (sEVs) have rapidly emerged as versatile mediators of intercellular communication with significant potential to transform the diagnosis and treatment of neurodegenerative diseases (NDDs). Increasing evidence shows that sEVs not only participate in the propagation of pathogenic proteins but also serve as accessible, CNS-informative carriers of molecular signatures that reflect neuronal, glial, and systemic disease processes. This dual role positions sEVs at the intersection of biomarker discovery and therapeutic innovation. In the diagnostic domain, advances in immunoaffinity capture, single-vesicle analysis, and multi-omics profiling have enabled increasingly precise characterization of neuron-, astrocyte-, and microglia-derived sEVs, revealing candidate markers for Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and related disorders. However, translation remains limited by methodological heterogeneity, a lack of large-scale validation, and the need for standardized pre-analytical and analytical pipelines aligned with the ISEV/MISEV guidelines. On the therapeutic front, native and engineered sEVs, particularly those derived from mesenchymal and neural stem cells, demonstrate promising neuroprotective effects, including the modulation of neuroinflammation; the enhancement of synaptic resilience; and the delivery of antioxidant, anti-amyloid, or gene-modifying cargo across the blood-brain barrier. Scalable GMP manufacturing, cargo-loading strategies, targeting specificity, and long-term safety remain key challenges for clinical translation. This narrative review synthesizes current advances in sEV-based biomarkers and therapeutics, outlines technological and regulatory barriers, and proposes a translational roadmap spanning mechanistic discovery, platform standardization, and integration into precision-medicine frameworks. Collectively, emerging data position sEVs as powerful tools capable of reshaping the diagnostic and therapeutic landscape of NDDs, provided that coordinated multidisciplinary efforts address the remaining gaps in validation, scalability, and regulatory readiness.}, } @article {pmid41764146, year = {2026}, author = {Ciuro, M and Sangiorgio, M and Leanza, G and Gulino, R}, title = {Neuroinflammation and Oxidative Stress in SOD1 Animal Models of ALS: A Meta-analysis Study of Their Effects on Disease Onset and Progression.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41764146}, issn = {1559-1182}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Oxidative Stress/physiology ; *Disease Progression ; Disease Models, Animal ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; *Neuroinflammatory Diseases/pathology ; *Inflammation/pathology ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder characterized by progressive motor neuron degeneration. Among the key mechanisms implicated in ALS pathogenesis, neuroinflammation and oxidative stress have emerged as prominent contributors to disease progression. This systematic review with meta-analysis involved 344 preclinical studies conducted on SOD1 animal models of ALS, to quantitatively evaluate the effects of treatments targeting neuroinflammation and oxidative stress on functional outcomes such as disease onset, survival, motor neuron degeneration, and locomotion. Data extraction and validation were performed using a combination of a large language model and human review. Results show that while most interventions led to reduced astrogliosis, M1 microgliosis, and oxidative stress, and increased M2 microgliosis, these effects were more strongly associated with improved survival and motor outcomes than with delayed disease onset. The analysis also revealed that treatment timing significantly influences outcomes, with interventions initiated during the late pre-onset window showing the highest efficacy. Furthermore, sex differences were noted, with male mice displaying better outcomes in progression metrics but worse in the age at onset. Overall, this meta-analysis indicates that inflammation and oxidative stress are important contributors to ALS progression in SOD1 animal models, identifies potentially critical therapeutic windows, and supports the consideration of sex-balanced and stage-specific treatment strategies at the preclinical level.}, } @article {pmid41765421, year = {2026}, author = {Niidome, T and Ishida, T}, title = {[Mechanism of action and clinical trial results of a new drug for amyotrophic lateral sclerosis (ALS), Mecobalamin (Rozebalamin[®]) for intramuscular injection, 25 mg].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {161}, number = {2}, pages = {115-122}, doi = {10.1254/fpj.25066}, pmid = {41765421}, issn = {0015-5691}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Clinical Trials as Topic ; Injections, Intramuscular ; *Vitamin B 12/analogs & derivatives/administration & dosage/therapeutic use/pharmacology/analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, intractable neurodegenerative disease characterized by generalized muscle atrophy and weakness, dysarthria, dysphagia, and respiratory muscle paralysis. Respiratory dysfunction due to muscle weakness is the primary cause of death; without mechanical ventilation, death typically occurs within 2 to 5 years after onset. Mecobalamin, an active form of vitamin B12, is thought to suppress homocysteine-induced neuronal cell death in ALS by acting as a coenzyme for methionine synthase, which catalyzes the conversion of homocysteine to methionine. Since the 1990s, research on neurodegenerative diseases supported by Japan's Ministry of Health, Labour and Welfare has suggested that high-dose mecobalamin may confer clinical benefits in ALS. This led to the initiation of clinical development. A Phase II/III double-blind, placebo-controlled comparative trial was conducted, but did not meet its primary endpoint. Based on these trial findings, an investigator-initiated Phase III placebo-controlled, double-blind comparative trial was conducted primarily at Tokushima University Hospital, targeting patients who developed ALS within one year before starting the trial. The trial demonstrated the efficacy of high-dose mecobalamin in slowing the decline in the Revised ALS Functional Rating Scale total score, which was the primary endpoint. Safety was also confirmed. Based on these results, mecobalamin received regulatory approval in September 2024 for the indication "slowing the progression of functional impairment in ALS." It is expected to offer a new treatment option for patients with ALS.}, } @article {pmid41772227, year = {2026}, author = {Rizzo, GEM and Vanella, G and Fuccio, L and Facciorusso, A and Mazza, S and Catena, F and Fabbri, C and Anderloni, A and Tarantino, I}, title = {Endoscopic ultrasound-guided gastrointestinal anastomoses for the treatment of afferent limb syndrome: a systematic review and meta-analysis.}, journal = {Surgical endoscopy}, volume = {40}, number = {5}, pages = {3944-3955}, pmid = {41772227}, issn = {1432-2218}, mesh = {Humans ; *Afferent Loop Syndrome/surgery ; *Endosonography/methods ; Anastomosis, Surgical/methods ; *Ultrasonography, Interventional/methods ; *Jejunostomy/methods ; *Gastric Bypass/methods/adverse effects ; }, abstract = {BACKGROUND AND STUDY AIMS: Afferent limb syndrome (ALS) is a rare condition resulting in a mechanical obstruction in the afferent loop after surgical gastrointestinal (GI) reconstruction. Endoscopic ultrasound (EUS)-guided gastrojejunostomy (GJ) or jejunojejunostomy (JJ) is increasing in clinical practice. Therefore, the aim of this systematic review with meta-analysis is to evaluate the efficacy and safety of EUS-GJ or EUS-JJ for ALS.

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

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

CONCLUSIONS: EUS-guided GI anastomosis is an effective treatment for ALS, showing high technical and clinical success rates and a low incidence of AEs. The use of LAMS over FCSEMS seems to reduce the recurrence rate, suggesting the routine use of LAMS in the case of EUS-guided GI anastomosis for treating ALS.}, } @article {pmid41776544, year = {2026}, author = {Hirota, R and Lankford, KL and Nakazaki, M and Toyoshima, M and Kocsis, JD}, title = {Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.}, journal = {Molecular brain}, volume = {19}, number = {1}, pages = {}, pmid = {41776544}, issn = {1756-6606}, mesh = {Animals ; Administration, Intranasal ; *Mesenchymal Stem Cells/metabolism/cytology ; Humans ; *Extracellular Vesicles/metabolism/transplantation ; Disease Models, Animal ; *Disease Progression ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/pathology/therapy/physiopathology ; *Superoxide Dismutase/metabolism ; *Superoxide Dismutase-1/metabolism ; Body Weight ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.}, } @article {pmid41777232, year = {2026}, author = {Yerraguntla, S and Bakshi, B and Chandran, K and Foucher, J and Benatar, M and Wicks, P and Bedlack, R and Shirilla, D and Sun, Y and Maragakis, N and Greenstein, E and Mascias Cadavid, J and Rao, A and Allen, O and Dyckman, K and Wang, O and Beauchamp, M and Chang, V and Brown, A and Carbunar, O and Paganoni, S and Bertorini, T and Pioro, E and Elsharif, B and Jiang, N and Pattee, G and Carter, G and Breevoort, S and Tito, E and Nathaniel, G and Jackson, C and Olby, N and McDermott, C and Ratner, D and Li, X}, title = {ALSUntangled #82: N-acetylcysteine.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {717-721}, doi = {10.1080/21678421.2026.2638590}, pmid = {41777232}, issn = {2167-9223}, mesh = {*Acetylcysteine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Animals ; Oxidative Stress/drug effects ; *Antioxidants/therapeutic use ; }, abstract = {N-acetylcysteine is a thiol-containing compound and a precursor of glutathione, with mechanistic plausibility for ALS, including reducing oxidative stress, regulating neuroinflammation, and mitigating mitochondrial dysfunction. Preclinical studies have yielded conflicting results on whether N-acetylcysteine can delay the onset of motor impairment and prolong survival in ALS mouse models. Several case studies of oral or subcutaneous administration of N-acetylcysteine in patients with ALS did not demonstrate convincing benefits. Clinical trials to date have also failed to demonstrate efficacy in slowing ALS progression. While N-acetylcysteine shows theoretical promise, further research is needed to clarify its therapeutic role in ALS. At present, ALSUntangled does not support the use of N-acetylcysteine as a treatment to slow ALS progression.}, } @article {pmid41778725, year = {2026}, author = {Rizvi, FAS and Jimoh, Y and Allouh, MZ and Rahmon, D and Chaudhry, GR}, title = {Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01147}, pmid = {41778725}, issn = {1673-5374}, abstract = {Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.}, } @article {pmid41783572, year = {2026}, author = {Liu, W and Xue, Y and Cao, C and Yang, L and Zhang, L}, title = {Copper Homeostasis and Cuproptosis in Neurological Disorders.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {580005}, pmid = {41783572}, issn = {1177-8881}, mesh = {Humans ; *Cuproptosis ; *Homeostasis ; *Copper/metabolism ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; }, abstract = {Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.}, } @article {pmid41789732, year = {2026}, author = {Scarpa, E and D'Amora, U and De Cesare, N and Bonadies, I and Dubbioso, R and Nolano, M and Dardano, P and De Stefano, L and Fasolino, A and Zeppetelli, S and Silvestri, A and Zanardi, C and Milella, E and Fasolino, I}, title = {3D Artificial Skin Model As a Novel Strategy for the Detection of Pyroptosis-Cascade Activation in Amyotrophic Lateral Sclerosis.}, journal = {ACS applied materials & interfaces}, volume = {18}, number = {10}, pages = {14603-14616}, pmid = {41789732}, issn = {1944-8252}, mesh = {Humans ; Biopsy ; *Skin, Artificial ; *Skin/metabolism/pathology ; *Pyroptosis ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Polyesters/chemistry ; Printing, Three-Dimensional ; Hyaluronic Acid/chemistry ; Biomarkers ; Cell Proliferation ; Biocompatible Materials/chemistry ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe adult-onset neurodegenerative disease with limited treatment approaches. Evidence has shown that degeneration of cutaneous nerves may reflect neurodegenerative processes occurring within the central nervous system. Although skin biopsy is widely adopted in clinical practice, the procedure is invasive and requires multiple patients' tissue removals. Therefore, we developed a 3D innervated skin model by combining 3D printing of methacrylated hyaluronic acid as an innovative tool for better reproducing the dermis and epidermis and electrospinning of polylactic acid for mimicking skin innervation. Later, 3D artificial skin was colonized with a preneuronal cell line (SH-SY5Y) and fibroblasts isolated from skin biopsy of ALS patients at different disease stages. 3D skin possesses a porosity suitable for cell colonization and a high stability. Importantly, biological results reveal an increase of TAR DNA-binding protein 43 aggregates, NOD-like receptor pyrin domain containing protein 3, interleukin (IL)-18, IL-6, and nitrites in 3D skin of ALS patients, thus indicating pyroptosis activation linked to neurodegeneration. This physiologically relevant 3D skin model reduces the need for repeated biopsies, allows standardized experimental conditions, and supports biomarker research and preclinical drug testing in ALS.}, } @article {pmid41792996, year = {2026}, author = {Magen, I and Kaneb, HM and Masnata, M and Pulimood, N and Emde, A and Genge, A and Hornstein, E}, title = {Cell-free miRNAs are pharmacodynamic biomarkers for enhanced DICER activity by enoxacin in human patients with ALS.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {34}, number = {6}, pages = {3224-3230}, pmid = {41792996}, issn = {1525-0024}, mesh = {Humans ; *Enoxacin/pharmacokinetics/pharmacology/administration & dosage/cerebrospinal fluid/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/blood/metabolism/cerebrospinal fluid ; *MicroRNAs/blood/genetics/cerebrospinal fluid ; *Ribonuclease III/metabolism/genetics ; Female ; Biomarkers/cerebrospinal fluid/blood ; Male ; Middle Aged ; *DEAD-box RNA Helicases/metabolism ; Aged ; Double-Blind Method ; Adult ; }, abstract = {The activity of the RNase III enzyme DICER is downregulated in both sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). Accordingly, hundreds of microRNAs (miRNAs) are broadly downregulated, leading to de-repression of their mRNA targets. Enoxacin is a fluoroquinolone that enhances DICER activity and miRNA biogenesis. Here, we tested for the first time the molecular effect of enoxacin on miRNA biogenesis in ALS patients and demonstrated that enoxacin's engagement with DICER can be pharmacodynamically monitored via miRNA levels in human subjects. In an investigator-initiated, first-in-human study (REALS1), we explored miRNAs as pharmacodynamic biomarkers of DICER activation. Patients with sporadic ALS received oral enoxacin twice daily for 30 days in a double-blind, randomized clinical trial. The study demonstrated comparable enoxacin levels in plasma and cerebrospinal fluid (CSF). Furthermore, an increase in cell-free miRNA levels in both plasma and CSF at all time points following enoxacin treatment (400 or 800 mg/day), was measured relative to baseline. Additionally, no serious adverse events were reported. In conclusion, pharmacological enhancement of DICER activity by enoxacin increases miRNA biogenesis in patients with ALS. These results support further investigation of enoxacin efficacy in larger clinical trials.}, } @article {pmid41795667, year = {2026}, author = {Burgess, A and Allen, O and Barkhaus, P and Barnes, B and Benatar, M and Bertorini, T and Bowser, R and Mascias Cadavid, J and Carter, GT and Cudkowicz, M and Denson, K and Dyckman, K and Elsharif, B and Feldman, E and Foucher, J and Fullum, T and Glass, J and Helmold, B and Jackson, C and Jhooty, S and Leday, A and Mallon, E and Mcdermott, C and Olby, N and Ostrow, L and Pattee, G and Pioro, E and Ratner, D and Sang, H and Tito, E and Vieira, F and Wicks, P and Bedlack, R and Gelevski, D}, title = {ALS untangled #83: clenbuterol.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2638588}, pmid = {41795667}, issn = {2167-9223}, abstract = {ALS Untangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review clenbuterol, a β-2 adrenergic agonist, as a potential treatment for amyotrophic lateral sclerosis (ALS). Clenbuterol has biological effects that could be relevant to the pathophysiology of ALS such as inducing muscle hypertrophy, improving mitochondrial function, and reducing neuroinflammation. Two studies in mouse models of motor neuron disease and two open label trials suggest possible benefits. However these have methodological flaws which limit interpretation. Clenbuterol can have an array of side effects, some severe. Drop-outs due to side effects were very common in one of the ALS trials and in a separate expanded access program. Based on this information, we cannot currently endorse clenbuterol as an ALS treatment, but we do hope to see further studies of it, or another long acting β-2 adrenergic agonist in people with ALS.}, } @article {pmid41798433, year = {2026}, author = {Matsuzawa, K and Takahashi, T and Sakata, J and Uchida, T and Suzuki, T and Sakai, T}, title = {Effectiveness of a Progressive Rehabilitation Approach Without Sport Activity Restriction for Acute Lumbar Spondylolysis in High-Level Athletes: A Retrospective Case Series.}, journal = {Cureus}, volume = {18}, number = {2}, pages = {e103041}, pmid = {41798433}, issn = {2168-8184}, abstract = {OBJECTIVE: This study aimed to examine the characteristics and clinical outcomes of high-level athletes with acute lumbar spondylolysis (ALS) treated with a progressive rehabilitation (PR) approach without rigid bracing or activity restriction.

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

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

CONCLUSIONS: A PR approach without rigid bracing or activity restriction enabled early RTS in high-level athletes with ALS, with symptom improvement and no recurrence. This approach may allow modification of pain-provoking or injury-related movements and help minimize declines in physical fitness and body composition associated with activity restriction. It may be suitable for post-growth high-level athletes who understand the risks related to bone healing and require timely RTS, although further research is needed to clarify stage-specific indications and long-term outcomes.}, } @article {pmid41804301, year = {2026}, author = {Koropouli, E and Bellos, S and Aristeidou, S and Daponte, A and Gklinos, P and Athanasopoulos, F and Tsionis, A and Andreadou, E and Zouvelou, V and Rentzos, M}, title = {Motor neuron disease can present as a paraneoplastic neurologic syndrome with various phenotypes.}, journal = {Brain communications}, volume = {8}, number = {2}, pages = {fcag024}, pmid = {41804301}, issn = {2632-1297}, abstract = {Paraneoplastic motor neuron disease is an uncommon paraneoplastic neurologic syndrome whose existence has fallen into ambiguity. Epidemiologic studies that have addressed the association between cancer and motor neuron disease have provided conflicting results. Case studies that report motor neuron disease presentation at the time of active malignant disease, in the presence of another paraneoplastic neurologic syndrome or onconeural antibody or with neurologic response to antineoplastic treatment provide strong evidence for paraneoplastic motor neuron disease. However, conclusive evidence about the existence and the clinical and laboratory profiles of this neurologic syndrome is lacking. In this study, we report four new cases of paraneoplastic motor neuron disease, two of whom with expression of Sry-like high mobility group box 1 (SOX1) antibody. We also present a systematic review of all cases of paraneoplastic motor neuron disease reported to date that fulfill prespecified inclusion criteria with individual participant data meta-analysis of the demographic, clinical and laboratory features of the disease. Our data demonstrate that motor neuron disease can present as a paraneoplastic neurologic syndrome. Paraneoplastic motor neuron disease spans the whole motor neuron disease phenotypic spectrum, and it is associated with a wide variety of neoplastic diseases, onconeural antibodies and it may present concurrently with other well-recognized paraneoplastic neurologic syndromes. Paraneoplastic motor neuron disease may be clinically indistinguishable from idiopathic motor neuron disease. Its only distinctive clinical feature is the rapidly progressive course. A subset of cases display immune derangements in cerebrospinal fluid, including increased white cell count, elevated protein, albumin index, IgG index and/or oligoclonal band expression. Cancer-induced inflammatory pathways may trigger the disease in genetically predisposed individuals harboring amyotrophic lateral sclerosis-causing genetic deficits. A thorough evaluation for neoplastic diseases should be carried out upon strong suspicion of this rare paraneoplastic neurologic syndrome to increase the diagnostic yield for this entity. Paraneoplastic motor neuron disease apparently results from complex interactions between degenerative and immune pathways and its pathophysiology may elucidate previously unresolved aspects of idiopathic motor neuron disease pathogenesis.}, } @article {pmid41804597, year = {2026}, author = {Georgiadou, P and Erkaya, B and Niwa-Kawakita, M and Oltan, M and Keskin, YK and Sahin, E and Öztürk, H and Tiryaki, F and Yildiz, K and Özgenç, I and Odabasi, E and Pekbilir, E and Dogan, SA and Lallemand-Breitenbach, V and Vargas, S and Prochiantz, A and Firat-Karalar, EN and de Thé, H and Sahin, U}, title = {Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset.}, journal = {The FEBS journal}, volume = {293}, number = {17}, pages = {5170-5185}, pmid = {41804597}, issn = {1742-4658}, support = {679140//H2020 European Research Council/ ; 119N095//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; Installation Grant IG3336//European Molecular Biology Organization/ ; }, mesh = {Animals ; *NIMA-Related Kinase 1/genetics/metabolism ; Humans ; *Promyelocytic Leukemia Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; Proteolysis ; Sumoylation ; Disease Models, Animal ; Mutation ; }, abstract = {Germinal mono-allelic loss-of-function mutations of NEK1 drive amyotrophic lateral sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1[t]) is aggregation-prone, particularly in alpha-motoneurons (αMNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1[t/t]). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1[wt/t] animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1[t] proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1[t] puncta in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, yielding dramatic clinical improvement. These observations provide strong proof-of-concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.}, } @article {pmid41804798, year = {2026}, author = {Jagaraj, CJ and Saravanabavan, S and Parakh, S and Jayakumar, M and Kashani, SA and Shadfar, S and Mehta, P and Gautam, S and Farzana, F and Suchowerska, AK and Yap, K and Vidal, M and Ragagnin, AMG and Jamali, MS and Yang, S and Fath, T and Craik, D and Atkin, JD}, title = {Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag096}, pmid = {41804798}, issn = {1460-2156}, abstract = {Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neurodegeneration and developing new therapeutic targets in these conditions. Cofilin is a multi-functional protein with a crucial role in regulating the actin cytoskeleton. Actin has important neuronal-specific activities in dendritic spines, axonal growth cones and synapses and it is in constant equilibrium between two forms: monomeric globular actin (G-actin) and polymeric filamentous actin (F-actin). Cofilin controls actin dynamics by depolymerising and severing actin filaments. When cofilin is phosphorylated (at Serine-3) by LIM kinase1 (LIMK1), it becomes inactive, leading to production of more F-actin. Defects in cofilin are well described in other neurodegenerative disorders, unlike in ALS. We examined phosphorylation of cofilin and actin dynamics in post-mortem spinal cord tissue from sporadic ALS (SALS) patients, the TDP-43 rNLS8 transgenic mouse model, and NSC34 motor neuronal cells expressing cytoplasmic TDP-43. F-actin was pharmacologically stabilized to mimic cofilin hyperphosphorylation, and TDP-43 pathology was assessed. Neuronal cells were treated with a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN), and TDP-43 pathology and apoptosis were evaluated. Here, we show that cofilin is hyper-phosphorylated in human ALS and disease models compared to controls. This was detected in spinal motor neurons from sporadic ALS (SALS) patients and a TDP-43 mouse model (rNLS8) displaying key ALS phenotypes, and in motor neuronal NSC34-cells expressing cytoplasmic TDP-43. Supporting this observation, more F-actin relative to G-actin was present in cortical/spinal cord lysates from SALS patients and TDP-43 rNLS8 mice, and NSC34-cells expressing TDP-43. We also show that mimicking cofilin hyperphosphorylation by pharmacological stabilization of F-actin induced TDP-43 pathology: cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, and fragmentation, and promoted its recruitment into stress granules (SGs). Furthermore, we detected increased levels of LIMK1 phosphorylation and tropomyosin isoforms 4.1 and 4.2 in SALS patients. These findings reveal aberrant cofilin hyperphosphorylation disrupts actin dynamics, triggering TDP-43 pathology and SG recruitment in SALS. They imply that preventing cofilin phosphorylation is a novel therapeutic strategy applicable to most ALS cases. Treatment of neuronal cells with the S3A peptide prevented features of TDP-43 pathology and apoptosis compared to control peptides. These findings thus describe a novel pathogenic mechanism producing TDP-43 pathology, applicable to most ALS cases and other neurodegenerative diseases.}, } @article {pmid41807703, year = {2026}, author = {Guo, S and Jin, H and Sun, H and Huang, S and Chen, Y and Chang, Y and Zhang, Y and Ding, L and Chen, S and Fu, C and Yin, Y and Cheng, W}, title = {TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.}, journal = {EMBO molecular medicine}, volume = {18}, number = {4}, pages = {1318-1341}, pmid = {41807703}, issn = {1757-4684}, support = {82472014//MOST | National Natural Science Foundation of China (NSFC)/ ; 24ZR1450000//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; 23ZR1441200//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; }, mesh = {Animals ; *Microglia/pathology/metabolism ; *Necroptosis ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics/antagonists & inhibitors ; *Neuroinflammatory Diseases/pathology/metabolism ; Humans ; *Cognitive Dysfunction/pathology/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Quinolines ; Benzothiazoles ; }, abstract = {Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.}, } @article {pmid41807991, year = {2026}, author = {Solheim, MH and Riise, T and Cortese, M and Nakken, O and Tysnes, OB and Igland, J and Bjornevik, K}, title = {Distinct Prescription Patterns Emerge Years Before ALS Diagnosis: A Nationwide Registry-Based Study.}, journal = {Annals of neurology}, volume = {99}, number = {6}, pages = {1516-1525}, pmid = {41807991}, issn = {1531-8249}, support = {F-12830//Helse Vest/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology ; *Registries ; Female ; Male ; Norway/epidemiology ; Case-Control Studies ; Middle Aged ; Aged ; *Prodromal Symptoms ; *Drug Prescriptions/statistics & numerical data ; Adult ; *Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {OBJECTIVE: The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre-diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.

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

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

INTERPRETATION: Prescription pattern changes occurred as early as 6 years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. ANN NEUROL 2026;99:1516-1525.}, } @article {pmid41809457, year = {2026}, author = {Maurya, P and Gupta, A and Gupta, N}, title = {Influence of blood transfusion on outcomes in patients with gastric cancer.}, journal = {World journal of gastroenterology}, volume = {32}, number = {10}, pages = {115683}, pmid = {41809457}, issn = {2219-2840}, mesh = {Humans ; *Blood Loss, Surgical/prevention & control ; *Blood Transfusion/statistics & numerical data ; *Gastrectomy/adverse effects ; *Stomach Neoplasms/surgery/mortality/immunology/therapy ; *Transfusion Reaction/immunology ; Treatment Outcome ; }, abstract = {Chen et al's research provides valuable data supporting the cautious use of transfusions during gastric cancer surgery. However, to interpret causality, it must be acknowledged that recent tend-adjusted studies have consistently shown that the independent effect of transfusions may be smaller than that shown in unadjusted analyses. Future research should employ the following approaches: (1) Extended temporal characterization; (2) Functional immunological assessment; (3) Prospective designs incorporating detailed transfusion data; (4) Machine learning methods; and (5) Mechanistic studies. The relationship between transfusions and cancer treatment outcomes goes far beyond simple immunosuppression or inflammation. It reflects a complex interplay between patient vulnerability, surgical factors, and immune responses, requiring a comprehensive study across multiple biological levels and temporal dimensions.}, } @article {pmid41809632, year = {2026}, author = {Mazurek, CY and Kaniuk, JK and Ahuja, CS}, title = {Mesenchymal stem cells and the central nervous system: historical perspectives and future directions.}, journal = {Frontiers in molecular neuroscience}, volume = {19}, number = {}, pages = {1742864}, pmid = {41809632}, issn = {1662-5099}, abstract = {Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.}, } @article {pmid41809878, year = {2026}, author = {Xu, S and Zhu, Z and Zhang, HM and Xu, YT and Shi, PH and Zheng, Y and Chen, YT and Lu, GR and Zheng, BJ}, title = {Targeting Dialister-driven succinate accumulation: A novel strategy for Crohn's disease activity control and recurrence prevention.}, journal = {World journal of gastroenterology}, volume = {32}, number = {8}, pages = {116173}, pmid = {41809878}, issn = {2219-2840}, mesh = {Humans ; *Crohn Disease/microbiology/metabolism/surgery/blood ; *Succinic Acid/metabolism/blood ; Recurrence ; Secondary Prevention/methods ; *Gastrointestinal Microbiome/drug effects/immunology ; Feces/microbiology ; Severity of Illness Index ; Quality of Life ; }, abstract = {Crohn's disease (CD) activity and postoperative recurrence significantly affect patients' quality of life, highlighting the need for new treatment and prevention strategies. We read with interest Boronat-Toscano et al's study on Dialister-driven succinate accumulation in CD. By analyzing the fecal microbiota, circulating succinate levels, and clinical indices using clinical samples, the researchers explored the roles of Dialister and succinate in CD, a previously unaddressed area. They revealed that active CD is characterized by high succinate levels, which are associated with disease severity and inflammatory indicators. The enrichment of Dialister, linked to impaired succinate clearance and postoperative recurrence, offers new insights. The study identified succinate and Dialister as potential therapeutic targets, advancing understanding of CD pathophysiology and paving the way for further investigations. Future studies should involve large, multicenter cohorts for validation, explore Dialister's strain-specific metabolic mechanisms, and develop treatments targeting the "succinate axis", thus connecting fundamental research with clinical applications.}, } @article {pmid41811044, year = {2025}, author = {Wang, Y and Lu, Z and Cheng, S and Wang, Y and Yuan, H and Yuan, H}, title = {[Clinical phenotype and genetic analysis of a child with Acid-labile subunit deficiency due to variant of IGFALS gene].}, journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics}, volume = {42}, number = {12}, pages = {1465-1470}, doi = {10.3760/cma.j.cn511374-20241122-00615}, pmid = {41811044}, issn = {1003-9406}, mesh = {Humans ; Male ; Phenotype ; Child, Preschool ; *Carrier Proteins/genetics ; Insulin-Like Growth Factor Binding Protein 3/genetics/blood ; *Glycoproteins/deficiency/genetics ; Insulin-Like Growth Factor I/metabolism/genetics ; Pedigree ; Exome Sequencing ; }, abstract = {OBJECTIVE: To explore the clinical phenotypes and genetic characteristics of a child with Acid-labile subunit deficiency (ALS).

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

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

CONCLUSION: The IGFALS gene variants NM_004970.2: c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31 may be the genetic etiology in this family. This study has expanded the variant spectrum of the IGFALS gene and provided valuable information for the diagnosis, genetic counseling and clinical treatment of the disease.}, } @article {pmid41813136, year = {2026}, author = {Perry, CM and Martin, DDO}, title = {ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {46}, number = {10}, pages = {}, pmid = {41813136}, issn = {1529-2401}, mesh = {Humans ; *Huntington Disease/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Huntingtin Protein ; Animals ; *Nerve Tissue Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are lethal neurodegenerative diseases affecting motor function. Though their etiology and pathology are distinct, recent evidence suggests commonalities between TAR DNA-binding protein (TDP-43), which is associated with 97% of ALS cases, and huntingtin (HTT), the causative protein of HD. ALS is a heterogeneous, lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, as well as brainstem and spinal cord degeneration. The causes of ALS are complex, variable, and, in some cases, unknown, but most cases involve mislocalization of the protein TDP-43. In contrast, HD is a monogenic, autosomal dominant, lethal neurodegenerative disease caused by polyglutamine expansion in HTT protein and characterized by the progressive loss of neurons in the brain, particularly in the striatum, which results in motor, cognitive, and behavioral changes. Although HD is not typically associated with motor neuron loss, recent evidence suggests a link between HTT and TDP-43 within the context of both ALS and HD, as well as links to related neurodegenerative diseases, such as frontotemporal dementia (FTD) and spinocerebellar ataxia type 2 (SCA2). Herein, we discuss confirmed cases of concurrent ALS and HD and the overlap of underlying disease mechanisms that potentially contribute to the onset and progression of these two devastating neurodegenerative diseases, with a focus on commonalities between TDP-43 and HTT. We propose that elucidating these commonalities will aid in the identification of broad-spectrum disease risk factors and potential overlapping treatment targets.}, } @article {pmid41813498, year = {2026}, author = {Reimer, RJ and Soper, B and Wilson, JL and Goncalves, AR and Cadena, J and Suarez, P and Gryshuk, AL and Osborne, TF and Grimes, KV and Ray, P}, title = {Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study.}, journal = {The Lancet. Digital health}, volume = {8}, number = {3}, pages = {100963}, doi = {10.1016/j.landig.2025.100963}, pmid = {41813498}, issn = {2589-7500}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Humans ; *Electronic Health Records/statistics & numerical data ; Retrospective Studies ; *Drug Repositioning ; United States ; Male ; Female ; Middle Aged ; Aged ; Veterans/statistics & numerical data ; United States Department of Veterans Affairs ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3-5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS.

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

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

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

FUNDING: Congressionally Directed Medical Research Programs, US Department of Defense.}, } @article {pmid41817655, year = {2026}, author = {Bakshi, V and Pathak, B and Majie, A and Ghosh, A and Gupta, A and Jain, N and Pandey, M and Nair, AB and Jacob, S and Mazumder, PM and Sharma, N and Kumari, N and Gorain, B}, title = {Advancement in therapeutic application of quantum dots in amyotrophic lateral sclerosis: current opportunities and challenges.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {41817655}, issn = {2190-3948}, abstract = {Despite advancements in healthcare settings in developed countries, the early detection and higher mortality rate associated with amyotrophic lateral sclerosis (ALS), a fatal motor neuronal disorder, remain challenging. Recently, quantum dots (QDs) have emerged as a promising nanocarrier in the prognosis and treatment of ALS owing to their unique multifunctional properties. QDs, through their photoluminescence properties upon excitation, can facilitate the identification and real-time monitoring of disease biomarkers. They also act as a nanocarrier for the targeted delivery of therapeutics, avoiding accumulation at the non-targeted sites and minimising toxicity. QDs can be fabricated to conjugate with protein biomarkers linked to ALS, such as specific proteins, nucleic acids, or genetic variants, for the diagnosis of the disease. Such fabrication could lead to enhanced identification and diagnostic patterns of ALS, thereby contributing to improved therapeutic intervention strategies. Furthermore, these tiny structures could be applied in combined biosensor formats to identify ALS-associated biomarkers in body fluids, which would be a highly sensitive diagnostic system. Subsequently, comprehensive multiomics techniques have demonstrated improved identification of newer protein targets associated with neurological complications. Overall, QDs can be explored as a potential tool to identify biomarkers relevant to ALS, diagnose the disease at its early stages, and track the effectiveness of the treatment. The integration of QD with omic-based strategies and network analysis can potentially catalyse a breakthrough in the management of ALS. Therefore, this review aims to explore the application of QDs in ALS diagnosis and management, advancements in research, clinical trials, and patents.}, } @article {pmid41821014, year = {2026}, author = {Sligar, C and Sluyter, R and Ooi, L}, title = {Immune imbalance between T helper 1, T helper 17 and regulatory T cells fuels amyotrophic lateral sclerosis pathogenesis: disease trajectory, diagnosis and therapeutic implications.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {}, pmid = {41821014}, issn = {1742-2094}, support = {AL210095//U.S. Department of Defense/ ; CE230100021//Australian Research Council Centre of Excellence in Quantum Biotechnology/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/diagnosis/therapy/pathology ; *T-Lymphocytes, Regulatory/immunology ; Animals ; *Th17 Cells/immunology ; *Th1 Cells/immunology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease, causing motor neuron loss and with limited treatment options. Although traditionally considered non-immune in origin, accumulating evidence implicates the adaptive immune system, particularly CD4+ T cell subsets, as key modulators of disease progression. Among these, T helper (Th)1 and Th17 cells are elevated in ALS blood, cerebrospinal fluid and central nervous system tissues, and drive pro-inflammatory cascades. By contrast, regulatory T cells (Tregs) suppress pathogenic inflammation and maintain immune homeostasis; however, in ALS, both Treg number and suppressive function decline, with remaining Tregs showing reduced FOXP3 (the master transcription factor governing Treg function) expression and impaired regulatory capacity. Integrating human and preclinical evidence, we describe how ALS-associated proteins can act as autoantigens that trigger adaptive immune responses, and how Th1/Th17 amplification and Treg insufficiency couple to microglial activation, blood–brain barrier disruption, and motor neuron degeneration, to impact disease trajectory. Convergent signalling pathways and their intersection with metabolic stress provide a mechanistic link between the adaptive immune response and neurodegeneration. We outline biomarker frameworks, spanning immune cell phenotypes, cytokine signatures and transcriptional readouts that define alterations in Th1, Th17 and Treg responses in ALS. Finally, we address the emerging immunomodulatory therapeutic approaches, including the targeted blockade of specific cytokines and signalling pathways, augmentation of Treg number and function, and attenuation of Th1/Th17 activity, while preserving protective Tregs using selective small-molecule approaches. Collectively, the evidence we provide establishes adaptive T cell imbalance as a central, targetable driver of ALS neuroinflammation and provides a rationale for biomarker-guided therapeutics designed to rebalance adaptive immunity and slow disease progression.}, } @article {pmid41821425, year = {2026}, author = {Bilić, H and Begović, M and Sitaš, B and Hančević, M and Šepec, BI and Zemba Čilić, A and Peček, V and Gotovac Jerčić, K and Mateševac, J and Bahčić, T and Peček, L and Borovečki, F and Njirić, N and Nemir, J and Petrović, M and Jurjević, I and Klarica, M and Merćep, I and Bilić, E}, title = {Tofersen treatment in SOD1 p.Leu145Phe ALS: real-world outcomes in a genetically homogeneous Croatian cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {689-695}, doi = {10.1080/21678421.2026.2638589}, pmid = {41821425}, issn = {2167-9223}, mesh = {Humans ; *Superoxide Dismutase-1/genetics ; Female ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/epidemiology ; Middle Aged ; Male ; Cohort Studies ; Aged ; Croatia/epidemiology ; Treatment Outcome ; Mutation/genetics ; Adult ; *Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Background: Antisense oligonucleotide tofersen targets SOD1 mRNA and reduces production of misfolded SOD1 protein, with demonstrated biomarker and functional signals in clinical trials and open-label extensions. Real-world reports from genetically heterogeneous SOD1 ALS cohorts describe variable functional trajectories. Data from genetically homogeneous founder populations remain limited. We investigated clinical trajectories in a cohort carrying the same pathogenic SOD1 variant to better characterize mutation-specific patterns in a real-world setting. Methods: We conducted a single-center observational study at the National Referral Center for Neuromuscular Diseases and Clinical Electromyoneurography (UHC Zagreb, Croatia). Eight adults with genetically confirmed SOD1 p.Leu145Phe ALS received intrathecal tofersen according to the approved regimen. ALS Functional Rating Scale-Revised (ALSFRS-R) scores were recorded at each dosing visit, and longitudinal slopes were calculated using linear regression. Safety and tolerability were evaluated descriptively. Biomarker and formal respiratory measurements were not routinely available. Results: All patients exhibited lower limb-onset, predominantly lower motor neuron phenotypes consistent with a slow-progressing founder variant. Median age at symptom onset was 60 years, and median therapeutic delay was 48 months. Median on-treatment ALSFRS-R slope was -0.28 points/month (range +0.04 to -0.57). Two patients demonstrated stable trajectories, while the remainder showed gradual decline. These patterns fall within the slower range reported in heterogeneous real-world SOD1 cohorts and are consistent with the known natural history of this mutation. Tofersen was well tolerated, with no serious treatment-related adverse events. Conclusions: In this genetically homogeneous SOD1 p.Leu145Phe cohort, functional trajectories during tofersen therapy reflected the mutation's slow-progressing phenotype. These findings provide real-world clinical context but do not permit conclusions regarding treatment efficacy. Further mutation-specific studies incorporating prospective baseline assessment and biomarker monitoring are needed to clarify therapeutic impact.}, } @article {pmid41822688, year = {2026}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41822688}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

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

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

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with substantially reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.}, } @article {pmid41830107, year = {2026}, author = {Chen, Y and Feng, Y and Sonksen, M and Wang, T and Jin Song, J}, title = {Propensity Score-Based Stratified Win Ratio for Augmented Control Designs.}, journal = {Statistics in medicine}, volume = {45}, number = {6-7}, pages = {e70487}, doi = {10.1002/sim.70487}, pmid = {41830107}, issn = {1097-0258}, mesh = {Humans ; *Propensity Score ; Amyotrophic Lateral Sclerosis/drug therapy ; Computer Simulation ; Models, Statistical ; Research Design ; Endpoint Determination ; }, abstract = {This paper proposes a propensity score (PS)-based stratified win ratio method to address challenges of small patient populations in clinical trials, especially for rare or pediatric diseases, by incorporating external control data. Our approach enhances traditional win ratio analysis by leveraging PS stratification to account for heterogeneity between the current and external studies. Additionally, down-weighting based on the overlapping coefficient of PS distributions of current treatment and external control groups further mitigates the patient bias due to heterogeneity. Simulations show significant improvements in statistical power for detecting treatment effects within the composite endpoint combining continuous and time-to-event components, over nonborrowing and pooling methods, with utilizing Mantel-Haenszel (MH)-type weights achieving the highest power. The proposed methods are also applied to an amyotrophic lateral sclerosis (ALS) study incorporating the external control arm from a prior ALS trial. The proposed PS-based stratified win ratio method thus provides a rigorous framework for borrowing external data and analyzing composite endpoints with limited patient availability.}, } @article {pmid41831326, year = {2026}, author = {Furlan, R and Di Sapio, A and Ferraro, D and Rossi, E and Valentino, P and Terracciano, D}, title = {Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.}, journal = {Clinical chemistry and laboratory medicine}, volume = {64}, number = {9}, pages = {1904-1918}, pmid = {41831326}, issn = {1437-4331}, mesh = {Humans ; *Neurofilament Proteins/blood/analysis ; Biomarkers/blood/analysis ; Multiple Sclerosis/diagnosis ; }, abstract = {Neurofilament light chain (NfL) has been identified as a sensitive and broadly validated biomarker of neuroaxonal injury across multiple neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and atypical parkinsonian syndromes. This position paper provides a multidisciplinary roadmap for translating circulating NfL testing into routine clinical practice, integrating analytical, interpretative, and organizational dimensions. It summarizes the biological basis and clinical evidence supporting NfL as a diagnostic, prognostic, and monitoring tool, emphasizing its high sensitivity to neuroaxonal injury across both acute inflammatory and chronic degenerative processes. Comparative analysis of immunoassay technologies identifies strengths and critical sources of variability, while operational guidelines highlight the need for pre-analytical standardization, inter-laboratory harmonization, and participation in quality control schemes. Confounders such as age, BMI, renal function, and comorbidities are shown to significantly influence interpretation, supporting the use of age-adjusted Z-scores, percentiles, and longitudinal normalization for accurate patient-level evaluation. From a clinical standpoint, the paper focuses on practical indications for NfL testing in MS, recommending its use for disease activity prediction and monitoring, treatment decisions and treatment response assessment. Integration of blood NfL with magnetic resonance imaging (MRI), glial fibrillary acidic protein (GFAP) and other biomarkers measurement is proposed as a core strategy for biomarker-driven precision neurology. The authors outline an implementation model encompassing laboratory validation, structured reporting and alignment with national neurological care pathways. They conclude that the transition of NfL into clinical use requires harmonized analytical procedures, interdisciplinary education, and sustainable governance frameworks. Priority actions include regulatory qualification, establishment of international reference materials, and development of pragmatic real-world trials to consolidate its clinical utility. When these measures are achieved, NfL will represent a cornerstone biomarker for precision neurology and neurodegeneration monitoring.}, } @article {pmid41837970, year = {2026}, author = {Cudkowicz, M and Drory, VE and Chio, A and Lunetta, C and Shoesmith, C and van Eijk, RPA and Salomon-Zimri, S and Shtossel, D and Kerem, N and Shapira, G and Shomron, N and Russek-Blum, N and Tracik, F and Rosenfeld, J and Shefner, J}, title = {Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {83}, number = {5}, pages = {471-480}, pmid = {41837970}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Double-Blind Method ; Female ; Middle Aged ; Male ; *Celecoxib/therapeutic use/adverse effects/administration & dosage ; Aged ; Drug Combinations ; Treatment Outcome ; }, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs.

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

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

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

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

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

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

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05357950.}, } @article {pmid41845971, year = {2026}, author = {Dahlhaus, R and Braun, RJ}, title = {The role of TDP-43 fragments in regular cellular functions and homeostatic failure.}, journal = {Neurobiology of disease}, volume = {222}, number = {}, pages = {107349}, doi = {10.1016/j.nbd.2026.107349}, pmid = {41845971}, issn = {1095-953X}, mesh = {Humans ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Homeostasis/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *TDP-43 Proteinopathies/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons, leading to severe muscle weakness, loss of voluntary movement, and respiratory failure. A widely noted feature of the disease is the presence of TDP-43 proteinopathies. Under homeostatic conditions, the RNA/DNA-binding protein TDP-43 mainly resides in the nucleus, where it functions to regulate gene expression, controlling not only RNA transcription and splicing, but also stability and transport to the cytoplasm. Upon the arrival at ribosomes, TDP-43 may further moderate translation, acting as a global repressor of protein synthesis. However, in over 95% of ALS cases, TDP-43 mislocalises from the nucleus to the cytoplasm, where it enriches in cytoplasmic inclusions that are marked by the presence of misfolded, ubiquitinated, phosphorylated and fragmented protein species of TDP-43. Although recent studies have tried to untangle the relationship between TDP fragments on the one hand, and cytotoxicity as well as neurodegeneration on the other, the results are still a matter of debate. Here, we review our current understanding of the different TDP fragments derived from proteolytic cleavage as well as alternative splicing, addressing the different N-terminal and C-terminal species and evaluating differences in rodent and primate models. We focus our analysis on potential homeostatic functions of TDP fragments in the context of viral infections and myelination control, which could be pivotally interconnected. The findings illustrate several facets of fragmented TDP-43 protein species in scenarios of enhanced cellular stress. Gaining a detailed understanding could help to reveal new treatment options for ALS and other TDP-43 proteinopathies.}, } @article {pmid41846014, year = {2026}, author = {Yang, L and Fan, W and Wang, Z and Wu, M and Chen, Y and Cheng, J and Zhou, F and Guo, Z}, title = {The role of IRF5 in Microglia-Mediated neuroinflammation in ALS.}, journal = {Neuroscience letters}, volume = {877}, number = {}, pages = {138580}, doi = {10.1016/j.neulet.2026.138580}, pmid = {41846014}, issn = {1872-7972}, mesh = {Animals ; *Microglia/metabolism/pathology ; *Interferon Regulatory Factors/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism/pathology ; NF-kappa B/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Mice ; Signal Transduction ; Apoptosis ; }, abstract = {The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implicated in the disease mechanisms of various conditions. However, its mechanism in ALS remains unclear. This study found that IRF5 expression was significantly increased in hSOD1-G93A transgenic ALS mice and cell models, primarily localized in activated microglia. Silencing IRF5 altered microglial polarization, suppressed the release of inflammatory factors, enhanced phagocytic function, and reduced motor neuron apoptosis in a co-culture system. Mechanistic studies suggested that IRF5 may regulate microglial function through the NF-κB signaling pathway. This study reveals the key role of IRF5 in microglia-mediated neuroinflammation and neuronal damage in ALS, indicating that targeting IRF5 could represent a promising treatment strategy for this disease.}, } @article {pmid41850233, year = {2026}, author = {Guise, AJ and Ferber, KL and Young, D and Edwards, AL and Sabouri, S and Fraser, KB and Milliman, E and Plowey, ED and Zoghbi, J and Fradette, SM and Graham, DL}, title = {Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics.}, journal = {Cell reports. Medicine}, volume = {7}, number = {3}, pages = {102648}, pmid = {41850233}, issn = {2666-3791}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid ; GPI-Linked Proteins/cerebrospinal fluid ; Membrane Glycoproteins/cerebrospinal fluid ; *Proteomics/methods ; Superoxide Dismutase-1/genetics ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; }, abstract = {Tofersen, the first approved genetically targeted therapy for amyotrophic lateral sclerosis (ALS), demonstrates significant lowering of plasma neurofilament in adults carrying mutations in the superoxide dismutase 1 (SOD1) gene; however, additional biomarkers of treatment response in ALS are lacking. Here, we analyze longitudinally collected cerebrospinal fluid (CSF) samples from the phase 3 VALOR clinical trial to identify candidate tofersen treatment-response biomarkers in SOD1-ALS via quantitative proteomics. We observe significant modulation from baseline abundance for 56 proteins in tofersen-treated participants relative to placebo, including CSF GPNMB, which is significantly and continuously elevated across all post-baseline timepoints. We orthogonally confirm this observation by GPNMB immunoassay in independent tofersen-treated cohorts. Taken together, these data identify pharmacodynamic-response biomarkers of tofersen treatment that can be measured as early as 4 weeks post-treatment in SOD1-ALS patients and demonstrate the utility of leveraging unbiased proteomic screening integrated with targeted validation methods to identify pharmacodynamic-response biomarkers in clinical trial patient samples.}, } @article {pmid41852184, year = {2026}, author = {Gagliardi, D and Villella, C and Zanovello, M and Iacobelli, V and Corti, S and Comi, GP and Fratta, P and Houlden, H and Tucci, A and Ronchi, D}, title = {High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {99}, number = {6}, pages = {1502-1515}, pmid = {41852184}, issn = {1531-8249}, support = {//Italian Ministry of Health/ ; MR/Z506503/1//UK Medical Research Council/ ; MR/S006753/1//UK Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Superoxide Dismutase-1/genetics ; Female ; United Kingdom/epidemiology ; Middle Aged ; Male ; Biological Specimen Banks ; Adult ; Aged ; Prevalence ; Mutation/genetics ; UK Biobank ; Penetrance ; }, abstract = {OBJECTIVE: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.

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

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

INTERPRETATION: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026;99:1502-1515.}, } @article {pmid41853322, year = {2026}, author = {Elshaer, A and Thomas, L}, title = {Investigating inequality in Advanced Life Support courses: a retrospective, single-centre, survey-based pilot study.}, journal = {Resuscitation plus}, volume = {28}, number = {}, pages = {101283}, pmid = {41853322}, issn = {2666-5204}, abstract = {BACKGROUND: With more International Medical Graduates (IMGs) joining the United Kingdom's medical workforce, the demand for Advanced Life Support (ALS) courses has increased. Whilst differential attainment among IMGs is well-documented, little is understood about this phenomenon in ALS courses. This study explores the relationship between ALS course participants' background and course outcomes.

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

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

CONCLUSIONS: This exploratory study investigates IMGs' self-reported challenges and proposes interventions to promote the inclusivity of ALS courses. Further prospective research is required to evaluate the nature and generalisability of these findings and the applicability of the offered recommendations.}, } @article {pmid41863273, year = {2026}, author = {Singh, DD}, title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X438970260115164001}, pmid = {41863273}, issn = {1875-6190}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.}, } @article {pmid41863659, year = {2026}, author = {Mullick, S and Chakraborty, A and Porel, P and Nath, R and Chaudhary, P and Islam, A and Das, J and Pramanik, S and Panigrahy, UP and Sridhar, SB and Mondal, M and Debnath, B and Ashique, S}, title = {Decoding Neuroinflammatory Pathways: The Role of the CXCL12-CXCR4/CXCR7 Axis in ALS-Related Cognitive Impairment.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41863659}, issn = {1559-1182}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/complications/pathology ; *Chemokine CXCL12/metabolism ; *Receptors, CXCR/metabolism ; Animals ; *Receptors, CXCR4/metabolism ; *Signal Transduction/physiology ; *Cognitive Dysfunction/metabolism/complications/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; Inflammation/pathology ; }, abstract = {Cognitive impairment (CI) and accelerating neuronal deterioration are hallmarks of amyotrophic lateral sclerosis (ALS). Under these circumstances a crucial molecular mechanism in the pathophysiology of CI has been identified: the CXC chemokine receptor type 7 (CXCR7)/CXC chemokine receptor type 4 (CXCR4)/Cysteine-X-cysteine chemokine ligand 12 (CXCL12) region. Research on ALS shows that the CXCR7/CXCR4/CXCL12 complex plays a role in the degeneration of motor neurons and the resulting cognitive decline. JAK/STAT, PI3K/AKT, MAPK, and other signaling pathways are among the ways the axis controls neuronal inflammation, synaptic remodeling, and neuronal maintenance in each of these scenarios. The CXC motif chemokine ligand 12 (CXCL12) and CXC chemokine receptor type 4 (CXCR4) axis is crucial for the start of the inflammatory mechanism because of their function in mediating the chemotaxis of inflammatory cells. By preventing the migration of inflammatory cells via CXCL12 in the inflammatory area, the response to inflammation can be prevented or reduced. Consequently, the development of CXCR4 antagonists has emerged as a cutting-edge strategy for inflammation treatment. Recent research suggests that managing this relationship could reduce cognitive deficits and offer neuroprotective benefits. According to the current review, the CXCL12/CXCR4/CXCR7 pathway may be a promising target for treating cognitive dysfunction in neurodegenerative disorder. It also emphasizes the need for additional research to completely comprehend its function and identify efficient treatments which may result in improved clinical treatment modalities for these debilitating illnesses.}, } @article {pmid41863721, year = {2026}, author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK}, title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {}, pmid = {41863721}, issn = {1573-7365}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/metabolism/therapy ; *Circadian Rhythm/physiology/drug effects ; Animals ; *Chronotherapy/methods ; Melatonin/metabolism ; }, abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.}, } @article {pmid41864292, year = {2026}, author = {Liu, H and Zhu, J and Chen, Y and Lin, X and Hua, C and Chen, H}, title = {Response to Jia et al's "Comment on the "Genetic classification helps with precise sirolimus treatment in slow-flow vascular malformations"".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {1}, pages = {e81-e83}, doi = {10.1016/j.jaad.2026.03.041}, pmid = {41864292}, issn = {1097-6787}, } @article {pmid41866066, year = {2026}, author = {Qian, J and Li, C and Wang, Y and Tong, J}, title = {Extracorporeal sliding knot technique for simplified hysteroscopic suture fixation of levonorgestrel-releasing intrauterine device.}, journal = {Journal of minimally invasive gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmig.2026.03.020}, pmid = {41866066}, issn = {1553-4669}, abstract = {OBJECTIVE: Approximately 20% of adenomyosis cases occur in women under 40 years of age [1]. Although LNG-IUD is the first-line medical therapy, its treatment failure is closely associated with uterine volume [2] with expulsion rates reported as high as 37.5% in uteri exceeding 12 gestational weeks [3]. Tong et al's hysteroscopic suture fixation technique (HCSS) reduced expulsion to 2.6% [4,5]. Although clinical studies have confirmed the safety and efficacy of this technique [5], its technical complexity and the requirement for repeated instrument exchanges have limited widespread adoption. We therefore developed an optimized extracorporeal sliding knot method to overcome these barriers.

SETTING: University hospital.

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

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

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

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

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

CONCLUSION: These insights will enable targeted improvements in education, personalized care, resource allocation, care coordination, policy development, and funding, ultimately improving patient outcomes.}, } @article {pmid41870813, year = {2026}, author = {Upadhayay, S}, title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41870813}, issn = {1559-1182}, mesh = {Humans ; *Pentacyclic Triterpenes/therapeutic use/pharmacology/chemistry ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.}, } @article {pmid41876403, year = {2026}, author = {Yan, K and Jiang, Y and Yong, Y and Zhang, T and Zhang, N and Zeng, Q and Gong, X and Meng, L and Bi, F and Liu, Y}, title = {ALDOA Promotes Glycolysis and NLRP3/GSDMD Pyroptosis to Accelerate ALS Progression.}, journal = {Annals of clinical and translational neurology}, volume = {13}, number = {9}, pages = {1903-1918}, pmid = {41876403}, issn = {2328-9503}, support = {81760238//National Natural Science Foundation of China/ ; 82171433//National Natural Science Foundation of China/ ; 2022JJ30918//Natural Science Foundation of Hunan Province/ ; 2023JJ30927//Natural Science Foundation of Hunan Province/ ; TSYC202401B119//Xinjiang Uygur Autonomous Region Health Commission "Tianshan Talent" High-Level Medical and Health Personnel Project/ ; 2025D01E38//Natural Science Foundation of Xinjiang Uygur Autonomous Region/ ; }, mesh = {Animals ; *Glycolysis/physiology/drug effects ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; *Fructose-Bisphosphate Aldolase/metabolism ; Mice ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pyroptosis/physiology ; Disease Progression ; Mice, Knockout ; Disease Models, Animal ; Motor Neurons/metabolism ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration. Glycolytic dysregulation is implicated in disease progression, yet the underlying mechanisms remain unclear. This study investigates how Aldolase A (ALDOA) drives ALS progression through glycolysis-mediated motor neuron pyroptosis.

METHODS: In vivo, tamoxifen-induced TDP-43 cKO mice were assessed for motor function (rotarod/suspension tests), motor cortex L-lactic acid, and ALDOA/NLRP3/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In vitro, TDP-43 KO NSC34 cells were used to measure viability, glucose uptake, and L-lactic acid.

RESULTS: ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L-lactic acid accumulation, and NLRP3/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3/GSDMD-mediated pyroptosis. In vitro, TDP-43-deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3/GSDMD pathway activation, and impaired proliferation.

CONCLUSION: We show that ALDOA-mediated glycolytic dysregulation activates the NLRP3/GSDMD inflammasome, leading to pyroptosis in motor neurons. Pharmacological inhibition of ALDOA alleviates glycolytic dysregulation and extends survival, identifying ALDOA as a potential therapeutic target.}, } @article {pmid41885541, year = {2026}, author = {Chen, RF and Liu, KF and Lee, CC and Li, YT and Chen, WY and Kuo, YR}, title = {Transcriptomic Analysis of Adipose-Derived Stem Cell Therapy Modulating B Cell Immune Tolerance in Vascularized Composite Allotransplantation.}, journal = {Plastic and reconstructive surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/PRS.0000000000013074}, pmid = {41885541}, issn = {1529-4242}, abstract = {BACKGROUND: Adipose-derived stem cells (ADSCs) have been shown to prolong vascularized composite allotransplantation (VCA) survival in rodent hindlimb transplantation. However, the mechanisms by which ADSCs modulate B cell responses and induce immune tolerance remain unclear. This study used next-generation sequencing (NGS) to investigate B cell gene expression after ADSC treatment.

METHODS: A rodent orthotopic hind-limb transplantation model was established using Brown-Norway to Lewis rats. The tolerance treatment group received a combination of ADSCs, short-term cyclosporine A (CsA) and anti-lymphocyte serum (ALS), while the control rejection group received no treatment. B cells were isolated from the spleens of rejection control group at 10-14 days post-transplantation when rejection was diagnosed, or tolerance group at least ≥100 days post-transplantation without rejection. RNA sequencing (RNA-Seq) was conducted to assess transcriptomic differences. Differentially expressed genes (DEGs) were analyzed using the EBSeq bioinformatics tool and pathway enrichment analyses, with validation by qPCR.

RESULTS: RNA-Seq identified 94 DEGs (out of 13,284 mRNAs) between the tolerance and rejection groups. Gene ontology and KEGG pathway analyses revealed significant enrichment in pathways associated with cytokine secretion, B cell receptor signaling, and humoral immunity. The tolerance group exhibited upregulation of key chemokines (e.g., Cxcl1, Cxcl2, Ccl4) and downregulation of pro-inflammatory genes (e.g., Tlr3, Siglec5, C3). qPCR validation confirmed the RNA-Seq findings. These results suggest that ADSCs modulate B cell-mediated immune responses and promote a shift toward an anti-inflammatory, tolerogenic profile.

CONCLUSIONS: ADSC-based therapy combined with short-term immunosuppression promotes immune tolerance in VCA by modulating B cell-related gene expression. These findings suggest that targeting B cell-mediated pathways may provide a novel approach may offer a novel therapeutic strategy for clinical application in VCA.}, } @article {pmid41895196, year = {2026}, author = {Schmidlin, D and Thaysen, EM and Platikanov, S and Xu, J and Chesa, MJ and Tauler, R and Vázquez-Suñé, E and Teixidó, M}, title = {Impact of the superblock model on key components of the urban water cycle: Trace metals and dissolved organic matter dynamics across the built environment.}, journal = {Journal of hazardous materials}, volume = {508}, number = {}, pages = {141867}, doi = {10.1016/j.jhazmat.2026.141867}, pmid = {41895196}, issn = {1873-3336}, abstract = {Climate change, growing urban pollution, and increasing water scarcity are forcing cities to adopt strategies that enhance resilience to both climatic and anthropogenic pressures. The Barcelona Superblock model is a novel urban planning strategy that highly restricts vehicle traffic, converts streets into pedestrian-priority corridors, and promotes green spaces. Within this framework, green infrastructures, also called sustainable urban drainage systems (SUDS), are implemented as local, site-specific measures to capture (i.e., flood control), treat, and infiltrate treated stormwater (i.e., aquifer recharge). To evaluate the Superblock model impact on urban water quality, we conducted seven sampling campaigns across three Barcelona districts, targeting rainfall, stormwater "first-flush" from roads and pedestrianized streets, as well as SUDS influent and effluent within and in the vicinity to Superblocks, with a focus on dissolved trace metals and dissolved organic matter (DOM). Results showed that Superblocks reduced pollutant loads and mitigated ecotoxicological risks. Trace metal and DOM concentrations followed the trend: Rain < SUDS effluent < Pedestrian Street runoff < Road runoff, highlighting traffic-related impacts and SUDS treatment capacity (23-70% in best case scenario). Risk assessment indicated episodic ecotoxicological risk in stormwater, especially in road runoff due to elevated concentrations of Cu and Zn, while SUDS consistently remained below risk thresholds. SUDS also transform DOM into more stable, humic-like forms. Trace metals and DOM emerged as biogeochemical proxies for stormwater quality, enabling more effective and sustainable urban water management. These findings support the integration of Superblock-like strategies into urban planning to control and reduce contaminant urban discharges.}, } @article {pmid41897327, year = {2026}, author = {Romano, R and Ruotolo, G and Perrone, F and Tomaselli, S and Mazzoni, M and Spataro, R and Conforti, FL and Rosati, J and Bucci, C}, title = {Selective Silencing of TDP-43 P. G376D Mutation Reverses Key Amyotrophic Lateral Sclerosis-Related Cellular Deficits.}, journal = {Biomolecules}, volume = {16}, number = {3}, pages = {}, pmid = {41897327}, issn = {2218-273X}, support = {PRIN2022 N. 2022XTM2S3//Ministero dell'università e della ricerca/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; RNA, Small Interfering/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Mutation ; Oxidative Stress ; Cell Survival/genetics ; *Gene Silencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is currently no cure. Dominant mutations in the TARDBP gene are causative of ALS. In particular, the p. G376D substitution in TDP-43 causes familial ALS and it is associated with TDP-43 mislocalization in the cytosol, increased presence of cytoplasmic aggregates, and lysosomal and mitochondrial dysfunction. We previously designed a small interfering RNA (siRNA) that specifically targets and silences the mutant allele and we demonstrated that, in patient-derived fibroblasts, it can reduce TDP-43 aggregation, decrease oxidative stress, and improve cell viability. Here, we investigated the ability of this siRNA to revert some ALS-associated pathological phenotypes in motor neurons derived from induced pluripotent stem cells (iPSCs), as motor neurons are the primary cells affected in ALS. siRNA treatment reduced TDP-43 mislocalization, enhanced lysosomal function and cell viability, and decreased oxidative stress. These findings indicate that this allele-specific siRNA effectively reverses key ALS-related cellular deficits in motor neurons, representing a promising candidate for targeted therapy in patients carrying the TDP-43 G376D mutation.}, } @article {pmid41899342, year = {2026}, author = {Hermann, M and Stoiber, A and Schmid, A and Hamp, T and Santos, AA and Grassmann, D and Krammel, M and Lintschinger, JM and Ulbing, S and Stria, A and Hafner, C}, title = {Relevance of Reversible Causes of Out-of-Hospital Cardiac Arrest: The "REBECCA" Interactive Checklist.}, journal = {Journal of clinical medicine}, volume = {15}, number = {6}, pages = {}, pmid = {41899342}, issn = {2077-0383}, abstract = {Background/Objectives: Adequate cardiopulmonary resuscitation (CPR), defibrillation, and treatment of reversible causes are essential for improving the survival of patients suffering from out-of-hospital cardiac arrests (OHCAs). The Advanced Life Support (ALS) algorithm includes reversible causes for cardiac arrest. This study aimed to develop an interactive mobile checklist to identify reversible causes of OHCA (REBECCA) and evaluate their usability and usefulness among emergency physicians. Methods: This mixed-methods study was conducted at the Emergency Medical Service Vienna, Austria. All participants were emergency physicians from the Medical University of Vienna. An interactive mobile checklist was developed using a participatory design approach involving a focus group of 10 emergency physicians. Usability and applicability were assessed using structured questionnaires. Descriptive statistics were used to summarize participant characteristics and evaluation outcomes. Results: Among the included participants, 70% were specialists with a median prehospital experience of 2.0 (1.0-4.3) years. Although most participants were confident about their level of professional experience with OHCA, 85% still found the checklist to be helpful. The majority of the participants preferred the digital checklist over the paper-based checklist and appreciated its integration with the point-of-care ultrasound (POCUS) application. Although the participants did not communicate a significant need for further details on most causes, a small majority favored more information on intoxication and electrolyte disorders. Conclusions: The majority of the included emergency physicians found the REBECCA checklist helpful regardless of training level, whereas almost no physician needed further detailed information on the reversible causes. Our findings underscore the potential importance of future investigations aiming to reduce the cognitive load of emergency physicians during OHCA scenarios.}, } @article {pmid41903869, year = {2026}, author = {Yang, Y and Yang, Y and Zhang, X and Ma, H and Ji, S and Zou, F and Yu, X and Du, G and Zhu, X and Tian, J}, title = {Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy.}, journal = {Neuropharmacology}, volume = {293}, number = {}, pages = {110940}, doi = {10.1016/j.neuropharm.2026.110940}, pmid = {41903869}, issn = {1873-7064}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/agonists ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Mice, Transgenic ; Oxidative Stress/drug effects ; Mice ; Oxidation-Reduction/drug effects ; Kelch-Like ECH-Associated Protein 1/metabolism ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; Humans ; Mitochondria/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress representing core pathological features. Epidemiological studies indicate geographical variations in incidence, and recent multi-omics evidence identifies a hypermetabolic state and mitochondrial dysfunction as key drivers of disease progression. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which regulates antioxidant response and metabolism, represents a promising therapeutic target; however, the exploration of specific activators remains insufficient. This study evaluated the efficacy and mechanism of a novel KEAP1-NRF2 activator, MKL01351, in SOD1 G93A transgenic mice and NSC-34 motor neuron-like ALS models. Behavioral analyses demonstrated that MKL01351 significantly delayed disease onset, improved motor coordination in the rotarod and hanging tests, and extended survival. The compound alleviated oxidative stress by reducing malondialdehyde (MDA) levels and restoring the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, while also ameliorating the energy deficit by modulating glycolytic and mitochondrial functions, as confirmed by Seahorse analysis. Mechanistic investigations revealed that MKL01351 activated the NRF2 pathway, upregulating downstream targets such as NQO1 and HO-1, and specifically enhanced the expression of malic enzyme 1 (ME1). Loss-of-function experiments confirmed that ME1 knockdown abolished the protective effects, indicating that the NRF2-ME1 axis is a central hub for the synergistic regulation of metabolic and oxidative homeostasis. In conclusion, MKL01351 concurrently ameliorates oxidative stress and metabolic dysregulation via the NRF2-ME1 signaling pathway, offering a novel neuroprotective strategy for ALS treatment.}, } @article {pmid41905645, year = {2026}, author = {Martín-Sánchez, FJ and Marcos Sastre, MC and Muñoz de Maya, E and Sánchez-Pinto Pinto, B and Trueba Vicente, Á and Artero Ortiz, J and Arribas Guerrero, J and Soto Vargas, N and García Sánchez, IM and Marco Martínez, J and , }, title = {Six months of experience at a specialized daytime care center for people with amyotrophic lateral sclerosis (ALS) in the Community of Madrid.}, journal = {Neurologia}, volume = {41}, number = {5}, pages = {502006}, doi = {10.1016/j.nrleng.2026.502006}, pmid = {41905645}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Spain ; Male ; Retrospective Studies ; Aged ; Female ; Middle Aged ; Quality of Life ; Patient Satisfaction ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to motor deterioration and a reduced quality of life. In the Community of Madrid, the ALS Network was established to improve patient care. In April 2024, the Specialised Day Care Centre for ALS (CEADELA) was inaugurated, complementing the care provided by the ALS Network. The aim of this study was to describe the experience of CEADELA during its first six months.

MATERIALS AND METHODS: A retrospective descriptive study was conducted on a cohort of CEADELA patients between April and October 2024. Clinical, functional, and therapeutic data were analysed, along with overall satisfaction levels.

RESULTS: A total of 91 patients were included, with a mean age of 65.2 years (SD 11); of these, 59 (64.8%) were men. Most had spinal-onset ALS and were receiving treatment with riluzole. A significant increase was observed in the use of physiotherapy, speech therapy, and occupational therapy after referral to the centre. Functionality significantly declined over six months. The mortality rate was 12.1% (18.2% opted for assisted dying). Overall, 76 patients (83.5%) responded to the survey, with 100% reporting satisfaction or high satisfaction with the centre (80.2% very satisfied and 18.4% satisfied).

CONCLUSIONS: CEADELA has improved access to specialised therapies with a high level of satisfaction, although disease progression remains a challenge. The need to continue developing integrated, evidence-based care models to optimise ALS management is highlighted.}, } @article {pmid41910849, year = {2026}, author = {Akram, SW and K, C}, title = {Enhancing Parkinson's Disease Staging: An Integrative Deep Learning Framework for Multimodal Feature Selection.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {2}, pages = {}, pmid = {41910849}, issn = {1559-1166}, mesh = {Humans ; *Parkinson Disease/diagnostic imaging/genetics/diagnosis/pathology ; *Deep Learning ; Neuroimaging/methods ; Multilayer Perceptrons ; Support Vector Machine ; Particle Swarm Optimization ; }, abstract = {Parkinson's disease (PD) affects 10 million globally, with accurate staging essential for personalized treatment planning. Current UPDRS assessments achieve < 93% accuracy due to subjective clinical judgment and unimodal data limitations, failing to capture complex genetic-neuroimaging-clinical interactions driving disease heterogeneity. This study introduces MAFNet, a novel deep learning framework pioneering Iterative Adaptive Vold-Kalman Filter (IAVKF) temporal denoising, Accelerated Binary Particle Swarm Optimization (ABPSO) swarm feature selection, Multilayer Perceptron-Lagrangian Support Vector Machine (MLP-LSVM) classification, and Graph-Attention Based Multimodal Fusion Network (GAMF). Applied to PPMI cohort (200 patients) with genetic SNPs (50), neuroimaging voxels (1,024), and UPDRS-III scores, the end-to-end pipeline delivers 97.6% accuracy, 98.2% precision, 96.8% recall, and 97.3% F1-score-outperforming CNN (92.4%), Autoencoder (90.8%), InceptoFormer (96.6%), and HCT (97.0%). IAVKF boosts SNR + 15.2dB (+ 2.9% accuracy vs. PCA/t-SNE); ABPSO reduces 1,276→340 features (73% reduction); regularization cuts overfitting gap to 0.9% (vs. 4.2% baseline). SHAP interpretability validates clinical plausibility (top predictors: LRRK2 SNPs, UPDRS-III tremor, hippocampal volume). Five-fold CV confirms stability with the Indian cohort external validation. Real-time inference (0.2s/patient, RTX 3090) enables clinical deployment. Future scope includes longitudinal temporal modelling, modality-agnostic fusion, edge deployment, federated learning, and extension to Alzheimer's/ALS. MAFNet transforms PD staging from subjective assessments to objective precision medicine, enabling biomarker discovery, progression forecasting, and personalized therapies across diverse global populations.}, } @article {pmid41911331, year = {2026}, author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP}, title = {Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag115}, pmid = {41911331}, issn = {1460-2156}, abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.}, } @article {pmid41912988, year = {2026}, author = {Zheng, H and Yu, S and Zhou, T and Fu, S and Zhang, J and Zhang, N and Liu, Y and Huang, Y and He, Z and Zhang, J and Liu, P and Gong, M and Zhou, C}, title = {Distinct amino acid metabolic subtypes predict prognosis and stratify treatment response in acute-on-chronic liver failure: a multicenter prospective study.}, journal = {Hepatology international}, volume = {20}, number = {3}, pages = {864-874}, pmid = {41912988}, issn = {1936-0541}, support = {82305067//National Natural Science Foundation of China/ ; 2018ZX10725506-002//National Science and Technology Major Project of China during the 13th Five-Year Plan Period/ ; }, mesh = {Humans ; *Acute-On-Chronic Liver Failure/mortality/therapy/metabolism/blood ; Prospective Studies ; Prognosis ; *Amino Acids/metabolism/blood ; Female ; Male ; Middle Aged ; Liver, Artificial ; Metabolomics ; Treatment Outcome ; Adult ; Aged ; }, abstract = {BACKGROUND: Acute-on-chronic liver failure (ACLF) exhibits high mortality and heterogeneity, demanding precise risk stratification. We aimed to identify metabolic subtypes and explore their association with prognosis and real-world artificial liver support (ALS) responsiveness.

METHODS: This prospective, multicenter, observational cohort study enrolled 142 ACLF patients. Serum was collected at baseline, prior to ALS initiation. Patients were subtyped via metabolomics clustering. ALS exposure was analyzed using inverse probability of treatment weighting (IPTW) and Cox models to test for heterogeneity of treatment effect.

RESULTS: Two subtypes were identified (Cluster 1/2). Cluster 2 showed significantly higher 90 day mortality (p = 0.032) and severe amino acid metabolic reprogramming, particularly in branched-chain amino acid and glutamine pathways. Exploratory analysis suggested a differential association between ALS and survival across subtypes (interaction p = 0.12). ALS showed a weaker survival association in Cluster 2 after IPTW adjustment.

CONCLUSION: ACLF patients possess distinct amino acid-based metabolic subtypes that are potent prognostic indicators. Baseline metabolic profiling can serve as a stratification tool to identify patients who may derive the greatest clinical benefit from ALS therapy, guiding personalized treatment strategies.}, } @article {pmid41916622, year = {2026}, author = {Addington, C and Davies, N and Howell, P and Cruickshank, S and Hainsworth, E}, title = {Lived experiences of cancer care for people living with HIV who are treated for anal cancer: a scoping review.}, journal = {BMJ open}, volume = {16}, number = {3}, pages = {e114180}, pmid = {41916622}, issn = {2044-6055}, mesh = {Humans ; *Anus Neoplasms/therapy/psychology/complications ; *HIV Infections/complications/psychology ; Quality of Life ; }, abstract = {OBJECTIVE: This scoping review aims to identify existing evidence on the lived experiences of people living with HIV and treated for anal cancer, and to identify what aspects of health and well-being are addressed in clinical guidance.

DESIGN: A preregistered protocol (Open Science Framework, 2025) guided the review. We followed the Arksey and O'Malley framework, incorporating Levac et al's refinements around stakeholder consultation. Joanna Briggs Institute (JBI) guidance informed eligibility and data for charting, and reporting adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines.

DATA SOURCES: Systematic searches were performed across multiple databases, including CINAHL, MEDLINE, PsycINFO and Embase, using EBSCOhost and Ovid, supplemented handsearching reference lists. Two search strategies were used: one for research studies and one for clinical guidelines.

ELIGIBILITY CRITERIA: Sources included people living with HIV treated for anal cancer, capturing lived experiences directly through qualitative studies or indirectly via quantitative patient-reported outcomes and/or health-related quality of life. Guidelines addressing HIV or anal cancer were also included.

DATA CHARTING AND SUMMARIES: Data were charted to capture patient experiences and outcomes on living with and beyond cancer, and how these are addressed in clinical management and guidance, including biomedical, psychosocial, sexual and functional aspects, and patient-reported outcomes.

RESULTS: Of 945 records, three studies and four guidelines met criteria. No study focused exclusively on people living with HIV; findings reflect broader anal cancer populations with HIV-positive subsets. Studies addressed aspects of health-related quality of life which we mapped into physical, psychosocial and sexual domains. Clinical guidance prioritised treatment dosage and survival, with limited attention to broader effects. Stakeholders highlighted that existing research and guidance miss important nuances of lived experience and care needs.

CONCLUSIONS: No identified research solely explored the lived experiences of people living with HIV treated for anal cancer, leaving guidance non-specific and biomedical. The identified domains offer a starting point for future research; however, to inform patient-centred care, stakeholders emphasised the need to understand how living with HIV and anal cancer shapes health needs.}, } @article {pmid41917198, year = {2026}, author = {Yin, H and Ren, Z and Zhang, Y and Wang, Y and Sun, Y and Fu, X and Yan, W and Zhang, F and Zeng, L}, title = {Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {41917198}, issn = {2399-3642}, support = {20250206017ZP//Department of Science and Technology of Jilin Province (Jilin Province Science and Technology Department)/ ; }, mesh = {Animals ; *Lipid Metabolism/drug effects ; *Lisinopril/pharmacology ; *Autophagy/drug effects ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; Mice ; *Apoptosis Regulatory Proteins/metabolism/genetics ; Humans ; Signal Transduction/drug effects ; *Membrane Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves disrupted lipid metabolism. Bax inhibitor 1 (BI1), an endoplasmic reticulum protein downregulated in ALS neuroprotective, represents a therapeutic target, but its metabolic regulatory mechanisms are incompletely understood. Using transcriptomics in skeletal muscle of ALS mice pre- and post-BI1 treatment, we identified BI1-regulated pathways. Structure-based virtual screening of FDA-approved compounds nominated lisinopril as a BI1 activator. Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and protecting against SOD1[G93A]-induced apoptosis in NSC34 cells. Concurrently, it regulated TGF-β1/mTOR-dependent autophagy, maintained NMJ integrity, and reshaped triglyceride/sphingolipid/glycerophospholipid metabolism to attenuate spinal cord pathology in ALS mice, promoting energy metabolism shift toward glucose oxidation. Additionally, lisinopril inhibited the TGF-β1/Smad2/3 pathway to alleviate muscle fibrosis, downregulate Acp5/FN expression, and reduce type I collagen deposition. In conclusion, this study provides evidence that pharmacological activation of BI1 by lisinopril suppresses TGF-β1, modulates lipid metabolism, and ameliorates ALS pathology, demonstrating promising therapeutic repurposing potential.}, } @article {pmid41921847, year = {2026}, author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D}, title = {Unveiling the UFMylation Pathway: Implications in Neurodegenerative Diseases.}, journal = {Journal of molecular biology}, volume = {438}, number = {12}, pages = {169772}, doi = {10.1016/j.jmb.2026.169772}, pmid = {41921847}, issn = {1089-8638}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Processing, Post-Translational ; Ubiquitination ; Animals ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; *Proteins/metabolism ; }, abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.}, } @article {pmid41922953, year = {2026}, author = {Xing, Z and Cheng, Z and Yang, X and Hu, L and Wang, K and Wang, Y and Hu, D and Wang, YH and Du, J and Wang, L and Li, J}, title = {Integrated genomic and transcriptomic analysis reveals candidate genes underlying herbicide resistance in Sorghum.}, journal = {BMC plant biology}, volume = {26}, number = {1}, pages = {}, pmid = {41922953}, issn = {1471-2229}, support = {32372134//The National Natural Science Foundation of China/ ; }, mesh = {*Sorghum/genetics/drug effects ; *Herbicide Resistance/genetics ; Gene Expression Profiling ; *Herbicides/pharmacology ; Genes, Plant ; Genomics ; }, abstract = {BACKGROUND: Herbicide-resistant germplasms provide critical genetic resources for improving weed control and understanding resistance mechanisms in crops. OBJECTIVE: To screen sorghum accessions for tolerance to ACCase and ALS inhibitor herbicides at the seedling stage, identify the major locus and strong candidate gene associated with feproxydim resistance, and verify the gene expression pattern and genetic variation by quantitative real‑time PCR (qRT‑PCR) and KASP genotyping. METHOD: A total of 316 sorghum accessions were screened for seedling-stage herbicide tolerance using gradient herbicide treatments. Bulked segregant analysis sequencing (BSA-Seq) was performed on resistant and susceptible gene pools constructed from the F2 population derived from IS1219 × RTx430. Transcriptome sequencing (RNA-Seq) was conducted on leaf tissues after feproxydim treatment to identify candidate genes within the mapped interval. KASP markers were developed for the functional variation site of the key candidate gene for genotyping validation. Quantitative real‑time PCR (qRT-PCR) was used to measure the relative expression level of the target gene and compare it with the susceptible control line. Protein sequence comparison was used to detect variations in the key candidate gene between resistant and susceptible lines. RESULT: In the screening with the ACCase inhibitor 10% feproxydim, IS1219 exhibited high-level resistance. Preliminary screening under the ALS inhibitor mesosulfuron-methyl treatment identified only SJ304 with visible tolerance, which was not subjected to further mapping or validation. BSA-Seq identified a major feproxydim resistance QTL on chromosome 1. RNA-Seq revealed five co-expressed candidate genes in the target interval, among which Sobic.001G431500 (encoding carboxylesterase 17, an α/β‑hydrolase) was markedly upregulated in the resistant line IS1219 but not in the susceptible line RTx430. Quantitative real‑time PCR (qRT-PCR) analysis confirmed that Sobic.001G431500 was significantly upregulated in the resistant line IS1219 compared with the susceptible control. KASP genotyping demonstrated that the IS1219 allele cosegregated with feproxydim resistance. Protein sequence comparison showed that the IS1219 allele carried a missense mutation V300A and a deletion P301_P303 at and after position 300. CONCLUSION: These findings identify a major QTL and a strong candidate gene Sobic.001G431500 associated with feproxydim resistance in the sorghum line IS1219, based on differential expression, genetic variation, and genotype–phenotype cosegregation. This study provides valuable genetic resources and functional markers for marker-assisted selection and breeding of feproxydim-tolerant sorghum varieties.}, } @article {pmid41925076, year = {2026}, author = {Krajewski, T and Koch, G}, title = {Randomization-Based Covariance Analysis for Confidence Intervals of Treatment Comparisons Based on Restricted Mean Survival Time With Categorized Time-to-Event Data.}, journal = {Statistics in medicine}, volume = {45}, number = {8-9}, pages = {e70422}, doi = {10.1002/sim.70422}, pmid = {41925076}, issn = {1097-0258}, support = {T32 ES007018/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Survival Analysis ; Confidence Intervals ; Amyotrophic Lateral Sclerosis/drug therapy ; Analysis of Variance ; Double-Blind Method ; Models, Statistical ; Computer Simulation ; }, abstract = {This paper introduces a randomization-based method for covariate-adjusted comparisons of restricted mean survival time (RMST) between treatment arms in randomized controlled trials. Existing approaches for covariate-adjusted RMST analysis have model-based assumptions that may not be compatible with the complexity of survival data. We estimate the treatment difference in RMST using randomization-based analysis of covariance (RB-ANCOVA) for categorized time-to-event data by constraining the covariate mean differences between treatment groups to zero. Accordingly, we provide corresponding confidence intervals that offer greater precision than those based on unadjusted RMST differences. The methodology is detailed for comparing two treatment groups for a single or multiple time intervals, as well as for multiple treatment groups over a single interval. We demonstrate the application of these methods using data from a randomized, double-blind, placebo-controlled clinical trial evaluating three doses of a test treatment for ALS.}, } @article {pmid41929167, year = {2026}, author = {Mahrous, AA and Heit, BS and Heckman, CJ}, title = {Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929167}, issn = {2692-8205}, support = {R01 NS110953/NS/NINDS NIH HHS/United States ; }, abstract = {Riluzole is the most commonly prescribed among the limited approved therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motoneuron loss and paralysis. It is thought to act by suppressing motoneuron excitability and glutamate release, but its clinical benefits are modest and often diminish over time. We previously showed that homeostatic mechanisms in the SOD1[G93A] (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that chronic riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results suggest that hyperactive homeostatic mechanisms in ALS counteract the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, consistent with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, indicating normalization of cell size and potentially reduction in metabolic demand. Together, these findings help explain the limited clinical efficacy of riluzole while revealing a previously unrecognized neuroprotective mechanism of the drug in ALS.}, } @article {pmid41929709, year = {2026}, author = {Gazwi, K and Zaza, T and Mitwally, H and Davda, N and Ganaw, A}, title = {Botulinum toxin injection induced autoimmune thyroiditis and myxedema coma: A case report.}, journal = {SAGE open medical case reports}, volume = {14}, number = {}, pages = {2050313X261430649}, pmid = {41929709}, issn = {2050-313X}, abstract = {This case describes a 28-year-old female with amyotrophic lateral sclerosis and recurrent urinary tract infections who developed myxedema coma following a botulinum toxin type-A (Btx) injection for muscle spasticity. On intensive care unit admission, she presented with hypothermia, bradycardia, and reduced consciousness. Laboratory evaluation revealed markedly elevated thyroid-stimulating hormone levels, confirming myxedema coma. Prompt treatment with intravenous levothyroxine and hydrocortisone resulted in rapid improvement in temperature and mental status. Further investigation showed elevated antithyroid peroxidase antibodies, suggesting drug-induced autoimmune thyroiditis triggered by Btx. This case highlights the potential link between Btx injection and thyroid autoimmunity, emphasizing the importance of early recognition and monitoring of thyroid function to prevent life-threatening complications in at-risk patients.}, } @article {pmid41930586, year = {2026}, author = {Pavithra, N and Begum, RF and Ashwini, ST and Nirenjen, S and Singh, A and Manisha, M and Sridevi, S and Singh, SA}, title = {AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273436955260126215111}, pmid = {41930586}, issn = {1996-3181}, abstract = {Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are examples of neurodegenerative disorders (NDDs) that share overlapping neuropathological processes and largely affect motor coordination. For early diagnosis, illness monitoring, and treatment targeting, it is essential to find trustworthy biomarkers that represent motor circuit dysfunction. The purpose of this study is to summarize the state of the art regarding molecular, neurochemical, and imaging biomarkers that are pertinent to motor impairment and to investigate the function of artificial intelligence (AI) in their identification and verification Methods: With an emphasis on biomarker discovery, validation, and AI/ML applications in PD, HD, ALS, and SCAs, a thorough literature search was carried out in the PubMed, Scopus, and Google Scholar databases for research published between 2015 and 2025. The motor-specific correlations of key molecular (α-synuclein, tau, neurofilament light chain, TDP-43, mutant huntingtin), neuroimaging, and digital biomarkers were carefully examined Results: AI-driven methods, such as deep learning and machine learning, have shown great promise in combining multimodal data from digital, fluid, and imaging sources. These techniques enhanced the detection of disease-specific biomarker signatures, especially those associated with deficiencies in motor coordination Discussion: Data heterogeneity, biomarker standardization, model interpretability, and limited cross-disease validation are still issues despite encouraging developments. Improving the clinical reliability of AI-based biomarker models requires filling in these gaps Conclusion: An effective foundation for deciphering intricate motor neurological pathways is provided by AI-assisted biomarker discovery. Transparent algorithms, multicenter data integration, and ethical frameworks should be given top priority in future research to guarantee clinical translation and better patient stratification.}, } @article {pmid41930760, year = {2026}, author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK}, title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X385491251208144807}, pmid = {41930760}, issn = {1875-6190}, abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.}, } @article {pmid41932651, year = {2026}, author = {Scaricamazza, S and Nesci, V and Fenili, G and Tiberi, M and Percio, A and Rosina, M and Salvatori, I and Riggio, F and Candelise, N and Pieroni, L and Greco, V and Chiurchiù, V and Ferri, A and Valle, C}, title = {The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.}, journal = {Molecular metabolism}, volume = {107}, number = {}, pages = {102360}, pmid = {41932651}, issn = {2212-8778}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/immunology ; *Hypothalamus/metabolism/immunology ; *Mitochondria/metabolism ; Mice ; Mice, Transgenic ; Energy Metabolism ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Humans ; Proteomics ; }, abstract = {BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear.

METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival.

FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival.

INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.}, } @article {pmid41943810, year = {2026}, author = {Khandelwal, N and Geremakis, C and Riaz, F and Ryan, G and Saundankar, V and Sheer, R and Suehs, B}, title = {Epidemiology, Patient Characteristics, Real-World Treatment Patterns, and Healthcare Utilization and Spending for Patients with Multifocal Motor Neuropathy: A US Claims-Based Analysis.}, journal = {Journal of health economics and outcomes research}, volume = {13}, number = {1}, pages = {111-119}, pmid = {41943810}, issn = {2327-2236}, abstract = {BACKGROUND: Multifocal motor neuropathy (MMN) is a rare, progressive neurological disease characterized by asymmetrical limb weakness. The real-world healthcare burden of MMN is not well established.

OBJECTIVES: To characterize the epidemiology, diagnostic procedures, treatment patterns, healthcare resource utilization (HCRU), and healthcare spending associated with MMN in patients in the US.

METHODS: This retrospective, observational claims study extracted data from the Humana Healthcare Research Database, comprising US Medicare Advantage plan members. Eligible patients were aged 18-89 years, had ≥2 nondiagnostic medical claims (the first being the index date) associated with an MMN diagnosis code (January 1, 2017-June 30, 2022), and continuous enrollment for 12 months pre-index (baseline) and post-index (follow-up). Patients with amyotrophic lateral sclerosis, chronic inflammatory demyelinating neuropathy, or immunosuppressant use were excluded. Outcomes were assessed during the baseline and follow-up periods.

RESULTS: Deidentified data were extracted for 248 patients with MMN. Median (Q1, Q3) age at index was 70.0 (62.0, 77.0) years; most patients were male (53.6%) and White (78.2%). Diagnostic procedures included (baseline/follow-up periods) spinal magnetic resonance imaging (21.4%/18.1%), nerve conduction studies (19.8%/14.5%), and electromyography (17.7%/15.3%). Anticonvulsants, pain medications, corticosteroids, and central muscle relaxants were the most commonly used medications. Overall, 5.2% of patients had intravenous immunoglobulin (IVIG) during follow-up. Mean (standard deviation [SD]) time from index to IVIG initiation was 63.1 (52.2) days, with 6.5 (5.4) administrations, 28.7 (22.9) days between administrations, and 147.5 (133.9) days of total treatment. For all-cause HCRU, 23.8% of patients had ≥1 inpatient stay in the baseline period, with mean (SD) length of stay of 12.7 (14.5) days; during follow-up, 27.8% of patients had ≥1 inpatient stay (length of stay, 13.4 [16.2] days). During the baseline/follow-up periods, 43.1%/46.8% of patients had ≥1 emergency department visit, and 18.5%/28.6% used telehealth services. Median all-cause spending (baseline/follow-up) was 11   299 / 16 074 for total healthcare, 6745 / 10 630 for medical resources, and 1374 / 1701 for pharmacy.

DISCUSSION: Further studies are needed to enhance our understanding of the real-world diagnostic and treatment patterns associated with MMN and to determine long-term clinical outcomes.

CONCLUSION: These real-world data highlighted the considerable burden associated with MMN on the healthcare system and patients.}, } @article {pmid41953830, year = {2026}, author = {Baby, P and John, J and Binesha, PB and Keerthipriya, MS and Ramazanu, S and Nashi, S and Menon, D and Vengalil, S and Thomas, PT and Nalini, A}, title = {Amyotrophic Lateral Sclerosis: A Cross-sectional Survey on Sialorrhoea.}, journal = {Indian journal of palliative care}, volume = {32}, number = {1}, pages = {85-90}, pmid = {41953830}, issn = {0973-1075}, abstract = {OBJECTIVES: One of the major distressing symptoms related to Amyotrophic Lateral Sclerosis (ALS) is excessive drooling of saliva, also termed sialorrhoea. Evaluating its prevalence and severity among Indian patients with ALS is essential for understanding the magnitude and impact of the problem. A cross-sectional survey was conducted to estimate the prevalence and severity of sialorrhoea among individuals diagnosed with ALS. We also intended to assess the current pharmacological management practice for sialorrhoea in ALS patients.

MATERIALS AND METHODS: Patients with ALS enrolled in the Neuropalliative Registry of a quaternary care centre for neurological disorders were included in the study. As part of routine follow-up, telephonic interviews were conducted with either the patients or their next of kin. The extent of sialorrhoea was assessed using the sialorrhoea scoring scale.

RESULTS: Seventy patients were included in the study. The mean age at presentation was 51.8 (standard deviation [SD]-12.8) years. The majority were males (74.3%). The mean duration of illness was 21.6 (SD 15.7) months. The majority (80%) had limb onset ALS. Forty per cent of the patients in the study had some degree of sialorrhoea. Mild drooling was present in 15 patients (21.4%), moderate in 9 (12.9%), severe in 2 (2.9%) and profuse drooling in another 2.9% of patients. A total of 9 patients (12.9%) were receiving anticholinergic medication. Patients diagnosed with bulbar onset ALS had a significantly greater degree of sialorrhoea than those with limb onset presentation (P = 0.008). In addition, a longer duration of illness showed a positive correlation with the severity of sialorrhoea (r = 0.30, P = 0.012).

CONCLUSION: Sialorrhoea is a prevalent and clinically significant symptom in individuals with ALS. The severity of sialorrhoea is greater in patients with bulbar onset ALS and tends to increase with longer illness duration. A substantial proportion of patients may benefit from recommended treatment for excessive salivation and saliva-related issues. This study underscores the need for screening of distressing symptoms as sialorrhoea, in ALS patients. The treating teams need to have a heightened awareness regarding the same so that treatment options can be offered to the patients.}, } @article {pmid41954708, year = {2026}, author = {Luo, S and Zheng, Q and Wang, M and Wang, X and Ma, B and Liu, D and Li, L and Lu, Y and Sang, D and Yang, L}, title = {Synergistic Neuroprotection of MFSD2A Overexpression and DHA Supplementation in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {41954708}, issn = {1559-1182}, support = {202304295107020076//Clinical Medicine Research and Translational Project of Anhui Province/ ; 2022AH051480//University Natural Science Research Project of Anhui Province/ ; 2022//Anhui Province "Jianghuai Famous Doctors" Cultivation Project/ ; 2020byzd169//Natural Science Key Project of Bengbu Medical College/ ; BB21B032//Bengbu Think Tank Construction and Social Science Planning Project/ ; 20230131//Bengbu science and technology innovation guidance project/ ; BBWK2024B204//Bengbu Health and Health Research Project Intestinal Transplantation Technology Clinical Special General Project/ ; AHWJ2024Aa30089//Anhui Province Health and Health Research Project Youth Project/ ; }, mesh = {Animals ; *Docosahexaenoic Acids/pharmacology/therapeutic use/administration & dosage ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics/physiopathology ; *Neuroprotection/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; *Dietary Supplements ; *Symporters ; *Membrane Transport Proteins/metabolism/genetics/biosynthesis ; Humans ; Mice ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss, with limited effective therapies. Docosahexaenoic acid (DHA) exhibits neuroprotective effects, but its limited transport across the blood-brain barrier (BBB) restricts clinical utility. Major facilitator superfamily domain-containing protein 2A (MFSD2A) is the primary transporter of DHA into the central nervous system, yet its role in ALS remains unclear. This study investigated the therapeutic potential and mechanisms of MFSD2A overexpression combined with DHA supplementation in male SOD1^G93A ALS mice. We found that MFSD2A expression was markedly reduced in ALS mice and correlated with impaired motor function and neuronal damage. DHA supplementation or MFSD2A overexpression partially improved behavioral deficits, while their combination produced synergistic benefits. Histological analyses revealed attenuated neuronal degeneration and reduced muscle fibrosis following combined treatment. Furthermore, MFSD2A physically interacted with the E3 ubiquitin ligase TRIM21, regulating glycolytic metabolism by modulating key enzymes (GLUT1, HK2, LDHA, PDK1) and products (lactate/pyruvate and NADH/NADPH ratio). TRIM21 knockdown reversed MFSD2A-mediated neuroprotection and impaired glycolytic metabolism, indicating its critical role in this pathway. The combined intervention also suppressed systemic inflammation and oxidative stress by decreasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and restoring antioxidant enzyme activities (GSH-Px), while reducing lipid peroxidation (MDA). These findings suggest that MFSD2A facilitates DHA's neuroprotective effects by enhancing glycolytic metabolism and mitigating neuroinflammation. This study highlights MFSD2A and DHA as promising therapeutic targets in ALS and provides novel insights into overcoming BBB transport limitations for neurodegenerative disease treatment.}, } @article {pmid41973722, year = {2026}, author = {Ge, D and Wu, L and Yang, J and Sun, J and Wang, J and Wang, J and Song, H and Wei, R and Xu, Z and Zhao, B and Sun, R and Wang, Y}, title = {Adverse events in different administration routes of Edaravone: A pharmacovigilance study based on the FDA adverse event reporting system.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346797}, pmid = {41973722}, issn = {1932-6203}, mesh = {*Edaravone/adverse effects/administration & dosage ; United States ; Humans ; United States Food and Drug Administration ; *Adverse Drug Reaction Reporting Systems ; Administration, Oral ; *Pharmacovigilance ; Amyotrophic Lateral Sclerosis/drug therapy ; Administration, Intravenous ; Drug Administration Routes ; *Drug-Related Side Effects and Adverse Reactions/epidemiology ; }, abstract = {The U.S. Food and Drug Administration (FDA) approved intravenous edaravone for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, followed by the approval of the oral formulation in 2022. This study aims to utilize the FDA#39;s Adverse Event Reporting System (FAERS) to investigate the spectrum and timing of adverse events (AEs) associated with edaravone administration, employing repeatability analysis, the Reporting Odds Ratio (ROR) approach, Weibull distribution, and stratification methods. The investigation focuses on data collected from the first quarter of 2017 through the fourth quarter of 2024, aiming to identify adverse event signals and their temporal patterns related to both intravenous and oral edaravone administration. In total, 3,262 records of edaravone-related adverse reactions were identified; among these, 1,534 incidents were associated with intravenous administration, while 453 incidents pertained to oral administration. The analysis revealed distinct adverse reaction profiles for the two routes of administration. Notably, the spectrum of adverse reactions resulting from oral administration predominantly involved the respiratory system, digestive system, and skin damage. In contrast, intravenous administration was more frequently linked to complications associated with invasive procedures and local tissue damage. Furthermore, the timing of adverse reactions exhibited significant variability between the two routes. Weibull distribution analysis indicated that the median onset time for adverse reactions following intravenous administration was 35 days, whereas for oral administration, it was 27 days. Both analytical approaches identified early failure signals, suggesting that the risk of adverse events diminishes over time.}, } @article {pmid41977439, year = {2026}, author = {Bougea, A}, title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {7}, pages = {}, pmid = {41977439}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; MicroRNAs/genetics ; *RNA, Untranslated/genetics ; Exosomes/metabolism/genetics ; CRISPR-Cas Systems ; RNA, Long Noncoding/genetics ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.}, } @article {pmid41978444, year = {2026}, author = {Stokholm, JB and Küchen, SHL and Møller, K and Gätke, MR and Svenstrup, K and Staehr-Rye, AK}, title = {Outpatient versus inpatient initiation of home mechanical ventilation in patients with amyotrophic lateral sclerosis - a protocol for a randomised trial.}, journal = {Danish medical journal}, volume = {73}, number = {4}, pages = {}, doi = {10.61409/A09250733}, pmid = {41978444}, issn = {2245-1919}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Ambulatory Care ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Home Care Services ; *Hospitalization ; *Hypoventilation/therapy/etiology ; Inpatients ; *Noninvasive Ventilation/methods ; Patient Compliance ; Patient Satisfaction ; Quality of Life ; Remote Patient Monitoring ; *Respiration, Artificial/methods ; Telemedicine ; Randomized Controlled Trials as Topic ; Equivalence Trials as Topic ; }, abstract = {INTRODUCTION: In-home non-invasive ventilation (NIV) is associated with prolonged life and improved quality of life in patients with hypoventilation due to amyotrophic lateral sclerosis (ALS). The initiation of NIV is scheduled for a 1-2-night hospital stay. Telemedicine enables remote monitoring and adjustment of respiratory treatment. These possibilities should be examined to improve patients' experiences and adherence to treatment while freeing up resources in the healthcare system. We hypothesise that outpatient initiation of NIV combined with close telemonitoring in patients with ALS is non-inferior to standard initiation of NIV in adherence to treatment.

METHODS: This is a randomised, controlled, non-inferiority study. A total of 46 patients with ALS scheduled for initiation of NIV are randomised to start NIV either as an outpatient combined with close telemonitoring or during hospitalisation for 1-2 nights. The primary outcome is NIV adherence after three months, measured as minutes per day for the past seven days. Secondary outcomes are patient satisfaction with NIV treatment and its initiation after three months, assessed on a 1-5 rating scale.

CONCLUSIONS: The study is the first randomised, controlled study assessing the combination of outpatient initiation of NIV and close telemedical follow-up in patients with a progressive neuromuscular disease. The results may be applicable to other patient populations initiating NIV, e.g., patients with obesity hypoventilation syndrome.

FUNDING: The study was supported by grants from ALS-fonden and Muskelsvindfonden.

TRIAL REGISTRATION: NCT05829330.}, } @article {pmid41985161, year = {2026}, author = {Pervushina, EV and Rushkevich, YN and Turuspekova, ST and Kutlubaev, MA}, title = {Challenges in medical care for amyotrophic lateral sclerosis: a survey of physicians from Republic of Bashkortostan (Russia), Belarus, and Kazakhstan.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2652327}, pmid = {41985161}, issn = {2167-9223}, abstract = {OBJECTIVE: To identify and compare the main challenges in diagnosing and managing amyotrophic lateral sclerosis (ALS) from the perspective of neurologists in Republic of Bashkortostan (Russia), Belarus, and Kazakhstan.

METHODS: An anonymous online survey was distributed to neurologists via professional networks from May to October 2025. The questionnaire collected data on demographics, diagnostic and therapeutic approaches, barriers, and suggestions for improvement.

RESULTS: The survey included 294 neurologists. Over half (58.2%) diagnosed ALS less than once a year. Major diagnostic barriers were limited access to key investigations like electromyography (62.6%) and a lack of specialized ALS centers (37.8%). For treatment, 48% prescribed riluzole, while only 12.9% used edaravone. Critically low rates of gastrostomy placement and respiratory support provision (<10% of terminal patients) were noted by over 80% of respondents. Significant cross-country differences were found: neurologists in Kazakhstan utilized genetic testing and edaravone more frequently; neurologists in Belarus employed muscle/tongue ultrasound more often; neurologists in the Republic of Bashkortostan (Russia) reported higher use of speech therapy and gastrostomy. The most frequently proposed solutions were establishing specialized ALS centers (34%), enhancing physician training (20%), and improving palliative care services (16.5%).

CONCLUSIONS: This multinational survey provides important insights into ALS care in the studied countries, identifying key areas for further development. The results point to opportunities for enhancing diagnostic resources, therapeutic strategies, and palliative care approaches. Enhancing the quality of ALS care requires the development of specialized clinical pathways, the implementation of consensus-based protocols, and the expansion of professional education in multidisciplinary management.}, } @article {pmid41985725, year = {2026}, author = {Wintz, K and Lechtape, PL and Klenzendorf, J and Schemmert, S and Dingley, AJ and Willuweit, A and Kutzsche, J}, title = {Elucidation of the influence of the CaV2.2 calcium channel on ALS disease progression in the SOD1*G93A mouse model.}, journal = {Neurobiology of disease}, volume = {224}, number = {}, pages = {107396}, doi = {10.1016/j.nbd.2026.107396}, pmid = {41985725}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Mice, Transgenic ; *Calcium Channels, N-Type/metabolism/genetics ; Disease Progression ; Disease Models, Animal ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Motor Neurons/metabolism ; Humans ; *Superoxide Dismutase/genetics/metabolism ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal neurodegenerative disease affecting upper and lower motor neurons in the central nervous system. Drugs like riluzole, edaravone, and tofersen treat disease symptoms or are designed for a specific pathological mutation (e.g., SOD1), but they cannot prevent or halt the disease. For this reason, the search for new therapeutic strategies continues. The voltage-gated calcium channel CaV2.2 might be a novel target in ALS treatment as the channel was shown to be overexpressed in murine SOD1*G93A cortical neurons, resulting in higher mortality. Further, murine SOD1*G93A motor neurons showed increased calcium currents mainly by an increased expression of the CaV2.2 channel. In addition, inhibition of the channel was hypothesized as mode of action for the all-d-enantiomeric peptide RD2RD2, a novel drug candidate for the treatment of ALS, which already demonstrated its efficacy in SOD1*G93A mice. To investigate the influence of the CaV2.2 channel on the progression of disease symptoms in the SOD1*G93A mouse model, a new double-transgenic line was created, combining the ALS phenotype with a knockout of the CaV2.2 channel. The study showed that the CaV2.2 knockout on the SOD1*G93A background led to reduced SHIRPA and splay scores, and a delayed disease onset. Additionally, differences were detected between wildtype and single-transgenic CaV2.2 knockout mice. However, survival was not affected. Post mortem analysis of human tissue found more CaV2.2 in ALS cases in comparison to healthy control subjects confirming involvement of the channel in human ALS. These results indicate that the CaV2.2 calcium channel may play an influential role in early disease progression of ALS.}, } @article {pmid41987881, year = {2026}, author = {Li, R and Wang, L and Bu, W and Zhang, X and Li, X and Li, J and Shen, J and Li, J and Cai, Z}, title = {Autologous SVF therapy modulates neuroinflammation in ALS: phase I trial demonstrating safety and CSF biomarker dynamics.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1784115}, pmid = {41987881}, issn = {1663-4365}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with limited treatments. Stromal vascular fraction (SVF), a cell population derived from autologous adipose tissue, exhibits multimodal immunomodulatory and neuroprotective properties, positioning it as a promising therapeutic candidate.

METHODS: This trial aimed to assess autologous stromal vascular fraction (SVF) safety and efficacy in patients with ALS. 26 patients received combined intravenous (0.5 × 106 cells/kg) and intrathecal (20 × 10[6] cells) autologous SVF (An exploratory second dose of SVF was administered intrathecally to three patients 45 days later). The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2400091754).

RESULTS: SVF administration was well-tolerated. Five mild adverse events (adverse events, AEs) (subcutaneous bleeding, headache, and low-grade fever) occurred, with no serious AEs reported. Although ALSFRS-R scores showed non-significant improvement post-treatment, 15/26 participants (57.7%) self-reported symptomatic improvement after treatment. Critically, cerebrospinal fluid biomarker analysis revealed significant reductions in neurofilament light chain (NfL; Δ530.29 pg/mL, P = 0.039) and glial fibrillary acidic protein (GFAP; Δ622.23 pg/mL, P = 0.038), indicating attenuation of neuroaxonal degeneration and astroglial activation. While ALSFRS-R scores showed no significant change (Δ-0.53, P = 0.384), prognostic modeling identified female sex (OR = 0.011, P = 0.008) and shorter disease duration (OR = 1.35/month, P = 0.005) as predictors of response. Three patients who underwent the second treatment were well tolerated without any adverse events.

CONCLUSION: These findings indicate that Autologous SVF therapy might possess an acceptable safety profile for patients with ALS. The significant reduction in CSF NfL and GFAP levels provides objective evidence of their potential neuroprotective effects that modulates ALS-relevant neuroinflammation pathways. Female participants and those with shorter disease duration may derive greater benefits.}, } @article {pmid41989758, year = {2026}, author = {Ahmed, M and Volkening, K and Mclellan, C and Shoesmith, C and Balci, TB and Strong, MJ}, title = {Emerging strategies for interpreting variants of uncertain significance (VUS) in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/21678421.2026.2655734}, pmid = {41989758}, issn = {2167-9223}, abstract = {As the use of genetic testing for neurological diseases increases exponentially, interpreting variants of uncertain significance (VUS) has become a challenging problem. Nowhere has this become more evident than in amyotrophic lateral sclerosis (ALS) and the frontotemporal dementias (FTDs), both of which are complex heterogeneous disorders in which an increasing array of disease-causative and modifying genetic variants are observed. Moreover, while traditionally identified as distinct clinical syndromes, ALS and FTD are increasingly recognized to exist along a spectrum of clinical syndromes (termed the frontotemporal spectrum disorders of ALS; ALS-FTSD) with shared genetic risk. While VUS are generally not used in clinic for decision-making or counseling given their obvious limitations in being medically actionable, their correct interpretation is dynamic and rapidly evolving. VUS are increasingly the subject of intensive study as potential determinants of biological outcomes. It is timely therefore to review the current state of VUS interpretation and to critically evaluate how this can be applied to enhance both patient care and treatment decisions in the broader context of neurological disorders and more specifically in the context of ALS and ALS-FTSD. In doing so, we also explore the evolving challenge of defining pathogenicity of oligogenic inheritance in the context of multiple VUS detection in a single individual using an illustrative case example.}, } @article {pmid41991114, year = {2026}, author = {Zhang, W and Zhang, D and Han, L and Wang, D and Huo, D and Tan, X and Su, X and Wang, M and Xu, J and Cheng, J and Feng, H}, title = {The neuroprotective effect of guanabenz combined with α-lipoic acid in the hSOD1-G93A amyotrophic lateral sclerosis model.}, journal = {Brain research bulletin}, volume = {239}, number = {}, pages = {111890}, doi = {10.1016/j.brainresbull.2026.111890}, pmid = {41991114}, issn = {1873-2747}, mesh = {Animals ; *Thioctic Acid/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics/pathology ; *Neuroprotective Agents/pharmacology ; Mice, Transgenic ; *Guanabenz/pharmacology ; Disease Models, Animal ; Mice ; Endoplasmic Reticulum Chaperone BiP ; Humans ; Motor Neurons/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/drug effects ; Drug Therapy, Combination ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and although its pathogenesis is not yet clear, the multifactorial mechanisms that affect motor neuron death are intertwined, exacerbating the disease. Here, we explore the effectiveness and mechanism of a combination medication that combines guanabenz with α-lipoic acid in an in vitro as well as in vivo model of ALS. In this research, we initially determined the independent action targets and synergistic action targets of the two drugs through network pharmacology and molecular docking. Subsequently, we further investigated their specific action mechanisms in both in vivo and in vitro studies. In NSC34 cells transfected with hSOD1-G93A, we observed that the combined drugs could more effectively safeguard against cell damage and the production of reactive oxygen species (ROS) generated by mutant hSOD1, superior to monotherapy. This was achieved by upregulating the p-AKT/HO-1 pathway and synergistically suppressing the GRP78/CHOP pathway. Moreover, we found that combination drugs can effectively delay the decline in motor function of hSOD1-G93A transgenic mice by synergistically inhibiting GRP78/CHOP pathway. They can protect the motor neurons in the anterior horn of the spinal cord and suppress gliosis in hSOD1-G93A transgenic mice. In summary, our research indicates that the combination therapy of guanabenz and α-lipoic acid can serve as a viable treatment option for ALS.}, } @article {pmid41992463, year = {2026}, author = {Veith, PD and Leeming, MG and Chen, YY and Reynolds, EC}, title = {Cargo Secreted by the Type IX Secretion System of Porphyromonas gingivalis Are Tethered to O-Lipopolysaccharides via a Pentasaccharide Linker.}, journal = {MicrobiologyOpen}, volume = {15}, number = {2}, pages = {e70296}, pmid = {41992463}, issn = {2045-8827}, support = {1123866//Australian National Health and Medical Research Council/ ; DP200100914//Australian Research Council/ ; 20080108//Australian Government Department of Industry, Innovation and Science/ ; }, mesh = {*Porphyromonas gingivalis/metabolism/chemistry ; *Lipopolysaccharides/chemistry/metabolism ; *Bacterial Secretion Systems ; *O Antigens/metabolism/chemistry ; Mass Spectrometry ; *Oligosaccharides/chemistry/metabolism ; Bacterial Proteins/metabolism ; Virulence Factors/metabolism ; }, abstract = {The Gram-negative oral pathogen, Porphyromonas gingivalis, uses the Type IX Secretion System (T9SS) to secrete major virulence factors (cargo proteins) and anchor them to the cell surface via a novel linking sugar, 2-N-seryl, 3-N-acetylglucuronamide (SAGA), which is a component of a specific type of lipopolysaccharide, A-LPS. The reported structure of the polysaccharide component (A-PS) was a repeating phosphorylated mannan whereas the PS of conventional O-LPS (O-PS) is a repeating Gal-Glu-Rha-GalNAc unit. Here, we have performed extensive mass spectrometric analyses of cargo protein-linked LPS with and without proteinase K treatment to determine the structure of A-LPS. Limited acid hydrolysis of the PS backbone with trifluoromethanesulfonic acid enabled long PS fragments linked to cargo-derived peptides to be identified for the first time. Unexpectedly, rather than finding A-PS units, up to eleven O-PS repeating units were found linked to cargo via a novel pentasaccharide linker designated A-LS, composed of SAGA-Hex-dHex(C4H4O3)(Pent)-Hex. In addition, samples from a wzzP/porT double mutant that produced free truncated O-PS were specifically hydrolyzed to cleave lipid A prior to MS analysis. In these samples A-LS was found attached to a limited number of O-PS repeating units that in turn were associated with a putative core oligosaccharide that included the LPS-specific sugar, 3-deoxy-d-manno-octulosonic acid (Kdo). The proposed structure of A-LPS explains all 11 genes specific to A-LPS biosynthesis, and provides the first structural evidence that cargo proteins such as the gingipains are anchored to the cell surface via a complete LPS molecule.}, } @article {pmid42000269, year = {2026}, author = {Desnuelle, C and Couratier, P and Corcia, P and Duburcq, A and Torreton, E and Baffert, S and Nevoret, C and Turgeman, S}, title = {Treatment pathway, healthcare resource utilization and direct cost of ALS in France: A nationwide claims database study.}, journal = {Revue neurologique}, volume = {182}, number = {6}, pages = {528-538}, doi = {10.1016/j.neurol.2026.02.159}, pmid = {42000269}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/epidemiology ; France/epidemiology ; Humans ; Female ; Retrospective Studies ; Male ; *Patient Acceptance of Health Care/statistics & numerical data ; *Health Care Costs/statistics & numerical data ; Databases, Factual ; Aged ; Middle Aged ; *Health Resources/statistics & numerical data/economics ; Cohort Studies ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease, associated with high clinical burden. The aim of this study was to estimate ALS-related healthcare resource utilization (HCRU), associated direct costs and their determinants in France.

METHODS: A retrospective cohort study was conducted among newly diagnosed patients with ALS identified between 2012 and 2022 (11 years) in the French National Health Data System (SNDS) through a validated algorithm. This incident population was compared with non-ALS controls (1:2) matched on age, sex, and region. Direct all-cause healthcare reimbursable costs were estimated. Survival, HCRU and direct costs were analyzed over the first five years after diagnostic.

RESULTS: A total of 16,814 newly diagnosed ALS patients were identified who could be matched with 33,628 non-ALS controls. The median age was 68.0 year and 55.3% were males. Over the first year after diagnosis, the direct all-cause medical cost per patient was €19,497 of which 47.2% was related to inpatient care, compared to €4,921 for controls which led to an ALS-attributable cost of €14,474 per patient per year. ALS patients had significantly (P<0.0001) higher HCRU than controls in all items of inpatient and outpatient care but especially for utilization of medical devices, frequencies of nurse and physiotherapist visits and acute care hospitalizations. The annual direct cost per patient who survived the successive annual period after diagnosis increased during the second, third and fourth year to €22,358, €22,276 and €21,372 respectively and then declined in year 5 to €19,720. These results largely underestimated the real cost of the management of ALS by not considering the out-of-pocket expenses associated with informal care and home renovation as well as productivity loss.

CONCLUSIONS: Patients with ALS had higher HCRU and direct medical cost, compared with controls. The economic burden of ALS was substantial even when restricted to the medical costs covered by the public health insurance system. There is an important need for novel therapies that might lower disease progression in early disease stages.}, } @article {pmid42006515, year = {2026}, author = {Cheung, N}, title = {Synaptic Plasticity Fragility Underlies a Microglial Pruning Continuum in Major Depressive Disorder and Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e107259}, pmid = {42006515}, issn = {2168-8184}, abstract = {Background Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are clinically distinct yet show intriguing comorbidity, often early in the disease course. We hypothesized a shared microglia-mediated synaptic pruning vulnerability, amplified differently by disorder-specific pathways, autophagy collapse in ALS versus RNA processing and immune dysregulation in MDD, thereby creating a biological continuum. Methods Using large-scale genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC) (MDD, N=829,249) and Project MinE (ALS, effective N=87,381), we applied Multi-marker Analysis of GenoMic Annotation (MAGMA) for gene- and set-level associations, Gene Set Enrichment Analysis (GSEA)/Differential Gene Set Enrichment Analysis (DGSEA) for pathway enrichment and differential enrichment, S-PrediXcan transcriptome-wide association study (TWAS) across 14 GTEx tissues, and linkage disequilibrium score regression (LDSC) for partitioned heritability and cross-trait genetic correlation. Eight gene sets (housekeeping controls, monoaminergic, neurosteroid, glutamatergic, synaptic pruning, autophagy/protein quality, RNA processing, and immune/neuroinflammation) were tested for convergence and divergence. Results Synaptic pruning emerged as the sole consistent cross-disorder signal, with robust enrichment in MDD (LDSC 1.32×, GSEA NES=1.415, p=0.0001) and nominal but consistent signals in ALS (GSEA NES=1.40, p=0.011; TWAS HLA-B). Autophagy dominated ALS (LDSC 2.20×, TWAS C9orf72 Z=13.43, GSEA NES=1.94) but was depleted in MDD. RNA processing and immune pathways were prominent in MDD (LDSC 1.48× and 1.89×, respectively), with only nominal signals in ALS. Overall genetic correlation was near zero (rg=-0.044, p=0.196). Conclusions These findings support a microglial pruning continuum model: shared pruning liability as the foundation, with autophagy failure driving ALS neurodegeneration and RNA/immune dysregulation shaping MDD stress sensitivity. The low rg explains the modest overlap, while pathway specificity accounts for comorbidity and divergent progression. This framework offers testable predictions for polygenic risk score (PRS) stratification, complement modulators in ALS mood subsets, and microglial therapies in treatment-resistant MDD.}, } @article {pmid42006781, year = {2026}, author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD}, title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42006781}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; R01 AG063826/AG/NIA NIH HHS/United States ; T32 AG061897/AG/NIA NIH HHS/United States ; }, abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A[2]ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A[2]ND glucose dysregulation spatial signature remains undescribed.

OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A[2]ND.

DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).

STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.

DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.

MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t- or Z- values, and annotations indicating the disease of interest, whether the outcome was for hyper- (disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.

RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A[2]ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A[2]ND which included both hypo- and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A[2]ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.

CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A[2]ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A[2]ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.}, } @article {pmid42008451, year = {2026}, author = {Pena, C and Sinar, MK and Koza, LA and Boehler, N and Buechler, E and Smith, AC and McGarr, A and Baybayon-Grandgeorge, AN and Herda, MS and Jaques, S and Linseman, DA}, title = {Preclinical study of red dragon fruit (Hylocereus polyrhizus) betacyanins in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/1028415X.2026.2661760}, pmid = {42008451}, issn = {1476-8305}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of cortical and spinal motor neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Betacyanins, betalain pigments found in red dragon fruit and beetroot, display powerful anti-inflammatory and free-radical scavenging properties which may help ameliorate ALS pathology and slow disease progression. The present study characterized the therapeutic effects of a betacyanin-rich red dragon fruit extract (DFE) in the G93A mutant hSOD1 transgenic mouse model of ALS. Mice were treated orally with 5% (v/v) DFE in drinking water ad libitum, from disease onset until end-stage. DFE treatment had a statistically significant effect on survival, with an approximate 13-day extension of median lifespan in the treated G93A mutant hSOD1 group. Treatment with DFE also significantly preserved muscle strength and endurance, as assessed by grip strength and rotarod behavioral testing. This was associated with a modest but statistically significant preservation of gastrocnemius muscle weight in the DFE-treated group. Histopathological analyses demonstrated improvements in NMJ size and complexity, an increase in surviving spinal cord motor neurons, and a reduction in spinal cord astrogliosis in G93A mutant hSOD1 mice treated with DFE, when compared to their untreated mutant littermates. Overall, these findings indicate that DFE, or purified betacyanin compounds, should be investigated further as potential therapeutic agents for patients with SOD1-related ALS. Additional preclinical studies in non-SOD1 models of ALS will need to be completed to determine the potential benefit of betacyanin compounds in sporadic ALS.}, } @article {pmid42008764, year = {2026}, author = {Stone, AK and Veinot, TC}, title = {Access to Technology-Mediated Community Mental Health Care Among Low-Socioeconomic Status Consumers With Serious Mental Illness: Qualitative Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e79608}, pmid = {42008764}, issn = {2561-326X}, mesh = {Humans ; *Mental Disorders/therapy/psychology ; *Health Services Accessibility/standards/statistics & numerical data ; Qualitative Research ; Low Socioeconomic Status ; Female ; Adult ; *Community Mental Health Services/methods/statistics & numerical data ; Male ; Middle Aged ; Anthropology, Cultural/methods ; Digital Health ; Telemedicine ; }, abstract = {BACKGROUND: Access to mental health care is critical for the effective management of serious mental illness (SMI), but consumers with low socioeconomic status (SES) have lower rates of service usage and worse retention in care. Digital technologies are often lauded as a way to bridge access gaps; however, little is known about how technology-mediated care may influence care access among low-SES consumers and how consumers use technology in care access.

OBJECTIVE: This study aimed to examine the applicability of Levesque et al's access framework to technology-mediated care for SMI and analyze how low-SES consumers use technology to facilitate care access. Furthermore, the study assesses whether and how technologies are involved in care access at multiple points within the process of accessing care.

METHODS: This study used 2 qualitative methods: ethnographic observations at a mental health treatment court and interviews with low-SES consumers with SMI using community mental health care (n=14) and key informant interviews with health and service providers working with this population (n=14). Observations occurred from July 2022 through September 2023, and interviews occurred between January 2022 and May 2024. Data analysis involved both inductive and deductive coding approaches. Data from both the interviews and observations were analyzed in NVivo and further triangulated through analytic memos.

RESULTS: Levesque et al's framework required several extensions to accommodate technology-mediated care related to SMI for low-SES consumers: (1) a cyclical rather than linear trajectory; (2) simultaneous care acquisition from multiple health and service providers; (3) staying in care long-term; (4) identification of both one-time and ongoing health needs; and (5) an emergency pathway for entering care. Consumers often faced challenges related to the varied digital requirements of each provider and a dearth of integrative, patient-facing tools like portals. Within this context, some consumers use mobile apps, communication, and telehealth technologies across various care access stages. Consumers used technology by figuring out how to navigate technology-mediated care, especially by leaning on others, such as case managers, for support. These others provided consumers with temporary technologies, showed them how to use technologies, and accompanied them through the process of using technology for accessing care.

CONCLUSIONS: This study highlights that accessing care is iterative and ongoing, involving multiple forms of co-occurring service provision. A theoretical contribution of this work is its extension of Levesque et al's care access framework to better reflect technology-mediated care for SMI among low-SES consumers. This work also underscores ongoing challenges for accessing technology-mediated care and the importance of human support in addressing access difficulties. Clinical implications include incorporating digital readiness assessments and providing comprehensive guidance on how consumers can effectively use technologies for care. Future work should investigate how technology-mediated care can make care access easier rather than harder.}, } @article {pmid42013406, year = {2026}, author = {Weemering, DN and van Unnik, JWJ and Genge, A and van den Berg, LH and van Eijk, RPA}, title = {Heterogeneity in the Analysis of the ALSFRS-R in ALS Clinical Trials and its Effect on the Validity and Precision of Trial Conclusions.}, journal = {Neurology}, volume = {106}, number = {9}, pages = {e214937}, pmid = {42013406}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/therapy ; *Randomized Controlled Trials as Topic/standards ; Reproducibility of Results ; *Disability Evaluation ; }, abstract = {BACKGROUND AND OBJECTIVES: Disability rating scales play a pivotal role in clinical trials, but there is a notable lack of guidance on how to analyze these scales. Using amyotrophic lateral sclerosis as a case study, our aim was to explore how disability rating scales have been analyzed in completed clinical trials and to assess how these different approaches influence both the risk of false-positive findings and the statistical power to detect true treatment effects.

METHODS: We searched PubMed and Embase to systematically identify randomized, placebo-controlled clinical trials using the revised ALS functional rating scale (ALSFRS-R) as primary end point, with ≥20 randomly assigned patients and ≥12-weeks of follow-up. Data were extracted on the statistical analysis approaches and strategies for handling missing data. Variability in statistical methods was mapped to the various research questions that the trials aimed to address. A simulation study assessed how each statistical method influenced validity (false-positive rate) and precision (statistical power), using the Ceftriaxone trial data set to model a realistic trial scenario.

RESULTS: Our analysis included 45 randomized clinical trials, comprising a total sample size of 7,338 patients, and identified 39 distinct statistical methods using a mixture of longitudinal and cross-sectional techniques. Most trials (55.6%) did not use all available (longitudinal) ALSFRS-R measurements, resulting in suboptimal utilization of patient data and reduced statistical precision. Applying the different statistical methods to the same trial data set resulted in large differences in the estimated treatment effect size, ranging from a negative 1.33 to a positive 2.33 SD difference. Among the methods used, 38.9% (95% CI 24.8%-55.1%) were at risk of increasing false-positive rates, potentially contributing to the erroneous advancement of ineffective treatments. Statistical power of valid strategies varied widely, ranging from 17.9% to 78.2%.

DISCUSSION: Our results demonstrate considerable variability in statistical methods, with the choice of method able to influence the estimated treatment effects, potentially resulting in misleading conclusions and uncertainty about treatment effects. This limits the interpretability and comparability of clinical trials and influences clinical decision-making and drug development. Establishing statistical consensus recommendations could improve the utility of disability scales in clinical trials and accelerate progress toward effective therapies for neurodegenerative diseases.}, } @article {pmid42031371, year = {2026}, author = {Kamate, DP and Neumayr, A and Blum, J}, title = {Konzo: a nutrition-related tropical spastic paraparesis.}, journal = {BMJ case reports}, volume = {19}, number = {4}, pages = {}, pmid = {42031371}, issn = {1757-790X}, mesh = {Humans ; *Paraparesis, Tropical Spastic/etiology/diagnosis ; *Manihot/adverse effects ; }, abstract = {Konzo, derived from the Yaka term for 'tired legs' (Democratic Republic of the Congo, DRC) and also known as Buka-buka in the Bandundu region of DRC, is a nutrition-related neurotoxic disorder confined to sub-Saharan Africa. It predominantly affects impoverished and underserved rural populations who depend on bitter cassava as a dietary staple. Cases of konzo most often arise during the dry season or prolonged droughts, when limited water availability hinders adequate soaking or processing of cassava roots, preventing the effective removal of their toxic cyanide content prior to consumption. Clinically, konzo presents as an acute-onset, symmetrical, isolated motor disorder characterised by non-progressive yet permanent spastic paraparesis. In the absence of a curative treatment, the lifelong consequences of konzo impose a substantial burden on affected individuals and their communities.}, } @article {pmid42031611, year = {2026}, author = {Etik, DÖ and Dişibeyaz, S and Özmert, EH}, title = {Pancreatitis due to afferent loop syndrome: A case report and a brief review of the literature.}, journal = {Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology}, volume = {27}, number = {3}, pages = {438-442}, doi = {10.1016/j.ajg.2026.02.003}, pmid = {42031611}, issn = {2090-2387}, mesh = {Humans ; Male ; *Afferent Loop Syndrome/complications/diagnosis ; Adult ; *Pancreatitis/etiology/diagnosis/therapy ; Gastric Bypass/adverse effects ; Gastrectomy/adverse effects ; Abdominal Pain/etiology ; Diagnosis, Differential ; }, abstract = {Afferent loop syndrome (ALS) should be a part of the differential diagnosis in a patient with acute pancreatitis with a history of gastric surgery. Although it is a rare clinical entity, association of ALS with acute pancreatitis can lead to poor clinical outcomes. Herein, we report the case of a 41-year-old man with a history of subtotal gastrectomy and Roux-en-Y gastric bypass who presented with abdominal pain and tenderness. Treatment of choice in this case was purely medical. A brief review of similar cases in the literature highlights the wide array of etiologies of acute pancreatitis due to ALS and reveals a broad spectrum of treatment options from medical to surgical.}, } @article {pmid42033202, year = {2026}, author = {Yusuf, S and Allen, MD and Kang, H and Phillips, DE and Genge, A}, title = {Opportunities and challenges related to participant stratification and cohort enrichment in ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2659128}, pmid = {42033202}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is marked by substantial clinical heterogeneity. This heterogeneity has impacted clinical trials by obscuring treatment effects and causing inefficiency. In this review, we summarize potential approaches for addressing heterogeneity in ALS via patient stratification and cohort enrichment methods and highlight potential challenges and limitations. These categories include stratification based on genetics, clinical characteristics (e.g. pattern of weakness, ALS Functional Rating Scale rates of progression), wet biomarkers (e.g. neurofilament light chain), neuroimaging, and novel methods employing statistical modeling or machine learning. These stratification methods have yet to be fully leveraged in clinical trial design. But these strategies must be employed thoughtfully and judiciously due to potential issues stratification can introduce. Future clinical trials should explore how participant stratification and cohort enrichment strategies may improve our ability to identify treatment effects, which may ultimately aid in the quest to establish more personalized medicine for persons with ALS.}, } @article {pmid42035155, year = {2026}, author = {Pedde, M and Adar, SD and Jang, DG and Feldman, EL and Goutman, SA}, title = {Air pollution and mortality in a University of Michigan amyotrophic lateral sclerosis cohort: a survival analysis.}, journal = {Environmental health : a global access science source}, volume = {25}, number = {1}, pages = {}, pmid = {42035155}, issn = {1476-069X}, support = {R01TS000327/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/mortality ; Humans ; Michigan/epidemiology ; *Air Pollutants/analysis/adverse effects ; *Air Pollution/adverse effects/analysis ; Female ; Particulate Matter/analysis/adverse effects ; Male ; Middle Aged ; Survival Analysis ; Prospective Studies ; Aged ; *Environmental Exposure/adverse effects ; Nitrogen Dioxide/analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, fatal, neurodegenerative disease. With limited treatment options, identifying modifiable risk factors that impact ALS survival is an important goal. Air pollution may be one such risk factor, yet the research on this topic is limited. METHODS: We assessed survival for ALS patients at the University of Michigan Pranger ALS Clinic who were recruited to participate in a prospective cohort study between 2009 and 2022. Participants’ personal characteristics were linked with residential air pollutant levels of fine particulate matter mass (PM2.5), nitrogen dioxide (NO2), and ozone (O3), as well as several particle components, including black carbon (BC), nitrate, sulfate, and sea-salt (as a negative control) over follow-up. To assess the role of air pollution on ALS mortality we used time-dependent Cox proportional hazards models with days from diagnosis as the time axis, adjusted for potential confounders and co-pollutants. RESULTS: Across the 1,276 total years of person-time during follow-up (2.7 ± 2.5 years per participant) there were 329 deaths. In fully adjusted multi-pollutant models, one interquartile range (IQR) (2.1 µg/m3) higher 1-year average PM2.5 was associated with a 66% (HR 1.66 per IQR; 95% CI 1.03–2.68) increase in the hazard of death. The other pollutants were not associated with death in participants with ALS . CONCLUSIONS: This finding suggests a seven month longer median survival for a 2.1 µg/m3 decrease in 1-year average PM2.5, which is significant given that ALS lacks a cure and that existing treatments only extend survival by a few months.}, } @article {pmid42038869, year = {2025}, author = {Behroozinia, M and Khosrawi, S}, title = {Rehabilitation Interventions in Adults with Amyotrophic Lateral Sclerosis: A Review :.}, journal = {Galen medical journal}, volume = {14}, number = {}, pages = {e3708}, pmid = {42038869}, issn = {2322-2379}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common and rapidly devastating neurodegenerative disease, which causes impairment of motor neurons in the upper and lower limbs, as well as in the bulbar muscles among adults. This leads to progressive weakness of voluntary muscles. The median survival after the emergence of initial symptoms is typically three years. During this period, due to the worsening of general well-being and independence, patients and their caregivers experience significant emotional stress. Furthermore, there is currently no definitive treatment for ALS. Consequently, patients face various challenges associated with motor impairment, including mobility disturbances, respiratory dysfunction, speech difficulties, and limitations in activities of daily living. Therefore, rehabilitation plays a vital role as a component of multidisciplinary care for managing these issues and reducing the impact of the disease on patients and their families. It is considered the optimal choice for alleviating the discomfort of ALS patients until a curative treatment is discovered.This narrative review aims to provide an overview of different aspects of rehabilitation, including physical therapy, occupational therapy, speech therapy, and respiratory strategies focused on enhancing independence, functional abilities, and overall quality of life while minimizing disabilities and complications in patients coping with this debilitating condition.}, } @article {pmid42045773, year = {2026}, author = {Rana, R and Mehan, S and Mukherjee, R and Khan, MDN and Das Gupta, G and Narula, AS}, title = {Caffeic Acid Phenethyl Ester Enhanced the Klotho/SIRT1/Nrf2/HO-1 Axis to Protect Against Methylmercury-Induced ALS-Like Neurodegeneration.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {}, pmid = {42045773}, issn = {1559-1182}, support = {DST-SERB, Govt. of India (Grant Number: CRG/2021/001009).//Science and Engineering Research Board/ ; }, mesh = {Animals ; *Caffeic Acids/pharmacology/therapeutic use ; *Phenylethyl Alcohol/analogs & derivatives/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/chemically induced/prevention & control ; Male ; Klotho Proteins ; Methylmercury Compounds/toxicity ; *Sirtuin 1/metabolism ; *Glucuronidase/metabolism ; *Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Antioxidants/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, and neuroinflammation. This study evaluated the neuroprotective potential of caffeic acid phenethyl ester (CAPE) against MTME + 5-induced neurotoxicity in an ALS-like pathology model. CAPE (50 and 100 mg/kg., p.o.) demonstrated significant therapeutic efficacy by improving motor and cognitive deficits, restoring oxidative balance, and mitigating neuroinflammatory and apoptotic pathways. Behavioral assessments, including the open field, grip strength, forced swim, and Morris water maze, highlighted CAPE's ability to restore neuromuscular coordination and cognitive function in a dose-dependent manner. Cellular and Molecular analyses revealed that MTME[+]5 exposure significantly disrupted Klotho/SIRT-1/Nrf2/HO-1 antioxidant signaling, increased pro-inflammatory cytokines (TNF-α, IL-1β), and elevated apoptotic markers (Bax, caspase-3) while depleting anti-inflammatory cytokines (IL-10) and neuroprotective proteins. Furthermore, CAPE treatment restored these parameters, reduced oxidative stress, and enhanced antioxidant defenses (SOD, CAT, r-GSH). Furthermore, CAPE normalized neurotransmitter imbalances, including acetylcholine, dopamine, GABA, serotonin, and glutamate, alleviating excitotoxicity. Histopathological and gross morphological analyses confirmed CAPE50 and CAPE100 ability to preserve neuronal and myelin integrity across key brain regions, including the cerebral cortex, hippocampus, striatum, midbrain, and cerebellum. CAPE also reduced methylmercury accumulation in the brain and cerebrospinal fluid, indicating detoxifying effects. Co-administration of vitamin B1 (VTB1(200)) further amplified CAPE's therapeutic efficacy. Complete blood count (CBC) analysis demonstrated MTME[+]5-induced hematological abnormalities, including reduced RBCs, hemoglobin, WBCs, and platelets, alongside elevated eosinophils and basophils. CAPE treatment normalized these parameters, indicating systemic recovery. These findings establish CAPE as a promising neuroprotective agent for ALS, capable of targeting neurocomplications.}, } @article {pmid42046889, year = {2026}, author = {Martinez-Gonzalez, L and Sanchez-Santos, C and Huang, CS and Gil, C and Martinez, A}, title = {Innovative therapies under clinical development for ALS treatment: small molecules.}, journal = {Expert opinion on investigational drugs}, volume = {35}, number = {5}, pages = {351-367}, doi = {10.1080/13543784.2026.2667249}, pmid = {42046889}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; *Drug Development/methods ; Clinical Trials as Topic/methods ; Precision Medicine/methods ; Patient Selection ; Molecular Targeted Therapy ; }, abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is a rapidly evolving field, characterized by significant obstacles but also by an increasing volume of novel therapeutics entering clinical research. Expanding on our 2022 work, this review examines the current state of the ALS clinical pipeline. Given the high volume of ongoing trials, the diversity of their biological targets and the nature of their therapeutic approaches, we focus this comprehensive update in providing a comprehensive overview of the current state of small-molecule development, focusing on agents that have entered or progressed through clinical evaluation since 2022 to the end of 2025.

AREAS COVERED: Clinical trials for ALS registered within the United States (ClinicalTrials.gov) and European Union (EU Clinical Trials Register/CTIS) databases have been systematically reviewed and are detailed in this report.

EXPERT OPINION: The implementation of advanced clinical trial platforms has introduced more efficient, adaptive strategies, leading to a significant increase in the breadth of explored therapies for ALS. Furthermore, the advent of precision medicine, powered by Artificial Intelligence (AI) for enhanced patient selection and stratification, offers a critical pathway toward overcoming the challenges posed by this severe and heterogeneous disease.}, } @article {pmid42055109, year = {2026}, author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H}, title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.}, journal = {Neuroscience}, volume = {606}, number = {}, pages = {126-137}, doi = {10.1016/j.neuroscience.2026.04.024}, pmid = {42055109}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Blood-Brain Barrier/metabolism ; Animals ; *Ultrasonic Therapy/methods ; }, abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.}, } @article {pmid42059647, year = {2026}, author = {Ma, X and Jiang, Z and Yang, T and Zhang, H and Lu, W and Liu, K and Fan, X and Yang, G and Wu, S}, title = {Integrated multi-omics analysis reveals gut dysbiosis and altered energy metabolism in Chinese ALS patients.}, journal = {Microbiology spectrum}, volume = {14}, number = {6}, pages = {e0060926}, pmid = {42059647}, issn = {2165-0497}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; Multiomics ; *Energy Metabolism ; *Dysbiosis/microbiology/metabolism ; *Gastrointestinal Microbiome ; Bacteria/classification/genetics/isolation & purification/metabolism ; China ; Metabolome ; Oxidative Stress ; Metabolomics ; Female ; Virome ; Male ; Middle Aged ; Feces/microbiology ; East Asian People ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a complex etiology. Emerging evidence implicates gut microbiota dysbiosis in ALS pathology via the gut-brain axis, yet the specific integrative profile of the gut microbiome, virome, and metabolome, particularly in Chinese patients, remains incompletely characterized. Although global diversity indices showed no significant differences, taxonomic analysis revealed distinct compositional shifts. The ALS microbiome was characterized by a significant depletion of beneficial anti-inflammatory genera, specifically Akkermansia and Faecalibacterium, and an expansion of opportunistic pathogens such as Escherichia and oral-associated taxa (e.g., Streptococcus). We also observed a specific alteration in the gut virome, with viral genera including Puppervirus and Donellivirus enriched in ALS patients. Functionally, the ALS microbiome exhibited a marked upregulation of pathways involved in L-ascorbate (vitamin C) degradation and fatty acid biosynthesis, suggesting a microbial contribution to systemic oxidative stress. Metabolomic analysis corroborated these findings, identifying 271 differentially expressed metabolites. ALS patients showed elevated levels of inflammatory lipids (e.g., LysoPC) and metabolic intermediates of the tricarboxylic acid (TCA) cycle, alongside a downregulation of antioxidants. Integrative analysis highlighted profound dysregulation in porphyrin metabolism, oxidative phosphorylation, and energy homeostasis. Our findings demonstrate that ALS is associated with a specific dysbiotic gut ecosystem characterized by the loss of protective commensals, unique viral signatures, and functional metabolic reprogramming that exacerbates host oxidative stress and energy deficits. These results provide new insights into gut-brain interactions and highlight microbial antioxidant depletion as a potential therapeutic target.IMPORTANCEAmyotrophic lateral sclerosis (ALS) is a devastating disease with no cure. While gut bacteria are known to influence brain health, we still do not understand exactly how they contribute to ALS progression. In this study, we used advanced DNA sequencing and chemical analysis to deeply examine the gut ecosystem of ALS patients. Beyond just cataloging which bacteria are present, we discovered what they are doing: the ALS microbiome actively breaks down vitamin C (a critical antioxidant) and disrupts energy metabolism. We also found a loss of protective bacteria that maintain the gut barrier. These findings are significant because they suggest that the gut microbiome in ALS patients may be actively fueling the disease by depleting the body's antioxidant reserves. This points to a new potential treatment strategy: targeting these specific bacterial functions or replenishing specific metabolites to protect motor neurons.}, } @article {pmid42060866, year = {2026}, author = {Kiernan, MC and Genge, A and Grosskreutz, J and Kuwabara, S and Lillo, P and Rosenfeld, J and Cummings, C}, title = {The World Federation of Neurology Specialty Group in ALS/MND: toward strategic partnership and new frontiers.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {27}, number = {5-6}, pages = {501-503}, doi = {10.1080/21678421.2026.2663915}, pmid = {42060866}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/epidemiology ; *Neurology/organization & administration ; *Societies, Medical ; *International Cooperation ; *Motor Neuron Disease/therapy/diagnosis/epidemiology ; }, abstract = {A memorandum of understanding was recently established between the World Federation of Neurology Specialty Group and the International Alliance of ALS/MND Associations. This new strategic partnership brings together leading clinicians and researchers with national and regional organizations dedicated to supporting ALS patients, their families, and caregivers. The purpose of partnership is to strengthen global coordination in research, education, advocacy, and clinical care for people living with MND. The agreement outlines shared priorities, including promoting equitable access to diagnosis and treatment, supporting capacity building in low- and middle-income regions, and facilitating the exchange of scientific knowledge and best practice. Both parties commit to joint initiatives such as international meetings, guideline development, clinical trials and data-sharing efforts that advance understanding of disease mechanisms and therapeutic approaches. Together, these organizations represent the scientific and human dimensions of the ALS challenge. Through partnership, the WFN Specialty Group and the International Alliance aim to accelerate progress toward improved outcomes and, ultimately, effective treatments for MND worldwide.}, } @article {pmid42072687, year = {2026}, author = {Fiorucci, C and Rossi, MN and Di Santo, R and Salvatori, I and Scaricamazza, S and Giuliani, S and Carletta, O and Filomena, E and Laurenti, D and Mattioli, R and Mosca, L and Valle, C and Ferri, A and D'Erchia, AM and Cervelli, M}, title = {Transcriptomic Analysis Reveals the Beneficial Effects of Spermidine in an ALS Mouse Model.}, journal = {Biomolecules}, volume = {16}, number = {4}, pages = {}, pmid = {42072687}, issn = {2218-273X}, support = {LSH-Puglia, T4-AN-01 H93C22000560003//INNOVA - Italian network of excellence for advanced diagnosis/ ; Grant Code IR0000010//ELIXIR-IT/ ; MAE0067342//Protocols of Scientific and Technological Bilateral Cooperation funded by the Ministry of Health/ ; L. 232/2016-art.1 cc. 314-337 awarded to the Department of Science of Roma Tre University (2023-2027)//MIUR-Italy Grants of Departments of Excellence/ ; CUP B83C22002820006//Progetto ECS 0000024 Rome Technopole/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Spermidine/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; Muscle, Skeletal/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Mice, Transgenic ; *Gene Expression Profiling ; Spinal Cord/metabolism/drug effects ; Humans ; Superoxide Dismutase-1/genetics ; *Transcriptome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of motor neurons and skeletal muscle. Gene expression analysis of the spinal cord and gastrocnemius of the SOD1-G93A ALS mouse model revealed a strong increase in inflammatory pathways and, specifically in the ALS gastrocnemius, a decrease in mitochondrial transcription and an increase in ribosomal protein expression. Treatment of ALS mice with the polyamine spermidine (SPD), a promising molecule in combating neurodegeneration and muscle atrophy, is able to partially restore the expression of more than four thousand genes in gastrocnemius tissue, including the mitochondrial regulator Pgc1α, as well as all the mitochondrial encoded genes and a large class of ribosomal proteins. SPD enhanced mitochondrial bioenergetics, as evidenced by Seahorse experiments, and delayed muscle weakness in vivo, as shown by grip strength records. These findings suggest that SPD can act as a potential supplement in the therapeutic strategy for ALS, offering a foundation for further research to improve patient outcomes.}, } @article {pmid42074010, year = {2026}, author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS}, title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074010}, issn = {1422-0067}, support = {FGFU-2025-0004//Russian state contract/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Humans ; *Radiation, Ionizing ; Disease Progression ; Disease Models, Animal ; Autophagy/radiation effects ; DNA Repair/radiation effects ; }, abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.}, } @article {pmid42074053, year = {2026}, author = {Ribeiro, GD and Queiroz, DD and Monteiro-Neto, JR and Gerhardt, E and de Souza, GF and Albino, PCSC and Paranhos, LH and Outeiro, TF and Eleutherio, ECA}, title = {Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074053}, issn = {1422-0067}, support = {CNE 201.174/2022//FAPERJ/ ; PROBRAL 88881.986154/2024-01//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; PQ 309635/2023-3//National Council for Scientific and Technological Development/ ; CNPq Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; 210.034/2026//FAPERJ/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Phosphorylation/drug effects ; Pyruvaldehyde/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Cytosol/metabolism ; Mutation ; Glycosylation ; Cell Line ; Protein Binding ; Cell Nucleus/metabolism ; }, abstract = {Glycation of superoxide dismutase 1 (SOD1) has been shown to modulate the cytosolic levels of phosphorylated TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) pathology. In this study, we investigated the interaction between TDP-43 and SOD1 and assessed how methylglyoxal (MGO)-induced glycation and the ALS-associated G93A SOD1 mutation affect this interplay in H4 cells. MGO exposure reduced SOD1 activity and TDP-43 phosphorylation in cells expressing WT SOD1, but not in those expressing G93A SOD1. Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol; however, cytosolic interactions were more prevalent in G93A-expressing cells. Although MGO did not significantly alter the overall interaction between TDP-43 and WT SOD1, it induced cytosolic inclusion formation at 0.4 mM, a concentration associated with reduced cell viability. These inclusions did not colocalize with stress granules, indicating alternative aggregation pathways. Treatment with cyclosporin A, which inhibits the phosphatase calcineurin, decreased both TDP-43-WT SOD1 inclusions and cytosolic interactions between TDP-43 and G93A SOD1. Together, these findings suggest that SOD1 damage, induced by glycation or ALS-linked mutation, may affect TDP-43 phosphorylation status and promote its cytosolic mislocalization and aggregation, providing new insights into ALS-associated proteinopathy.}, } @article {pmid42074133, year = {2026}, author = {Meltzer, M and Zamir, MS and Tzuri, N and Tan, AM and Geva, M and Hayden, MR and Lichtenstein, RG}, title = {Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation.}, journal = {International journal of molecular sciences}, volume = {27}, number = {8}, pages = {}, pmid = {42074133}, issn = {1422-0067}, mesh = {*Receptors, sigma/metabolism/agonists ; Humans ; Sigma-1 Receptor ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; *Neural Stem Cells/metabolism/drug effects ; *Piperidines/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Tunicamycin/pharmacology ; Mitochondria/metabolism/drug effects ; Transcription Factor CHOP/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington's disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 µM), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS.}, } @article {pmid42074537, year = {2026}, author = {Yesbek Kaymaz, A and Bora-Akoğlu, G and Erdem Yurter, H and Grunseich, C}, title = {Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.}, journal = {Genes}, volume = {17}, number = {4}, pages = {}, pmid = {42074537}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Genetic Therapy/methods ; *Muscular Atrophy, Spinal/genetics/therapy ; Animals ; Genetic Vectors ; *Neurodegenerative Diseases/genetics/therapy ; Gene Editing ; *Gene Targeting/methods ; Gene Therapy Agents ; }, abstract = {Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing highly personalized therapies for other neurodegenerative disorders. As intensive research and efforts to advance gene targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-based gene editing offers the potential for one-time corrective therapies for monogenic disorders like SMA and SOD1-ALS.}, } @article {pmid42074613, year = {2026}, author = {Quak, ZX and Wang, F and Tay, SKH and Koh, PL and Yap, ES and Ng, KWP}, title = {Thrombosis in Neuromuscular Medicine: Current Evidence, Unmet Needs, and Future Directions.}, journal = {Journal of clinical medicine}, volume = {15}, number = {8}, pages = {}, pmid = {42074613}, issn = {2077-0383}, abstract = {Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population.}, } @article {pmid42081010, year = {2026}, author = {Li, J and Yang, X and Liu, J and Zhao, K}, title = {Unraveling the Pathophysiological Link Between ALS and SCA: The Role of Ischemic Cerebral Vascular Dissection and the Efficacy of Endovascular Therapy.}, journal = {Cerebellum (London, England)}, volume = {25}, number = {3}, pages = {}, pmid = {42081010}, issn = {1473-4230}, support = {YXJL-2022-00351-0183//Neuroscience Innovation Development Research Project/ ; PW2022A-28//Pudong New Area Health Commission/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/complications/genetics ; *Spinocerebellar Ataxias/physiopathology/diagnostic imaging/complications/genetics ; Young Adult ; *Endovascular Procedures/methods ; *Brain Ischemia/diagnostic imaging/physiopathology/complications/therapy ; Treatment Outcome ; Dissection, Blood Vessel ; }, abstract = {To explore the role of ischemic cryptogenic vascular dissection (CVD) in a patient presenting with overlapping symptoms of amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA), and the impact of endovascular treatment on posterior circulation hypoperfusion, cerebellar atrophy, and clinical symptoms. A 22-year-old male patient with progressive neurological symptoms underwent MRI, CTA, and genetic testing, revealing cerebellar atrophy, a novel TGM6 gene variation associated with SCA type 35, and SETX gene deletions linked to ALS type 4. Ischemic CVD was diagnosed via dynamic contrast-enhanced CT (DCE-CT) and treated with endovascular stent repair followed by dual antiplatelet therapy. Following endovascular treatment, posterior circulation hypoperfusion and cerebellar atrophy were significantly improved. MRI follow-up showed increased cerebellar size and reduced interlobar spacing, with cerebellar dimensions expanding by up to 26.98% and interlobar spacing narrowing by up to 27.14%. Concurrently, the patient experienced marked improvement in clinical symptoms. At the 21-month follow-up, the patient's Modified Rankin Scale (MRS) score was rated as favorable. Ischemic CVD may underlie overlapping ALS and SCA symptoms, suggesting a genetic-vascular link. Endovascular treatment of CVD led to improvements in posterior circulation hypoperfusion, cerebellar atrophy, and clinical symptoms, supporting further investigation into this potential pathogenic nexus.}, } @article {pmid42081880, year = {2026}, author = {Schnieders, C and Scholl, C and Hoeflich, A and Schmicke, M}, title = {A pilot study on the influence of early pregnancy interferon τ to the expression of IGF-binding proteins in primary bovine hepatocytes.}, journal = {Domestic animal endocrinology}, volume = {96}, number = {}, pages = {107018}, doi = {10.1016/j.domaniend.2026.107018}, pmid = {42081880}, issn = {1879-0054}, mesh = {Animals ; Cattle ; Female ; *Hepatocytes/metabolism/drug effects ; *Interferon Type I/pharmacology ; Pregnancy ; *Pregnancy Proteins/pharmacology ; *Insulin-Like Growth Factor Binding Proteins/genetics/metabolism ; Cells, Cultured ; *Gene Expression Regulation/drug effects ; Pilot Projects ; RNA, Messenger/genetics/metabolism ; }, abstract = {The implantation period is crucial for the establishment of pregnancies in cows. Interferon τ (IFNτ) is produced during early implantation and acts in autocrine, paracrine and endocrine fashions on other endocrine systems. One of these is the insulin-like growth factor 1 (IGF-1) system, which is important for cell growth, proliferation, and therefore pregnancy establishment. This study investigated the effect of IFNτ on the expression of hepatic IGF-binding proteins (IGFBPs) in vitro. Primary bovine hepatocytes in a 2D sandwich culture model were stimulated with recombinant bovine IFNτ (rbIFNτ; 0.1-10.0 ng/mL) for six hours. The mRNA expression of IGFBP-1 to -7 and acid labile subunit (ALS) was measured using qRT‒PCR, and protein production was confirmed using western ligand blotting. All the IGFBPs (1-7) and ALS were expressed at basal levels in primary bovine hepatocytes, with IGFBP-2 to -4 secreted at appreciable concentrations in the medium. The expression of IGFBP-2 to -6 was stimulated by IFNτ, (treatment with rbIFNτ vs. control; IGFBP-2: for 0.5 ng/mL rbIFNτ, p = 0.0166; IGFBP-3: for 0.5 ng/mL, 5.0 ng/mL, and 10.0 ng/mL rbIFNτ, p = 0.0293, p = 0.0252, and p = 0.0099; IGFBP-4: for 0.5 ng/mL rbIFNτ, p = 0.0024; IGFBP-5: for 0.5 ng/mL and 10 ng/mL rbIFNτ, p = 0.0008 and p = 0.0421; IGFBP-6: for 0.1-10.0 ng/mL rbIFNτ, p = 0.0498-0.0022). These results indicate modulation of the IGF-system through IFNτ, which may contribute to adaptations supporting the early establishment of pregnancies in cattle.}, } @article {pmid42084479, year = {2026}, author = {Liu, X and Dhakal, D and Gu, S and Li, G and Jing, M and Zhang, G and Wang, Y and Zhang, Z and Fan, D}, title = {Relationship between grip strength, functional outcome, and health-related quality of life measurements in amyotrophic lateral sclerosis patients.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/17582024.2026.2667425}, pmid = {42084479}, issn = {1758-2032}, abstract = {AIM: To explore how grip strength is related to functional status and health-related quality of life (HRQoL) in amyotrophic lateral sclerosis (ALS) patients.

METHODS: In the phase 2 trial of TBN for treatment of ALS, 148 patients in full analysis set received TBN (600 mg or 1200 mg) or a placebo for 180 days. Outcome measurements included ALS Functional Rating Scale-Revised (ALSFRS-R), 40-item ALS Assessment Questionnaire (ALSAQ-40), grip strength, and forced vital capacity (FVC). Spearman's rank correlation was used to examine associations between grip strength, ALSFRS-R and ALSAQ-40. A principal component analysis-ANCOVA model adjusted for sex was used to further explore the associations.

RESULTS: Grip strength was strongly correlated with ALSFRS-R fine motor function domain (rs = 0.740) and moderately correlated with ALSAQ-40 activities of daily living (ADL) domain (rs = -0.637) (p < 0.05). Weak correlations were observed between FVC and both ALSFRS-R total score (rs = 0.355) and respiratory domain (rs = 0.229) and ALSAQ-40 domains. Grip strength was a strong predictor of ALSFRS-R fine motor and ALSAQ-40 ADL domains.

CONCLUSION: Grip strength was associated with functional status and HRQoL, supporting its potential role as a meaningful clinical outcome measure in patients with ALS.}, } @article {pmid42088060, year = {2026}, author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD}, title = {E3 ubiquitin ligases in neurodegenerative diseases.}, journal = {Military Medical Research}, volume = {13}, number = {1}, pages = {100032}, pmid = {42088060}, issn = {2054-9369}, mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use/metabolism ; *Neurodegenerative Diseases/physiopathology/enzymology ; Animals ; Proteolysis Targeting Chimera ; Ubiquitination ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.}, } @article {pmid42095090, year = {2026}, author = {Tremblay, E and Arbour, D and Vallée, J and Piovesana, R and Vallières, G and Mechichi, E and Robitaille, R}, title = {Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.}, journal = {iScience}, volume = {29}, number = {5}, pages = {115565}, pmid = {42095090}, issn = {2589-0042}, abstract = {Neuromuscular junction (NMJ) denervation is an early pathological event in amyotrophic lateral sclerosis (ALS) causing motor dysfunction and paralysis. Glial cells at the NMJ, perisynaptic Schwann cells (PSCs), ensure a balance between maintenance and repair via muscarinic receptor signaling. However, in ALS mouse models, PSCs show an aberrant muscarinic hyperactivation. We posited that this excessive activation impairs the PSC capacity to support NMJ repair in ALS. Beginning at symptoms onset, SOD1 [G37R] mice received daily oral administration of darifenacin, a clinically approved type 3 muscarinic receptor antagonist, to reduce PSC hyperactivation. The treatment improved locomotion and preserved NMJ innervation in male mice, with comparable effects observed in females, and extended survival in males. Functional benefits were supported by signs of glial repair and enhanced survival of lumbar motor neurons. These preclinical data indicate that pathological PSC hyperactivity contributes to NMJ denervation in ALS and support therapeutic strategies targeting NMJs in ALS.}, } @article {pmid42107892, year = {2026}, author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H}, title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.}, journal = {International immunopharmacology}, volume = {182}, number = {}, pages = {116781}, doi = {10.1016/j.intimp.2026.116781}, pmid = {42107892}, issn = {1878-1705}, mesh = {Humans ; *Microglia/immunology ; *Neurodegenerative Diseases/immunology/therapy ; Animals ; *T-Lymphocytes/immunology ; }, abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.}, } @article {pmid42111077, year = {2026}, author = {Zhou, S and Li, X and Jiao, Y and Wu, J}, title = {Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1754716}, pmid = {42111077}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder for which disease-modifying treatment options remain limited. This study aimed to systematically assess the efficacy and safety of pharmacological and biological therapies for ALS via a network meta-analysis (NMA).

METHODS: PubMed, EMBASE, Cochrane, and Web of Science were searched until February 25, 2025. Randomized controlled trials (RCTs) evaluating any pharmacological or biological intervention in ALS were eligible. Risk of bias was assessed using the Cochrane RoB 2 tool. A Bayesian NMA was performed in R (gemtc package). Effect estimates were expressed as mean differences (MDs) or risk ratios (RRs) with 95% credible intervals (CrIs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Publication bias was explored with funnel plots (Stata 18.0). Subgroup analyses were conducted for drug classes demonstrating significant efficacy and including at least three RCTs.

RESULTS: 109 trials involving 16,353 participants were included. The primary outcome was the ALS Functional Rating Scale-Revised (ALSFRS-R); secondary outcomes included forced vital capacity (FVC), mortality, and serious adverse events (SAEs). Compared with placebo, the combination of cell therapy and neuroprotective agents produced the greatest attenuation of ALSFRS-R decline (MD: 3.65, 95% CrI: 1.27-6.05) and was associated with the lowest SAE risk. Receptor agonists ranked highest for preservation of FVC, whereas alkaloids ranked first for mortality reduction; however, no intervention demonstrated a statistically significant survival benefit versus placebo. Within-class subgroup analyses further identified several specific agents, such as masitinib, talampanel, and EH301, as demonstrating relatively consistent efficacy, although substantial heterogeneity remained among enzyme inhibitors.

CONCLUSION: Cell therapy combined with neuroprotective agents may slow functional decline in ALS. Receptor agonists may help preserve respiratory function. Survival benefits remain inconclusive, underscoring the continued importance of comprehensive supportive care.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000672, identifier CRD420251000672.}, } @article {pmid42116584, year = {2026}, author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S}, title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.}, journal = {Protein and peptide letters}, volume = {33}, number = {1}, pages = {258-274}, doi = {10.2174/0109298665429866260217115717}, pmid = {42116584}, issn = {1875-5305}, mesh = {Humans ; *alpha-Synuclein/metabolism/antagonists & inhibitors/genetics ; *Synucleinopathies/metabolism/drug therapy/therapy/pathology ; *Parkinson Disease/metabolism/drug therapy/pathology ; Animals ; Autophagy ; Oxidative Stress/drug effects ; }, abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.}, } @article {pmid42131110, year = {2026}, author = {Zhang, M and Su, L and Han, W and Song, F and Fu, Y and Chi, MB and Chen, X and Wu, YH and Gao, SJ}, title = {Single cell Raman spectroscopic profiles predict treatment responses in patients with de novo acute myeloid leukemia.}, journal = {Frontiers in cell and developmental biology}, volume = {14}, number = {}, pages = {1767226}, pmid = {42131110}, issn = {2296-634X}, abstract = {INTRODUCTION: Leukemia is a clonal malignant proliferative disease originating from hematopoietic stem cells. Although its treatment strategy has gradually developed from traditional chemotherapy to a multimodal treatment system including novel targeted therapy and immunotherapy, primary drug resistance in particular remains the core clinical problem leading to poor patient prognosis. This clinical dilemma indicates that the traditional genotyping system based on genomics has not been able to fully resolve the molecular heterogeneity of acute myeloid leukemia (AML), and it is urgent to establish a precise stratified model that can dynamically reflect the functional status of tumor cells in the initial stage of treatment.

METHODS: In this study, Raman spectroscopy (RS) combined with machine learning algorithm was used to construct a metabolic prognosis prediction model for AML chemotherapy response. Bone marrow single cell Raman spectroscopy data of newly diagnosed AML patients were collected, and the molecular fingerprint was analyzed by principal component analysis linear discriminant analysis (PCA-LDA) and multivariate curve resolute alternating least square method (MCR-ALS).

RESULTS: The results showed that the PCALDA model achieved complete remission or non-remission (CR/NR) classification through 24 principal components (cumulative variance contribution of 90.1%), the accuracy of external validation was 94.8% (sensitivity 97.9%, specificity 92.0%), and the AUC reached 96.27%. Protein, lipid, nucleic acid and mixed components were decomposed by MCR-ALS, and lipid and nucleic acid metabolic pathways were enriched in NR group (P < 0.001).

DISCUSSION: Studies have shown that RS single-cell metabolic fingerprint can decode the metabolic reprogramming features associated with chemotherapy resistance in AML, providing a new marker-free and highly sensitive tool for real-time prognostic stratification and targeted intervention.}, } @article {pmid42134658, year = {2026}, author = {Purushotham, SS and Chesworth, R and Keembiyage, N and Münch, G and Gyengesi, E and Buskila, Y}, title = {The impact of long-term feeding with curcuminoids phospholipids enriched diet on disease progression of fALS.}, journal = {Neurochemistry international}, volume = {197}, number = {}, pages = {106183}, doi = {10.1016/j.neuint.2026.106183}, pmid = {42134658}, issn = {1872-9754}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diet therapy/genetics/drug therapy/pathology ; *Curcumin/administration & dosage ; Female ; *Disease Progression ; Male ; *Phospholipids/administration & dosage ; Mice ; Mice, Transgenic ; *Diet ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease characterised by the progressive loss of motor functions affecting both upper and lower motor neurons. Although considered multifactorial with an unclear aetiology, it is believed that the interplay between genetic and environmental factors, with neuroinflammation playing a key role in disease progression, contributes to its development. There is currently no effective treatment for ALS. Curcumin has been recently highlighted for its potential therapeutic role in treating neurodegenerative diseases. Curcumin phospholipids, a highly bioavailable form of curcumin that allow the curcumin to be absorbed into the bloodstream more effectively than standard curcumin extracts, is considered as a natural cytokine-suppressive anti-inflammatory compound (CSAID) that is well-known for its therapeutic properties and is considered safe for humans and rodents at low to moderate concentrations. In this study, we investigated whether a long-term feeding regimen incorporating curcuminoids phospholipids-enriched diet early in disease progression could mitigate motor deficits and affect the lifespan of the SOD1 mouse model of familial ALS (fALS). Our results indicate sex-differences regarding the effect of curcumin supplementation on motor deficits and anxiety-like behaviour. While long-term feeding with curcuminoids phospholipids enriched diet had a complex effect on SOD1 female mice expressed as reduced anxiety like behaviour and motor deficits at the walking beam test, it had no effect on SOD1 male mice. Moreover, curcuminoids supplementation had a limited effect on disease onset and progression in SOD1 mice model for fALS.}, } @article {pmid42136278, year = {2026}, author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS}, title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249405308251210104405}, pmid = {42136278}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.}, } @article {pmid42136293, year = {2026}, author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M}, title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273444679260416064255}, pmid = {42136293}, issn = {1996-3181}, abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.}, } @article {pmid42143042, year = {2026}, author = {Ferrari, V and Tedesco, B and Cozzi, M and Pramaggiore, P and Gagliani, MC and Magdalena, R and Cornaggia, L and Casarotto, E and Chierichetti, M and Mohamed, A and Brodnanovà, M and Milioto, C and Piccolella, M and Galbiati, M and Crippa, V and Provenzani, A and Cortese, K and Rusmini, P and Cristofani, R and Poletti, A}, title = {VCP modulation ameliorates pathological features in C9orf72 models.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42143042}, issn = {2041-4889}, support = {23236//AFM-Téléthon (French Muscular Dystrophy Association)/ ; 29514//AFM-Téléthon (French Muscular Dystrophy Association)/ ; GGP19128//Fondazione Telethon (Telethon Foundation)/ ; GMR25T1103//Fondazione Telethon (Telethon Foundation)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022EFLFL8//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; National Center for Gene Therapy and Drugs Based on RNA Technology (CN3) CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2020PBS5MJ//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n.//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022KSJZF5//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. P2022B5J32//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Università degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; 2025-0708//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; Grant 2020//Kennedy's Disease Association (KDA)/ ; Grant 2018//Kennedy's Disease Association (KDA)/ ; }, mesh = {*Valosin Containing Protein/metabolism/genetics ; *C9orf72 Protein/metabolism/genetics ; Humans ; Autophagy ; Lysosomes/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Ubiquitin/metabolism ; Mutation ; Motor Neurons/metabolism ; Neurons/metabolism ; Frontotemporal Dementia/genetics/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.}, } @article {pmid42152867, year = {2026}, author = {Cho, Y and Won, SY and Kim, H and Lee, HK and Cho, SR}, title = {The effects of a mobile healthcare application on speech and swallowing in amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {12}, number = {}, pages = {20552076261452405}, pmid = {42152867}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) impairs oral motor function, negatively affecting patients' speech and swallowing abilities, as well as quality of life.

OBJECTIVE: This study aims to evaluate the effectiveness of A Successful Swallowing with Effortful Training (ASSET) program, included in the 'The 365 Healthy Swallow Health Coach application' in preserving speech and swallowing abilities in ALS patients through self-training.

METHODS: In this 8-week quasi-experimental study, 13 participants were allocated to either the app-guided ASSET training group (n=7; three sessions per day, five days per week) or a usual-care control group (n=6) based on their clinical visit schedules. To evaluate changes over time and compare the two groups, linear mixed models were employed. Changes in ALS severity scale (ALSSS), Diadochokinetic (DDK) task, speech intensity, Speech Handicap Index-15, Dysphagia Handicap Index, Swallowing Quality of Life (SWAL-QOL), and Brief Inventory of Swallowing Assessment-15 were assessed.

RESULTS: ALSSS speech scores was relatively preserved from 5.43 (95% CI 3.01-7.84) to 5.29 (95% CI 2.87-7.70) in the ASSET treatment group, but declined from 6.33 (95% CI 3.73-8.94) to 4.83 (95% CI 2.23-7.44) in the control group, with a significant group-by-time interaction (p=.017). DDK/tuh/and/kuh/were relatively preserved from 11.86 to 11.71 and from 12.29 to 11.57 respectively in ASSET group, but declined from 11.67 to 7.50 and from 11.83 to 7.17 in the control group, with significant interactions in/tuh/(p=.032) and/kuh/(p=.044). SWAL-QOL total score was relatively preserved from 155.86 to 149.71 in ASSET group, but declined from 154.67 to 125.17 in the control group, with a significant interaction (p=.011).

CONCLUSIONS: The findings suggest that ASSET program may help preserve speech and swallowing function in patients with ALS. Future research should validate the ASSET program with a larger, adequately powered sample size.}, } @article {pmid42153537, year = {2026}, author = {Shi, J and Wu, Y and Liu, X and Xia, W and Wu, J and Lou, J and Zhang, X and Zhang, J and Yang, N and Chi, W and Xiang, L and Zhang, Y and Shu, Y and Miao, R and Zhao, J and Zhu, X and Qi, J and Xiao, J and Zhou, K}, title = {MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.}, journal = {Autophagy}, volume = {22}, number = {10}, pages = {2695-2724}, doi = {10.1080/15548627.2026.2677180}, pmid = {42153537}, issn = {1554-8635}, mesh = {*Lysosomes/metabolism/drug effects ; Animals ; Humans ; Autophagy/drug effects ; *Intracellular Membranes/metabolism/drug effects ; *Mitochondrial Proteins/pharmacology ; Mitochondria/metabolism ; Permeability/drug effects ; Mice ; Ischemia/pathology ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Male ; }, abstract = {Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the MT-RNR1/12S rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, in vivo overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.Abbreviations: AA = arachidonic acid, AAV = adeno-associated virus, ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta, ALs = autolysosomes, BECN1 = beclin 1, CASP1 = caspase 1, CQ = chloroquine, CTSB = cathepsin B, CTSD = cathepsin D, CTSL = cathepsin L, Co-IP = co-immunoprecipitation, DEGs = differentially expressed genes, ELISA = enzyme-linked immunosorbent assay, F-CHP = 5-FAM-conjugated collagen hybridizing peptide staining, GSDMD = gasdermin D, GO = gene Ontology, GPT/ALT = glutamic pyruvic transaminase, soluble, GOT1/AST = glutamic-oxaloacetic transaminase 1, soluble, HE = hematoxylin-eosin, HUVECs = human umbilical vein endothelial cells, IP/MS = immunoprecipitation coupled with mass spectrometry, IL1B/IL-1β = interleukin 1 beta, IL18 = interleukin 18, IP = intraperitoneal injection, IV = intravenous injection, LDBF = laser Doppler blood flow, LMP = lysosomal membrane permeability, MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3, MAPK = mitogen-activated protein kinase, NAGLU = alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-κB = nuclear factor kappa B, NLRP1 = NLR family pyrin domain containing 1, NLRP3 = NLR family pyrin domain containing 3, PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1, PLA2G4A/cPLA2 = phospholipase A2, group IVA (cytosolic, calcium-dependent), PYCARD/ASC = PYD and CARD domain containing, PIK3C3/VPS34 = phosphatidylinositol 3-kinase catalytic subunit type 3, PMA = phorbol 12-myristate 13-acetate, ROS = reactive oxygen speciesSQSTM1/p62 = sequestosome 1, SPR = surface plasmon resonance, scRNA-seq = single-cell RNA sequencing, UMAP = uniform manifold approximation and projection, WB = western blotting.}, } @article {pmid42155417, year = {2026}, author = {Simpson, J and Zarotti, N}, title = {Distress, not symptoms: Reframing psychological difficulties in neurodegenerative diseases of the motor system.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {200}, number = {}, pages = {262-271}, doi = {10.1016/j.cortex.2026.05.004}, pmid = {42155417}, issn = {1973-8102}, mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Psychological Distress ; *Stress, Psychological/psychology ; *Motor Neuron Disease/psychology ; Huntington Disease/psychology ; Parkinson Disease/psychology ; Anxiety/psychology ; }, abstract = {Psychological distress is common among people living with neurodegenerative diseases of the motor system (NDMS) such as Parkinson's disease, motor neurone disease/amyotrophic lateral sclerosis, and Huntington's disease. Yet the way psychological difficulties are conceptualised in these populations is heavily shaped by medicalised language. Terms such as 'non-motor symptoms' and 'neuropsychiatric manifestations' were originally introduced to draw attention to difficulties beyond movement changes but they now risk positioning mood, anxiety, apathy, and related experiences solely as direct manifestations of neurological degeneration. This framing can obscure the rich psychosocial contexts in which distress arises, blur distinctions between emotional responses and disease processes, and reinforce deficit-based and disease-focused understandings that privilege biological explanations over person-centred ones. It may also influence clinical communication, treatment decisions, help-seeking behaviour, and access to psychological therapy and psychosocial interventions, contributing to inequities in care. This article argues that linguistic choices are not neutral: they construct the boundaries of what counts as legitimate knowledge, shape expectations about causality, and delimit the interventions considered appropriate. Without critical attention to these assumptions, individuals may experience distress as biologically inevitable and clinicians may overlook psychosocial contributors that are amenable to change. We propose that greater awareness of the power of language, coupled with empirical investigation into its effects, is essential for developing a linguistic reformulation of psychological distress in NDMS and more holistic, contextually grounded approaches to supporting psychological wellbeing.}, } @article {pmid42161327, year = {2026}, author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A}, title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awag178}, pmid = {42161327}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.}, } @article {pmid42163674, year = {2026}, author = {Qi, M and Fei, L and Cui, W and Ho, PW and Lee, SM and Li, J and Zhang, Z}, title = {Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X431460260227095109}, pmid = {42163674}, issn = {1875-6190}, abstract = {Amyotrophic lateral sclerosis (ALS) is an devastating neurodegenerative disorder with a very fast course and a very high fatality rate. The review discusses the intricate pathophysiology of ALS, such as the alterations caused by the genetic mutations of the C9orf72 and SOD1 genes, the misfolding and aggregation of proteins, oxidative stress, the excitotoxicity of glutamate, neuroinflammation, malfunctions in mitochondria, and axonal transport. Heterogeneity of the disease makes the development of biomarkers in ALS challenging; however, some promising candidates have been identified. Protein aggregation markers, including TDP-43 and SOD1, oxidative stress markers, such as 8-oxodG, neuroinflammatory markers, such as CRP and MCP-1, and neurological injury markers, such as NfL and pNfH, have potential in diagnosis, monitoring, and prediction. The miRNAs and particular metabolites can also provide clues to the molecular basis of ALS. The creation of biomarkers is challenged by the presence of a significant amount of disease heterogeneity and the lack of animal model reliability. The review highlights the importance of further research on biomarkers aimed at improving the diagnosis, treatment, and development of drugs for ALS. It supports the concept of a systematic biomarker development process, including genetic testing and molecular subgroup analysis, to enhance diagnostic accuracy and prognostic prediction capabilities. Exploring the interrelationship between the pathological process of ALS and the treatment based on multi-biomarker strategies is crucial for achieving effective management of this disease. As our understanding of ALS deepens, we expect to discover more new biomarkers in the future. This will significantly improve the diagnosis, treatment, and overall management of this devastating diseas.}, } @article {pmid42164014, year = {2026}, author = {Cheung, N}, title = {Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.}, journal = {Cureus}, volume = {18}, number = {5}, pages = {e109147}, pmid = {42164014}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.}, } @article {pmid42165374, year = {2026}, author = {Fernández-Gómez, P and Tosat-Bitrián, C and Marugán, T and Fernández-Hernández, L and Cano, A and Martinez-Mulero, JA and López-Carbonero, JI and Pignatelli, J and Corrochano, S and Palomo, V}, title = {Lighting Up Mislocalized Proteins: Quantum Dot Probes for Multiplexed Cytoplasm-Selective Cell Profiling in Neurodegeneration.}, journal = {ACS sensors}, volume = {11}, number = {6}, pages = {4285-4296}, doi = {10.1021/acssensors.5c01941}, pmid = {42165374}, issn = {2379-3694}, mesh = {*Quantum Dots/chemistry ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *DNA-Binding Proteins/metabolism/analysis ; *Cytoplasm/metabolism/chemistry ; Mice ; Biomarkers/analysis ; }, abstract = {Semiconductor quantum dots (QDs) provide unique stability, brightness, and multiplexed capacity for biomarker detection in complex diseases; however, their distinctive intracellular distribution has rarely been leveraged for spatially resolved diagnostics. Here, we show how QD-based sensors enable selective detection of cytoplasmic proteins and can quantify nucleo-cytoplasm protein mislocalization in patient-derived samples. We validated this approach labeling TAR DNA-binding protein 43 (TDP-43), a key mislocalized protein in amyotrophic lateral sclerosis (ALS). Spatial resolution is achieved in several patient-derived models and mouse brain tissue, underscoring the nanosensor's versatility across biological systems. Multiplexed QD-based immunolabeling, combined with confocal imaging and high-throughput flow cytometry, enables the detection of distinct cytoplasmic biomarker signatures that discriminate ALS patients from healthy controls. These signatures include variations in TDP-43 mislocalization and protein coexpression patterns, which were further modulated by pharmacological treatment. This work establishes QDs as spatially selective, multiplexable nanosensors capable of resolving subtle yet disease-relevant intracellular phenotypes in patient-derived samples. Compared to organic fluorophores, QDs enhance sensitivity, improve signal stability, and enable simultaneous spatially resolved biomarker quantification, broadening their potential for clinical diagnostics and personalized medicine. These findings establish QDs as powerful tools for neurodegeneration research, disease monitoring, and early biomarker discovery, with potential applications in translational neuroscience and precision medicine.}, } @article {pmid42168009, year = {2026}, author = {Corcia, P and Bernard, E and de la Cruz, E and Danel, V and Soriani, MH and Guy, N and Esselin, F and Bruneteau, G and Pradat, PF and Goutines, V and Catherine, J and Eyraud, N and Cheve, P and Fernandez, A and Erazo, D and Couratier, P}, title = {Primary Lateral Sclerosis French National Diagnostic and Care Protocol.}, journal = {Revue neurologique}, volume = {182}, number = {6}, pages = {555-562}, doi = {10.1016/j.neurol.2026.04.006}, pmid = {42168009}, issn = {0035-3787}, mesh = {Humans ; France/epidemiology ; *Motor Neuron Disease/diagnosis/therapy/epidemiology ; Diagnosis, Differential ; Clinical Protocols ; Amyotrophic Lateral Sclerosis/diagnosis ; }, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative motor neuron disease characterized by progressive and selective involvement of the central motor neuron within the bulbar and spinal regions. It is estimated to account for 1-5% of motor neuron diseases and typically presents in the fifth or sixth decade of life, with a slight male predominance. According to current consensus criteria, the diagnosis relies on the demonstration of progressive upper motor neuron dysfunction in the absence of lower motor neuron involvement, with persistence of isolated upper motor neuron signs for at least four years in order to exclude a slowly progressive upper motor neuron-predominant form of amyotrophic lateral sclerosis (ALS). The French Motor Neuron Disease Network (FILSLAN) developed a National Diagnostic and Care Protocol (PNDS) with the aim of standardizing diagnostic criteria, optimizing differential diagnosis, and providing evidence-based recommendations for therapeutic management and follow-up across the national territory. These recommendations were elaborated in accordance with the methodological framework of the French National Authority for Health for rare diseases. The protocol provides practical guidance for establishing PLS as a diagnosis of exclusion, distinguishing it from ALS and hereditary spastic paraplegias, and organizing appropriate clinical and paraclinical investigations. It also outlines indications for genetic testing in selected cases and defines a multidisciplinary management strategy centered on symptomatic treatment, early rehabilitation, respiratory and nutritional surveillance, and psychosocial support. Given the slower progression of PLS compared with ALS, biannual multidisciplinary follow-up is generally appropriate. This protocol aims to harmonize clinical practice and improve patient care while acknowledging the current absence of disease-modifying therapies.}, } @article {pmid42170793, year = {2026}, author = {Michelon, H and Lefèvre-Dognin, C and Paquereau, J and Guidoni, R and Boudy, V and Ruiz, F and Vallet, T}, title = {Acceptability of Atropine Eyedrops Administered Sublingually for Sialorrhea Treatment Related to Neurological Conditions.}, journal = {Pharmacology research & perspectives}, volume = {14}, number = {3}, pages = {e70250}, pmid = {42170793}, issn = {2052-1707}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; Administration, Sublingual ; *Atropine/administration & dosage ; Cross-Sectional Studies ; France ; *Nervous System Diseases/complications ; Off-Label Use ; Ophthalmic Solutions/administration & dosage ; *Patient Acceptance of Health Care ; *Sialorrhea/drug therapy/etiology ; }, abstract = {Off-label use of anticholinergic agents (atropine eye drops) administered sublingually are a first-line treatment in standard clinical practice in France to treat sialorrhea in patients with neurological conditions. The ability and willingness to using and administering such medication have become key factors to ensure safe and effective therapy. Given that the critical aspects for ophthalmic product development differ from those for oral medicine, the objectives of this study were to investigate patient acceptability of atropine eye drops for treating sialorrhea. A multi-centric, cross-sectional study using the CAST-ClinSearch Acceptability Score Test methodology was conducted in France between February 2021 and April 2023. In total, 31 evaluations were collected. Most patients were males (74.2%) and the mean age was 51.6 ± 20 years. Poor acceptability was reported in real-life settings. A lack of a suitable administration device combined with excessive saliva flow and patient disabilities made it difficult to ensure the required dose intake. Due to the bitter taste of the drug, poor palatability of the product appeared to be a key concern for oral administration. Designing a suitable form of atropine in accordance with the specificities of patients with neurological disabilities is needed to ensure the effective treatment of sialorrhea.}, } @article {pmid42171198, year = {2026}, author = {Tian, J and Jin, Z and Chi, Y and Wang, P and Sun, H}, title = {Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.}, journal = {Nanoscale}, volume = {18}, number = {24}, pages = {12930-12941}, doi = {10.1039/d6nr00300a}, pmid = {42171198}, issn = {2040-3372}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Edaravone/chemistry/pharmacology/therapeutic use ; *Kaempferols/chemistry/pharmacology/therapeutic use ; Mice ; *Nanoparticles/chemistry ; Mice, Transgenic ; Humans ; Liposomes/chemistry ; Blood-Brain Barrier/metabolism ; Ferroptosis/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by a progressive and selective loss of motor neurons in the central nervous system, particularly in the brain and spinal cord. However, the main cellular mechanisms and cell death pathways leading to motor neuron degeneration have not yet been clarified. Research indicates evidence of ferroptosis in ALS, and the natural compound kaempferol has been demonstrated to inhibit neuronal ferroptosis. However, damage to the blood-brain barrier (BBB) prevents the drug from penetrating the central nervous system, which significantly reduces its therapeutic efficacy. Here, we developed a targeted delivery system named Eda/Kae@Lip-RGD (EKLR), which consisted of liposome-grafted RGD peptides for the co-delivery of the drugs kaempferol and edaravone, capable of crossing the BBB to provide co-delivery of kaempferol and edaravone for combined treatment of ALS. As expected, treatment with EKLR for one month significantly slowed down weight loss and improved athletic performance in SOD1[G93A] transgenic mice. Mechanistically, this nanomedicine suppressed ferroptosis by upregulating the antioxidant proteins GPX4 and SLC7A11, alongside the downregulation of Nrf2 and ACSL4 levels, thus collectively preserving neuronal integrity. Meanwhile, EKLR restored the normal morphology and the survival rate of neurons and maintained the mitochondrial structure and morphological integrity. Accordingly, this nanoplatform may represent a distinctive and potentially effective strategy for achieving neuroprotection in ALS as well as in other disorders of the central nervous system.}, } @article {pmid42171861, year = {2026}, author = {Condorelli, GA and Iozzia, A and Bonifacio, D and Pelin, A}, title = {TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.}, journal = {Neurochemical research}, volume = {51}, number = {3}, pages = {}, pmid = {42171861}, issn = {1573-6903}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/immunology ; Acetylation ; *DNA-Binding Proteins/metabolism/immunology ; Animals ; Inflammation/metabolism/immunology ; *Neuroimmunomodulation/physiology ; }, abstract = {Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and mislocalisation, TDP-43 enters the periphery; acetylation shapes its conformation, trafficking and immunogenicity. This narrative review synthesises single-cell transcriptomics, proteomic immunoprofiling and clinical inflammatory phenotyping to examine whether site-specific acetylated TDP-43 species may be associated with peripheral inflammatory signatures relevant to ALS immunopathology. By integrating separate datasets on acetylated TDP-43, monocyte phenotypes and cytokine modules, we propose two provisional endotypes characterised by monocyte reprogramming, cytokine modules and Blood-Brain Barrier (BBB) dysfunction-each representing clinically actionable pathways. Framed as a provisional neuroimmune interface, the acetylation state is considered here as a plausible molecular correlate and potential therapeutic entry point: a measurable clue to inform pharmacological targeting and, potentially, a modifiable target via p300CREB-Binding Protein (CBP)-Histone Deacetylase (HDAC) axes or sirtuin activity. Recasting TDP-43 from neuropathological hallmark to immunoactive sentinel supports a shift from descriptive nosology to stratified immunotherapy, in which treatment allocation is informed by acetylation-defined peripheral signatures.}, } @article {pmid42173382, year = {2026}, author = {Braza, AJ and Viñas-Bastart, M and Sureda-Rosich, M and García-Parra, B and Guiu-Segura, JM and Modamio, P}, title = {Tofersen in SOD1-associated amyotrophic lateral sclerosis: From molecular mechanisms to regulatory milestones.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {223}, number = {}, pages = {107563}, doi = {10.1016/j.ejps.2026.107563}, pmid = {42173382}, issn = {1879-0720}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Humans ; *Superoxide Dismutase-1/genetics/metabolism ; Animals ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; Mutation ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 2% of ALS cases and are associated with toxic protein misfolding and aggregation. Tofersen is an antisense oligonucleotide therapy designed to reduce the synthesis of mutant SOD1 protein through targeted mRNA degradation. While this strategy represents a gene-specific therapeutic approach for a subset of ALS patients, evidence regarding its efficacy, effectiveness and long-term outcomes continues to be evaluated in clinical trials and post-marketing studies.

OBJECTIVE: First, to describe the molecular mechanisms underlying SOD1-associated ALS and second, to analyze the therapeutic development, clinical outcomes, and regulatory evolution of tofersen.

METHODS: A narrative review was conducted in PubMed on preclinical and clinical studies published from 2016 through late 2025, complemented by an analysis of public registries and regulatory documentation. Clinical trials were identified through ClinicalTrials.gov and the Clinical Trials Information System (CTIS), and official reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were reviewed to contextualize their development and regulatory evaluation.

RESULTS: Fifty-three publications were identified, of which 20 met predefined inclusion criteria after screening and full-text review. Preclinical studies showed reduced mutant SOD1 expression and prolonged survival in transgenic models. Phase I-II trials demonstrated safety, favorable pharmacokinetics, and dose-dependent reductions in SOD1 in the cerebrospinal fluid and plasma neurofilament light chain (NfL) levels. Although the phase III VALOR trial did not meet the primary ALSFRS-R endpoint (a validated questionnaire-based functional rating scale-revised for determining ALS disease progression) at 28 weeks, significant reductions in the surrogate biomarker NfL indicated target engagement and supported accelerated regulatory approval. Extension data suggested potential clinical benefit with early treatment. Ongoing studies, including ATLAS in presymptomatic carriers, and real-world European data support continued evaluation, alongside accelerated regulatory approvals by FDA and EMA.

CONCLUSION: Tofersen marks a paradigm shift in ALS management, establishing the foundation for precision medicine in neurodegenerative diseases. Its ongoing evaluation in the ATLAS trial will determine whether early intervention can prevent or delay disease onset in presymptomatic SOD1 mutation carriers.}, } @article {pmid42180530, year = {2026}, author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L}, title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.}, journal = {Acta pharmaceutica Sinica. B}, volume = {16}, number = {5}, pages = {2601-2644}, pmid = {42180530}, issn = {2211-3835}, abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.}, } @article {pmid42181829, year = {2026}, author = {Kuru Çolak, T and Akçay, B and Weiss, HR and Nan, X and Elliott, L and Akkoyunlu, SZ and Borysov, M}, title = {Treatment outcomes across curve patterns and severities in adolescent idiopathic scoliosis treated with a pattern-specific CAD-CAM brace.}, journal = {Frontiers in rehabilitation sciences}, volume = {7}, number = {}, pages = {1826976}, pmid = {42181829}, issn = {2673-6861}, abstract = {BACKGROUND: Whether treatment outcomes differ according to curve pattern or baseline severity in adolescents with idiopathic scoliosis (AIS) remains a subject of debate. In particular, it is unclear whether pattern-specific, CAD-CAM-designed brace systems provide comparable effectiveness across different curvature types. This study aimed to evaluate the influence of curve pattern and initial curve magnitude on treatment outcomes in AIS patients treated with a pattern-specific CAD-CAM-designed brace.

METHODS: A retrospective analysis was conducted on female AIS patients aged 10-14 years (Risser 0-2) treated between 2015 and 2024. Cobb angle and angle of trunk rotation (ATR) were used as primary outcome measures. Data from four international clinics were analyzed for changes in spinal curvature and curve pattern.

RESULTS: A total of 145 patients were included (mean age 12.2 years; mean Cobb angle 38.4° ± 11.4°). Post-treatment, mean Cobb angle and ATR values decreased significantly (p < 0.001). The overall treatment success rate was 91%, with no significant differences based on apex vertebra location (p = 0.459), ALS patterns (p = 0.705), or baseline curve severity (p = 0.274).

CONCLUSION: In this multicenter cohort of skeletally immature adolescents with idiopathic scoliosis, pattern-specific brace treatment was associated with significant reductions in both radiographic curvature and trunk rotation. Improvements were observed across different curve patterns and baseline severities. However, given the retrospective design and absence of a comparison group, these findings should be interpreted with caution. Prospective controlled studies are warranted to further validate these observations.}, } @article {pmid42188341, year = {2026}, author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G}, title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.}, journal = {Journal of personalized medicine}, volume = {16}, number = {5}, pages = {}, pmid = {42188341}, issn = {2075-4426}, abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.}, } @article {pmid42190746, year = {2026}, author = {Zheng, P and Chen, L}, title = {Comments on Wu et al's "The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {4}, pages = {e355-e356}, doi = {10.1016/j.jaad.2026.03.126}, pmid = {42190746}, issn = {1097-6787}, } @article {pmid42190754, year = {2026}, author = {Wu, X and Wang, X and Zhang, Z}, title = {Response to Chen et al, "Comments on Wu et al's 'The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints'".}, journal = {Journal of the American Academy of Dermatology}, volume = {95}, number = {4}, pages = {e357-e358}, doi = {10.1016/j.jaad.2026.05.061}, pmid = {42190754}, issn = {1097-6787}, } @article {pmid42192558, year = {2026}, author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B}, title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.}, journal = {Animal models and experimental medicine}, volume = {9}, number = {8}, pages = {1527-1538}, pmid = {42192558}, issn = {2576-2095}, support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; }, mesh = {*Exosomes/metabolism/physiology ; *Neurodegenerative Diseases/therapy/physiopathology ; Animals ; Humans ; *Brain/metabolism ; Signal Transduction ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; Blood-Brain Barrier ; }, abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.}, } @article {pmid42193936, year = {2026}, author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK}, title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.}, journal = {Cells}, volume = {15}, number = {10}, pages = {}, pmid = {42193936}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.}, } @article {pmid42196191, year = {2026}, author = {Giordano, A and Mandrioli, J and Cerri, F and Lunetta, C and Saebfar, H and Catania, M and Battipaglia, C and Leone, L and Trojsi, F and Vizziello, M and Gerardi, F and Farè, M and Zulueta, A and Piras, R and Giacchino, M and Gianferrari, G and Dalla Bella, E and Domi, T and Bonanomi, D and Ganci, G and Lombardi, R and Lauria, G and Riva, N}, title = {Longitudinal CSF and Serum Biomarker Dynamics in Tofersen-Treated SOD1-ALS: A Real-World Multicentre Cohort Study.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196191}, issn = {1422-0067}, support = {IDEALS//AriSLA/ ; RF-2021-12373036//Ministero della salute Ricerca Finalizzata bando 2021/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; Giovanni Marazzina Project//Giovanni Marazzina Foundation/ ; }, mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/blood/cerebrospinal fluid/genetics ; Longitudinal Studies ; tau Proteins/blood/cerebrospinal fluid ; Ubiquitin Thiolesterase/blood/cerebrospinal fluid ; Male ; Glial Fibrillary Acidic Protein/blood/cerebrospinal fluid ; Middle Aged ; Neurofilament Proteins/blood/cerebrospinal fluid ; Retrospective Studies ; Aged ; }, abstract = {Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL-1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL-1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL-1 also showed increases during follow-up. ALS Functional Rating Scale-Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL-1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.}, } @article {pmid42196458, year = {2026}, author = {Prodromos, CC and Del Villar, R and Striegel, A and Pena, G and Dixit, R}, title = {The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.}, journal = {International journal of molecular sciences}, volume = {27}, number = {10}, pages = {}, pmid = {42196458}, issn = {1422-0067}, mesh = {Humans ; *Exosomes/metabolism/transplantation ; *Amyotrophic Lateral Sclerosis/therapy/metabolism ; *Parkinson Disease/therapy/metabolism ; Female ; Male ; *Lewy Body Disease/therapy/metabolism ; Aged ; *Mesenchymal Stem Cells/metabolism ; Middle Aged ; *Secretome/metabolism ; Case-Control Studies ; Administration, Intranasal ; }, abstract = {Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson's disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up.}, } @article {pmid42202610, year = {2026}, author = {Doğan, V and Sinanoğlu, GK}, title = {2D:4D ratio, affective lability, and impulsivity in men with cannabinoid and methamphetamine use disorders: A comparative analysis with healthy controls.}, journal = {Early human development}, volume = {221}, number = {}, pages = {106587}, doi = {10.1016/j.earlhumdev.2026.106587}, pmid = {42202610}, issn = {1872-6232}, mesh = {Humans ; Male ; Adult ; *Impulsive Behavior ; Case-Control Studies ; *Amphetamine-Related Disorders/psychology/epidemiology ; *Fingers/anatomy & histology ; Methamphetamine/adverse effects ; Cross-Sectional Studies ; *Marijuana Abuse/psychology/epidemiology ; }, abstract = {The second-to-fourth digit ratio (2D:4D) is considered a non-invasive marker of prenatal androgen exposure and has been proposed as a developmental indicator of behavioral vulnerability; however, findings in substance use disorders remain inconsistent. This study aimed to examine whether 2D:4D ratios are associated with substance use disorders and to compare their relative contribution with psychological factors, including affective lability, impulsivity, and anxiety. In this cross-sectional case-control study, male participants with cannabinoid use disorder (CUD; n = 47), methamphetamine use disorder (MUD; n = 48), and healthy controls (n = 53) were included. The mean age of participants was 32.7±8.95 years. All participants were assessed using the Structured Clinical Interview for DSM-5 (SCID-5), Affective Lability Scale-18 (ALS-18), Barratt Impulsiveness Scale-11 (BIS-11), and Generalized Anxiety Disorder-7 (GAD-7). The 2D:4D ratio was measured with a digital caliper by two trained psychiatrists, and 2D:4D ratios and right-left differences (Dr-I) were calculated. No significant group differences were observed in left or right 2D:4D ratios or Dr-I; however, a consistent trend toward lower 2D:4D values, particularly for right-hand 2D:4D, was observed in the CUD and MUD groups compared with controls. In contrast, affective lability, impulsivity, and anxiety scores were significantly elevated in both patient groups (p <0.05). In univariate logistic regression analyses, affective lability, impulsivity, anxiety, and lower right-hand 2D:4D were associated with substance use disorder; however, right-hand 2D:4D showed the weakest association among these predictors. In the multivariate model, lower right-hand 2D:4D, impulsivity, lower educational attainment, and smoking remained independently associated with substance use disorder. These findings suggest that while 2D:4D may reflect a distal developmental vulnerability, psychological factors, particularly impulsivity, have a more direct and clinically relevant role in substance use disorders. Incorporating the assessment of impulsivity into clinical evaluation and intervention strategies may improve risk identification and treatment planning.}, } @article {pmid42204279, year = {2026}, author = {Fowler, M and Carr, JM and Gold, J and Walker, A and Rogers, ML}, title = {Evaluation of triumeq treatment on a TDP-43 mouse model of amyotrophic Lateral sclerosis.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42204279}, issn = {2045-2322}, support = {DIS-202303-00932//FightMND/ ; IG1950//Motor Neurone Disease Research Australia/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the accumulation of TAR DNA Binding Protein (43 kDa; TDP-43) within the cytoplasm of neurons. Endogenous retroviruses (ERVs) have been implicated in ALS pathology and the application of antiretroviral therapy, specifically Triumeq, has been proposed for treatment of ALS. However, evidence to support the actions of Triumeq in ALS is lacking. This study investigates the effects of the antiretroviral treatment Triumeq on ALS disease that occurs through TDP-43 pathology by utilising the doxycycline (Dox)-suppressible rNLS8 TDP-43 expression mouse model. In this model, TDP-43 accumulation in the cytoplasm is induced after removal of Dox. Disease was assessed through measures of body weight, neurological score, motor function, urinary p75[ECD] and inflammatory marker expression. Mice were treated with Triumeq and TDP-43 pathology and inflammatory marker expression examined. Triumeq treatment significantly improved motor function early on in the disease course but did not impact other disease progression markers or disease endpoint. In this TDP-43 ALS mouse model, there was a positive association of TDP-43 mRNA levels with transcription factor ATF4, and inflammatory markers CXCL10 and IRF-1, and Triumeq treatment negated this association. Triumeq treatment transiently and modestly improved motor function and influenced TDP-43 associated inflammatory gene expression in an ALS mouse model. These findings support the potential use of Triumeq in treating TDP-43-associated ALS and supports further investigation to better understand if the beneficial actions of Triumeq are via disruption of TDP-43-driven inflammation in ALS.}, } @article {pmid42218400, year = {2026}, author = {Abbasi, H and Shafaatdoost, M and Mohajerani, A and Asadollahi, M and Rashidi, M and Malekahmadi, M and Sarraf, P}, title = {Association between body composition and disease progression in adults with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMC neurology}, volume = {26}, number = {1}, pages = {}, pmid = {42218400}, issn = {1471-2377}, support = {IR. TUMS.NI.REC.1401.059//Tehran University of Medical Sciences and Health Services/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Female ; Cross-Sectional Studies ; Male ; *Body Composition/physiology ; *Disease Progression ; Middle Aged ; Aged ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle wasting, and respiratory failure, with a median survival of 30 months. Due to the strong link between dysphagia, weight loss, and disease progression, this study investigates the relationship between body composition and clinical outcomes in ALS adults. This cross-sectional study involved 93 ALS adults (29 females, 64 males) from Imam Khomeini Hospital in Tehran, selected based on EI Escorial criteria. Researchers assessed body composition, functional abilities, and disease progression using ALSFRS-R, MRC scores, and DPR, analyzing associations through linear regression models with RStudio in conjunction with R software. In this study, significant differences were found between the third and first tertiles for various measures. Significant associations were observed between body composition and ALSFRS-R for MAC (β: 3.0; P = 0.006), with underweight and moderately active adults exhibiting notable differences. The MRC score was positively associated with FFM (β: 5.8; P = 0.002), SLM (β: 5.6; P = 0.002), SMM (β: 3.8; P = 0.001), MAC (β: 3.2; P = 0.002), ICW (β: 2.7; P = 0.002), and ECW (β: 1.5; P = 0.003), while underweight and low-to-moderate physical activity adults indicated inverse associations. For DPR, significant relationships were noted for weight (β: 4.5; 95% CI: 0.02, 9.3; P = 0.002) and FFM (β: 11; P < 0.001), influenced by gender and physical activity. The findings highlight the role of gender, weight, and activity in ALS management, suggesting that maintaining a healthy weight along and muscle mass along with regular activity is associated with better outcomes. This can inform personalized treatment strategies for better patient care.}, } @article {pmid42219616, year = {2026}, author = {Busi, R and Goggin, D and Eyres, N and Runge, F and Porri, A and Flower, K}, title = {A Trp574-Leu substitution confers resistance to three classes of acetolactate synthase inhibitors in Australian brome grass (Bromus diandrus).}, journal = {Pest management science}, volume = {82}, number = {10}, pages = {9437-9443}, pmid = {42219616}, issn = {1526-4998}, support = {UWA2007-002RTX//Grains Research and Development Corporation/ ; }, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Bromus/genetics/drug effects/enzymology ; Australia ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Amino Acid Substitution ; Imidazoles/pharmacology ; *Enzyme Inhibitors/pharmacology ; }, abstract = {BACKGROUND: Brome grass (Bromus diandrus) is a prevalent weed in southern Australian cropping regions which causes significant economic damage in crops and pastures. Before harvest 2023, two populations (named 6-24 and 7-24) suspected of resistance to imidazolinone herbicides were collected from separate fields. Preliminary screening indicated that these populations were resistant to several different acetolactate synthase (ALS)-inhibiting herbicides. Therefore, further characterisation of the level and mechanism of resistance was carried out.

RESULTS: There was high survival of the resistant populations at the maximum tested rates of sulfometuron (600 g ha[-1]) and imazamox + imazapyr (74 + 34 g ha[-1], 2× the label rate for use in imidazolinone-tolerant crops). All examined individuals (15 from each population) carried the same point mutation causing a tryptophan-to-leucine substitution at position 574 in the ALS protein. Application of the cytochrome P450 inhibitor malathion prior to herbicide treatment did not affect survival rates.

CONCLUSIONS: This is the first study reporting a Trp574-Leu mutation as the basis for cross-resistance to ALS-inhibiting herbicides (sulfonylureas, imidazolinones and triazolopyrimidines) in Australian populations of B. diandrus. Control of these populations will require strategic use of pre-emergence herbicides and herbicide-tolerant crops in combination with harvest weed seed control. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid42226981, year = {2025}, author = {Romina, A and Mohaddeseh, L and Mansour, B}, title = {Fabrication and Evaluation of PVA-NYS-THY Nanofiber Scaffolds as Antifungal Agents Against Fluconazoleresistant Candida glabrata.}, journal = {Archives of Razi Institute}, volume = {80}, number = {5}, pages = {1229-1238}, pmid = {42226981}, issn = {2008-9872}, mesh = {*Antifungal Agents/pharmacology/chemistry ; *Polyvinyl Alcohol/chemistry/pharmacology ; *Nanofibers/chemistry ; *Candida glabrata/drug effects ; *Fluconazole/pharmacology ; *Drug Resistance, Fungal ; *Nystatin/pharmacology/chemistry ; Microbial Sensitivity Tests ; }, abstract = {INTRODUCTION: The emergence of fluconazole-resistant Candida glabrata presents a significant challenge in antifungal therapy, necessitating the development of alternative treatment strategies. C. glabrata, an opportunistic yeast, is increasing resistance to common antifungals like fluconazole, often due to efflux pump overexpression, leading to compromised treatment efficacy, higher mortality, prolonged hospital stays, and increased healthcare costs. This study focused on fabricating and evaluating polyvinyl alcohol-nystatin-thymol (PVA-NYS-THY) nanofibrous scaffolds as a novel antifungal approach against fluconazole-resistant C. glabrata.

MATERIALS & METHODS: Clinical isolates were identified and assessed for resistance using culture methods, molecular assays, and antifungal susceptibility testing. PVA-NYS-THY nanofibers, produced via electrospinning, exhibited uniform fibers with an average diameter of ~100 nm as confirmed by scanning electron microscopy (SEM). Fourier transform infrared spectroscopy confirmed the successful incorporation of functional groups. Real-time polymerase chain reaction (PCR) was employed to evaluate the nanofibers' effect on the expression of secreted aspartyl proteinases (SAP) and agglutinin-like sequence (ALS) gene. Scaffold release kinetics were characterized, and antifungal efficacy was assessed using minimum inhibitory concentration (MIC) assays.

RESULTS: PVA-NYS-THY scaffolds showed favorable release profiles and significantly downregulated ALS and SAP gene expression. MIC values for PVA-NYS-THY, PVA-NYS, and PVA-THY were 7.81, 15.62, and 62.5 µg/mL, respectively, demonstrating superior antifungal activity of the PVA-NYS-THY formulation.

CONCLUSION: These findings suggest PVA-NYS-THY nanofibrous scaffolds offer a promising therapeutic strategy for combating fluconazole-resistant C. glabrata, providing a novel solution to overcome current limitations in antifungal treatment.}, } @article {pmid42232224, year = {2026}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.}, journal = {Frontiers in aging neuroscience}, volume = {18}, number = {}, pages = {1818660}, pmid = {42232224}, issn = {1663-4365}, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

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

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (< 1 year) to 0.25 (> 6 years). Risk reduction was greatest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.}, } @article {pmid42237658, year = {2026}, author = {Vesevick, DR and Ghosh, S and Kalmes, A and Ozdinler, PH and Gautam, M}, title = {Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {463-473}, pmid = {42237658}, issn = {1097-4598}, support = {//Revalesio/ ; //Queen B Foundation/ ; //A Long Swim/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/genetics/metabolism ; Mice ; Mice, Transgenic ; Mitochondria/drug effects/ultrastructure/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/drug effects/pathology ; Disease Models, Animal ; Spinal Cord/pathology/drug effects ; Neuromuscular Junction/drug effects/pathology ; Green Fluorescent Proteins/genetics/metabolism ; Male ; Muscle, Skeletal/drug effects ; Female ; }, abstract = {INTRODUCTION: TDP-43 pathology is broadly observed in the cerebral cortex of patients with amyotrophic lateral sclerosis (ALS). RNS60, an experimental treatment for acute ischemic stroke and ALS, enhanced mitochondrial biogenesis and function in other preclinical models. We investigated whether RNS60 improved mitochondrial stability and upper motor neuron (UMN) health in a TDP-43 mouse model of ALS.

METHODS: prpTDP-43[A315T]-UeGFP mice, in which UMNs express green fluorescent protein (eGFP), and WT-UeGFP mice were treated with RNS60 or placebo intraperitoneally every other day from post-natal day (P) 30 until P90. Astrogliosis and microgliosis in brain and spinal cord were quantified by immunocytochemistry. Mitochondrial ultrastructure was studied via electron microscopy, and mitochondrial function was assessed using flow cytometry. Neuromuscular junction (NMJ) integrity was assessed in gastrocnemius, tibialis, and diaphragm muscles.

RESULTS: RNS60 treatment reduced defective mitochondria in UMNs (prpTDP-43[A315T] + vehicle: 53.2% ± 0.71%; prpTDP-43[A315T] + RNS60: 19.6% ± 1.4%, p = 0.0001) and spinal motor neurons (prpTDP-43[A315T] + vehicle: 70.1% ± 0.4.48%; prpTDP-43[A315T] + RNS60: 33.5% ± 4.43%, p = 0.001). It increased mitochondrial membrane polarization (prpTDP-43[A315T]-UeGFP + vehicle: 7184 ± 1689 mean intensity; prpTDP-43[A315T]-UeGFP+RNS60: 22120 ± 4818 mean intensity, p = 0.032), reduced the extent of astrogliosis and microgliosis in motor cortex and spinal cord, protected UMNs compared to placebo, and enhanced the proportion of intact NMJs in leg and diaphragm muscles (prpTDP-43[A315T]-UeGFP + vehicle: 29.6% ± 3.6%; prpTDP-43[A315T]-UeGFP + RNS60: 64.3% ± 4.4%, p = 0.0002).

DISCUSSION: These results suggest that RNS60 treatment promotes motor neuron health in ALS by protecting mitochondrial structure and function, preserving NMJ integrity, and reducing gliosis.}, } @article {pmid42238865, year = {2026}, author = {Bouras, A and Adio, AA and Kumar, R and Phadke, R and Rice, SW and Mody, K and Ndu, A}, title = {Primary Tibiotalocalcaneal Nailing vs Open Reduction and Internal Fixation for Fragility Ankle Fractures in Older Adults: A Markov Model.}, journal = {Foot & ankle orthopaedics}, volume = {11}, number = {2}, pages = {24730114261450956}, pmid = {42238865}, issn = {2473-0114}, abstract = {BACKGROUND: Fragility ankle fractures are common in the elderly population. The cost-effectiveness of primary tibiotalocalcaneal (TTC) nailing compared with open reduction and internal fixation (ORIF) in this population remains unclear.

METHODS: We constructed a Markov cohort model with a 4-year time horizon to compare TTC nailing vs ORIF for fragility ankle fractures in patients aged 75 years and older. All complication rates were derived from the McDonald et al's (2025) systematic review and meta-analysis. Costs were in 2024 US dollars with 3% annual discounting for costs and outcomes. Probabilistic and deterministic sensitivity analyses were performed.

RESULTS: In the base case, ORIF yielded 3.210 quality-adjusted life years (QALYs) (95% credible interval [CrI] 2.785-3.584) at $30 091 (95% CrI $21 426-$40 852) compared with 3.207 QALYs (95% CrI 2.783-3.581) at $33 583 (95% CrI $23 741-$45 447) for TTC nailing. ORIF dominated incremental cost (+$3492, 95% CrI -$11 467 to +$18 273) and incremental QALYs (-0.003, 95% CrI -0.009 to +0.002). The cost differential was driven by the $3000 higher index procedure cost for TTC, partially offset by lower superficial infection (2.1% vs 10.2%). Probabilistic sensitivity analysis demonstrated 33% probability of cost-effectiveness at $100 000/QALY. All 4 scenario analyses confirmed that ORIF dominated.

CONCLUSION: Under McDonald's pooled estimates, TTC nailing is dominated by ORIF for fragility ankle fractures in older adults. The lower superficial infection rate with TTC does not offset its higher procedure cost and higher rates of nonunion and hardware failure. These findings support ORIF as the preferred strategy from a cost-effectiveness standpoint, although the small incremental differences should be considered alongside clinical factors when selecting treatment.

LEVEL OF EVIDENCE: Level IV, economic modeling.}, } @article {pmid42239283, year = {2026}, author = {Reedich, E and Chen, YT and Imhoff-Manuel, R and Li, D and Manuel, M}, title = {Chronic diazepam reveals excessive homeostatic gain in SOD1[G93A] mouse spinal motoneurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42239283}, issn = {2692-8205}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; R01 NS110953/NS/NINDS NIH HHS/United States ; }, abstract = {Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1[G93A] mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1[G93A] mice modulate excitability differently than wild type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1[G93A] versus wild type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1[G93A] motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.}, } @article {pmid42245509, year = {2026}, author = {Wang, Z and Li, L and Dong, Y and Zhang, Y}, title = {The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.}, journal = {Frontiers in microbiology}, volume = {17}, number = {}, pages = {1820111}, pmid = {42245509}, issn = {1664-302X}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.}, } @article {pmid42250142, year = {2026}, author = {Jalaiei, A and Kiani Darabi, AH and Sakkaki, E and Rezazadeh, M and Ghafouri-Fard, S}, title = {Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42250142}, issn = {1573-4978}, mesh = {*Brain-Derived Neurotrophic Factor/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; MicroRNAs/genetics/metabolism ; *RNA, Untranslated/genetics/metabolism ; Animals ; Gene Expression Regulation ; RNA, Long Noncoding/genetics/metabolism ; }, abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.}, } @article {pmid42252093, year = {2026}, author = {Arlt, FA and Miske, R and Appeltshauser, L and Zinnow, V and Borowski, K and Stenzel, W and Radbruch, H and Meisel, A and Ruprecht, K and Endres, M and Blau, I and Kirchner, M and Mertins, P and Sanchez-Sendin, E and Wernick, S and Pressler, H and Stascheit, F and Linke, J and Hümmert, S and Werner, HB and Wibisono, EA and Doppler, K and Komorowski, L and Spiliotis, ET and Dubey, D and Zeckeridou, A and Pittock, SJ and Mills, JR and McKeon, A and Scharf, M and Prüss, H}, title = {Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease.}, journal = {Brain : a journal of neurology}, volume = {149}, number = {8}, pages = {2731-2746}, pmid = {42252093}, issn = {1460-2156}, support = {EN343/16-1//University of Würzburg/ ; R01 NS126227/NS/NINDS NIH HHS/United States ; //NIH/ ; R35 GM136337/GM/NIGMS NIH HHS/United States ; 295-424778381//University of Würzburg/ ; WE 2720/2-2//University of Würzburg/ ; FOR3004//German Research Foundation/ ; PR1274/5-1//German Research Foundation/ ; RO1NS126227//University of Würzburg/ ; 821283-2//University of Würzburg/ ; EXC-2049-390,688,087//University of Würzburg/ ; Connect-Generate 01GM1908D//German Federal Ministry of Education and Research/ ; 504745852//German Research Foundation/ ; 2R35GM136337-07//University of Würzburg/ ; PR1274/9-1//German Research Foundation/ ; HIL-A03 BaoBab//Helmholtz Association/ ; }, mesh = {*Autoantibodies/immunology/blood ; Humans ; Male ; Female ; *Motor Neuron Disease/immunology/diagnosis ; Animals ; *Septins/immunology ; Retrospective Studies ; Middle Aged ; Mice ; Aged ; Sciatic Nerve/immunology ; Adult ; }, abstract = {Severe neuropathies with predominant involvement of motor fibres can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibres. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n = 86, Guillain-Barré syndrome n = 37, multifocal motor neuropathy n = 18, diabetic neuropathy n = 30, other inflammatory neuropathies n = 10), amyotrophic lateral sclerosis (n = 50), multiple sclerosis (n = 50) and healthy controls (n = 50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and the sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over 4 years. Among 3543 total samples tested, three patients (two male, one female)-diagnosed with the LMND variant of amyotrophic lateral sclerosis (aged 65, 72 and 79 years, respectively)-showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ('incisuropathy'). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over 3 years. The other two patients died of rapid disease progression: one of them received no immunotherapy while the other had ineffective treatments with single administrations of intravenous immunoglobulin and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor-predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome and responses to immunotherapy in larger cohorts.}, } @article {pmid42252587, year = {2026}, author = {Jin, H}, title = {PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {12}, pages = {2229-2237}, doi = {10.1021/acschemneuro.6c00338}, pmid = {42252587}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods ; Animals ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Receptors, GABA/metabolism ; *Molecular Probes/metabolism ; *Brain/metabolism/diagnostic imaging ; }, abstract = {Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.}, } @article {pmid42260986, year = {2026}, author = {Sun, X and Dong, J and Liang, X and Peng, J and Chen, Y and Yin, R and Tan, T and Bai, L and Lan, K}, title = {PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/15548627.2026.2686417}, pmid = {42260986}, issn = {1554-8635}, abstract = {Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several malignancies, including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease, harbors a DNA replication helicase encoded by ORF44 that is crucial for viral replication and pathogenesis. In this study, we identified the host PFN1 (profilin 1), a well-known actin-binding factor, as an inhibitor of KSHV lytic replication functioning via the macroautophagy/autophagy-lysosomal degradation pathway targeting ORF44. Mechanistic analyses revealed that PFN1 interacts with ORF44, leading to enhanced polyubiquitination of PFN1. Notably, the E3 ubiquitin ligase TRIM37 (tripartite motif containing 37) facilitates the polyubiquitination of lysine residues at position 116 of PFN1, which serves as a critical recognition motif for the cargo receptor SQSTM1/p62 (sequestosome 1), which is pivotal for the subsequent autophagic degradation of ORF44. Overall, our findings revealed a previously uncharacterized antiviral function of PFN1, highlighting its potential as a novel therapeutic avenue for the treatment of KSHV-associated malignancies.Abbreviations: ALS: amyotrophic lateral sclerosis; Baf A1: bafilomycin A1; co-IP: co-immunoprecipitation; KSHV: Kaposi sarcoma-associated herpes virus; LIR: LC3-interacting region; PFN1: profilin 1; SQSTM1/p62: sequestosome 1; TRIM37: tripartite motif containing 37; UBA: ubiquitin-associated domain.}, } @article {pmid42263252, year = {2026}, author = {Bétourné, A and Texakalidis, P and Raheb Khelo, R and Campbell, M and Sadiq, SA and Boulis, NM}, title = {Intrathecal Administration of Riluzole in Amyotrophic Lateral Sclerosis.}, journal = {Neurosurgery}, volume = {99}, number = {1}, pages = {218-222}, pmid = {42263252}, issn = {1524-4040}, mesh = {Humans ; *Riluzole/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Injections, Spinal/methods ; Female ; *Neuroprotective Agents/administration & dosage ; Male ; Middle Aged ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Riluzole is the only treatment known to improve survival in amyotrophic lateral sclerosis (ALS) patients. However, its efficacy and dosing are limited by hepatic toxicity and interindividual pharmacokinetic variability. Recent experimental studies in hounds have shown that continuous intrathecal (IT) administration of riluzole is well tolerated and achieves significantly higher spinal cord tissue levels. We report the first 2 human ALS cases treated with IT riluzole.

METHODS: A catheter was inserted into the lumbar cistern and advanced to the midcervical region under fluoroscopic guidance and connected to a subcutaneous pump. Therapy was initiated at 0.1 mg/h of riluzole. The infusion rate was gradually increased until it reached a maximum of 4.8 mg/d.

RESULTS: The 2 patients tolerated dose escalation and treatment for over 2 years without apparent motor or sensory complications. Patients reported no asthenia, a central side effect often reported as a reason to abandon oral therapy.

CONCLUSION: This is the first report of chronic IT riluzole infusion in humans at a dose found to be safe in canines. A phase 1 study is planned to establish the maximum tolerated human dose, followed by a randomized placebo-controlled trial to determine the safety and tolerability of IT riluzole in patients with ALS.}, } @article {pmid42264545, year = {2026}, author = {Vishwakarma, H and Chauhan, A and Kaur, L and Awasthi, A}, title = {Nanotechnology-enabled targeting strategies for neurodegenerative disorders: role of functionalized nanoparticles.}, journal = {The Journal of pharmacy and pharmacology}, volume = {78}, number = {6}, pages = {}, doi = {10.1093/jpp/rgag060}, pmid = {42264545}, issn = {2042-7158}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; Animals ; *Nanoparticles ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; Neuroprotective Agents/administration & dosage ; *Nanotechnology/methods ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Neurodegenerative disorders comprise a diverse group of progressive neurological diseases characterized by the gradual loss of neuronal structure and function. Conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis arise from multifactorial mechanisms involving genetic susceptibility, environmental factors, and age-related cellular decline.

PATHOPHYSIOLOGY: Key pathogenic processes include oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, impaired axonal transport, Golgi fragmentation, and chronic neuroinflammation, all of which disrupt neuronal homeostasis and synaptic communication, ultimately leading to neuronal death. Hormonal imbalances further exacerbate these effects by promoting oxidative damage, inflammation, and metabolic dysfunction.

CHALLENGES IN THERAPY: Despite advances in understanding disease mechanisms, effective drug delivery remains challenging due to the restrictive nature of the blood-brain barrier.

Recent developments highlight the potential of nanoparticle-based drug delivery systems to overcome these limitations. Functionalized nanoparticles enhance blood-brain barrier penetration, improve targeting specificity, and enable controlled drug release. These systems can deliver neuroprotective agents, antioxidants, peptides, and gene therapies directly to affected brain regions. Thus, integrating disease pathophysiology with nanotechnology-based strategies offers a promising approach for improving therapeutic outcomes and advancing precision treatment in neurodegenerative disorders.}, } @article {pmid42271582, year = {2026}, author = {Ito, M}, title = {[Re-evaluating ALS Medical Care in Japan: An International Comparison of Japan, Europe, the United States, and Canada-Insights from Mechanical Ventilation, Support for Social Participation, End-of-Life Care Options, Approved Drugs, and Precision Medicine].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {78}, number = {6}, pages = {654-657}, doi = {10.11477/mf.188160960780060654}, pmid = {42271582}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Terminal Care ; *Precision Medicine ; Japan ; United States ; Europe ; *Respiration, Artificial ; Canada ; Palliative Care ; }, abstract = {Amyotrophic lateral sclerosis (ALS) care in Japan should be re-evaluated not simply as a matter of clinical choice but as a function of the public support system structure. In Japan, care is distinguished by a publicly funded model that supports home-based living and social participation following tracheostomy invasive ventilation. In contrast, Europe reflects a model centered on non-invasive ventilation and palliative care, and the United States reflects a system in which precision therapies are approved earlier but access remains highly unequal. Further, Canada reflects a model integrating multidisciplinary ALS clinics with Medical Assistance in Dying within a shared policy framework. These differences extend beyond treatment preferences and instead reflect broader social, institutional, and ethical configurations that shape the future of individuals with ALS. As access to emerging disease-modifying therapies increasingly depends on genetic testing, the central challenge in ALS care is shifting from end-of-life decision-making to the equitable distribution of precision medicine. Comparative reappraisal of national care models is therefore critical for understanding ALS not only as a neurological disease but also as a condition shaped by welfare systems, care infrastructure, and policy design.}, } @article {pmid42272352, year = {2026}, author = {Lizio, A and Farè, M and Gerardi, F and Collesi, M and Sansone, VA and Lunetta, C and Diamanti, L and Cerri, F}, title = {Impact of treatment burden on medication adherence and quality of life in amyotrophic lateral sclerosis: a prospective multicentre study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2026.2683691}, pmid = {42272352}, issn = {2167-9223}, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) face substantial barriers to medication adherence as disease progression necessitates complex drug formulation adjustments, such as crushing tablets, mixing with liquids, or delivering via feeding tubes. These modifications may not only increase the time and effort required but could also impact drug efficacy and safety.

OBJECTIVE: To evaluate the prevalence and the impact of treatment burden on medication adherence and patient-reported quality of life (QoL) in ALS.

METHODS: This prospective multicenter study enrolled ALS patients across three Italian reference centers, with assessments at baseline, 6, and 12 months. Key measures included the Multimorbidity Treatment Burden Questionnaire (MTBQ), ALSFRS-R, DYALS (dysphagia), Morisky Medication Adherence Scale, SSS-8 (somatic symptoms), INQoL (QoL), SWAMECO (swallowing/medication difficulties), alongside comorbidities and current therapies. Associations between treatment burden, QoL, and adherence were analyzed using multivariable models.

RESULTS: A total of 114 consecutive ALS patients were enrolled. Clinically significant treatment burden was observed in 69.3% of patients, with over half reporting moderate-to-high levels according to the MTBQ classification. Elevated burden was independently related to greater somatic symptom severity and formulation modification needs. Moreover, higher burden associated with poorer QoL and diminished adherence after confounder adjustment. Longitudinally, patients experiencing worsening burden over 1 year showed accelerated QoL decline compared to those remaining stable, though adherence trajectories were unaffected.

CONCLUSION: Treatment burden, particularly driven by drug formulation complexities and somatic symptoms, emerges as a pivotal, modifiable determinant of adherence and QoL in ALS. Targeted interventions to alleviate modifiable burden components hold promise for optimizing clinical outcomes and enhancing patient-centred care.}, } @article {pmid42274906, year = {2026}, author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X}, title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {42274906}, issn = {1995-8218}, abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.}, } @article {pmid42275159, year = {2026}, author = {Ito, D and Iida, M and Iguchi, Y and Hashizume, A and Yamada, S and Kishimoto, Y and Komori, S and Obara, K and Nishisaki, S and Yokoi, S and Shimamura, T and Takemoto, Y and Nakatochi, M and Akashi, T and Hinohara, K and Lee-Okada, HC and Okada, Y and Niwa, J and Sobue, G and Tanaka, S and Takashina, K and Yokomizo, T and Katsuno, M}, title = {Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.}, journal = {JCI insight}, volume = {11}, number = {15}, pages = {}, pmid = {42275159}, issn = {2379-3708}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Humans ; Fatty Acid Amide Hydrolases ; Mice ; Mice, Transgenic ; *Amidohydrolases/antagonists & inhibitors/metabolism ; Motor Neurons/drug effects/pathology/metabolism ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Disease Models, Animal ; Disease Progression ; Female ; Male ; Endocannabinoids/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. Patients with ALS often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models and induced pluripotent stem (iPS) cells derived from patients with ALS and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.}, } @article {pmid42283246, year = {2026}, author = {Fikry, H and Saleh, LA and Sadek, DR}, title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/ca.70147}, pmid = {42283246}, issn = {1098-2353}, abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.}, } @article {pmid42286839, year = {2026}, author = {Wheeler, A and Mehta, K and Sanders, D and Chin, C and Zivalic, H and Carey, J and McCaffrey, A and Pant, P and Lewenhaupt, C and Luppino, S and Jacobs, G and Golden, S and Gifford, R and Scirocco, E and Keegan, M and Hatem, M and Yazdanian, T and Uysal, SP and Susco, N and Schwartzman, S and Branch, K and Hall, KE and Barnas, J and Lam, J and Hagar, J and Hannan, CA and Paganoni, S and Berry, JD and Garret, M and Scalia, J and Babu, S}, title = {Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {692-697}, pmid = {42286839}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Female ; Middle Aged ; Male ; Aged ; *Oligonucleotides, Antisense/therapeutic use/administration & dosage ; Superoxide Dismutase-1/genetics ; *Health Resources ; Adult ; }, abstract = {INTRODUCTION/AIMS: Tofersen is a gene-targeted therapy for individuals with superoxide dismutase 1 (SOD1) (+) amyotrophic lateral sclerosis (ALS). Prior to U.S. Food and Drug Administration (FDA) approval, tofersen was made available through expanded access protocol. This study describes the clinical and operational experience of administering tofersen through expanded access protocols at a single academic medical center in the U.S.

METHODS: Individuals with symptomatic SOD1(+) ALS (≥ 18 years), who were ineligible for traditional ALS clinical trials, received tofersen via bedside lumbar punctures at Massachusetts General Hospital. Treatment was provided through single-patient and intermediate-sized expanded access protocols prior to FDA approval. Demographic and clinical characteristics, referral-to-treatment timelines, safety outcomes, and operational costs were collected.

RESULTS: Eleven individuals with SOD1(+) ALS received monthly intrathecal tofersen over a two-year period (July 2021 to July 2023). Most participants were female, and 81.8% had leg-onset ALS. The mean (SD) referral-to-first dose duration was 36 (22.4) days. A total of 120 doses were administered over a two-year period. Tofersen was safe and well tolerated, with no treatment-related serious adverse events. Operational costs totaled $336,620, supported by philanthropy and insurance. The company provided the drug for free.

DISCUSSION: This experience demonstrates the feasibility of implementing a resource-intensive expanded access protocol within an academic medical center using a mixed funding model to facilitate early access to emerging ALS therapies.}, } @article {pmid42290559, year = {2026}, author = {Martyniuk, О and Mushii, O and Pavlova, A}, title = {Integrated Analysis of hsa-miR-26b-5p and hsa-miR-186-5p in Blood Serum and Tumor Tissue Reveals their Prognostic and Predictive Significance in Breast Cancer.}, journal = {Experimental oncology}, volume = {48}, number = {1}, pages = {31-39}, doi = {10.15407/exp-oncology.2026.01.031}, pmid = {42290559}, issn = {2312-8852}, mesh = {Humans ; *MicroRNAs/genetics/blood ; Female ; *Breast Neoplasms/genetics/blood/pathology/mortality ; Prognosis ; *Biomarkers, Tumor/genetics/blood ; Middle Aged ; Adult ; Gene Expression Regulation, Neoplastic ; }, abstract = {BACKGROUND: Breast cancer (BC) heterogeneity signifi antly complicates diagnosis, prognosis, and prediction of treatment response. MicroRNAs (miRNAs) have emerged as promising biomarkers due to their involvement in tu- mor progression and in regulating therapy sensitivity. however, the combined clinical signifi ance of circulating and tumor-associated miRNAs, such as hsa-miR-26b-5p and hsa-miR-186-5p, remains insuffi tly elucidated. Materi- als and Methods. Expression levels of hsa-miR-26b-5p and hsa-miR-186-5p were analyzed in serum and tumor tis- sue of 124 BC patients. Associations with clinicopathological parameters were assessed. The prognostic signifi ance was evaluated based on disease progression and recurrence within 3 years. The predictive value was determined in patients receiving neoadjuvant chemotherapy (4AC regimen) using response assessment and ROC analysis. Re- sults. young BC patients (≤45 years) demonstrated signifi antly lower circulating levels of both miRNAs. Serum hsa-miR-186-5p expression was associated with early-stage disease, tumor size, lymph node status, and molecular subtype. Increased circulating hsa-miR-26b-5p levels were linked to disease progression, whereas decreased hsa- miR-186-5p levels were observed in patients with unfavorable outcomes. In tumor tissue, hsa-miR-26b-5p expres- sion correlated with tumor grade, size, and metastatic status, showing elevated levels in poorly differentiated tumors and reduced expression in metastatic disease. In contrast, hsa-miR-186-5p was associated with the molecular sub- type and lymph node involvement, with the highest expression observed in hER2-positive tumors and in patients with recurrence. Elevated levels of hsa-miR-186-5p in both serum and tumor tissue were associated with reduced sensitivity to doxorubicin-based neoadjuvant chemotherapy. ROC analysis confi med its predictive value (AUC = 0.750 for serum and 0.818 for tumor tissue). No signifi ant association between hsa-miR-26b-5p and chemothe- rapy response was observed.

CONCLUSIONS: hsa-miR-26b-5p and hsa-miR-186-5p demonstrate complementary roles in BC biology. hsa-miR-26b-5p is primarily associated with tumor aggressiveness and cancer progression, whereas hsa-miR-186-5p refl cts its molecular characteristics and response to chemotherapy. Their combined assessment in serum and tumor tissue represents a promising approach for improving prognostic stratifi ation and predicting treatment effi acy in BC patients.}, } @article {pmid42290625, year = {2026}, author = {Tenenbein, M}, title = {Author response to: Mullins et al. comment on, "We need a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning".}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {64}, number = {8}, pages = {633-635}, doi = {10.1080/15563650.2026.2679164}, pmid = {42290625}, issn = {1556-9519}, mesh = {*Acetaminophen/poisoning ; *Acetylcysteine/administration & dosage/therapeutic use ; Humans ; *Antidotes/administration & dosage/therapeutic use ; *Analgesics, Non-Narcotic/poisoning ; North America ; }, abstract = {INTRODUCTION: I have reviewed Mullins et al's critique of my commentary "We need a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning".

DISCUSSION: I concur regarding this need, and I agree that the original three-bag regimen should be retired. However, we disagree upon its replacement. They challenge my recommendation for a two-bag regimen, and they favour the one-bag two-step approach. The impetus for a replacement acetylcysteine regimen is to decrease the adverse effects and errors associated with the three-bag protocol. However, the one-bag two-step regimen was not designed to decrease adverse effects, and their published reports do not find a decrease of errors. And a fatal adverse effect, acetylcysteine overdose, has emerged with use experience of this regimen.

CONCLUSIONS: The one-bag two-step regimen should be dismissed from the quest for a standardized North American acetylcysteine dosing regimen for the treatment of paracetamol (acetaminophen) poisoning.}, } @article {pmid42301686, year = {2026}, author = {Jomaa, AM and Khalid, H and Abozait, HJ and Mudassar, H and Kaur, R}, title = {Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Annals of Indian Academy of Neurology}, volume = {29}, number = {3}, pages = {343-352}, pmid = {42301686}, issn = {0972-2327}, abstract = {OBJECTIVE: To evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol (PB-TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB-TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial.

RESULTS: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] -1.01 to 4.02; P = 0.24; I² =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73-1.11; P = 0.31; I² = 61%). A separate trial of TUDCA monotherapy (n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5-10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE.

CONCLUSIONS: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB-TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.}, } @article {pmid42304808, year = {2026}, author = {Smith, SE and Hughes, B and Miller, TM and Bucelli, RC}, title = {Amyotrophic Lateral Sclerosis Recovery: A New Model System of Care Integrating Neuromuscular Rehabilitation With Clinical Stabilization in ALS.}, journal = {Muscle & nerve}, volume = {74}, number = {2}, pages = {321-327}, doi = {10.1002/mus.70320}, pmid = {42304808}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/drug therapy ; Humans ; *Recovery of Function/physiology ; Male ; Female ; }, abstract = {There is currently no consensus on how to define recovery for individuals with amyotrophic lateral sclerosis (ALS). Tofersen treatment for superoxide dismutase-1-related (SOD1) ALS marks a pivot in clinical management: for the first time, clinicians can target disease stabilization and functional recovery in some individuals. This advancement shifts the focus of ALS care toward optimizing functional recovery alongside symptomatic management. However, there are no evidence-based guidelines for prescribing neuromuscular rehabilitation (NMR) to improve functional recovery. Building on our preliminary single-center data of integrated NMR with tofersen, we propose a new ALS Recovery Model System of Care, utilizing a hub-and-spoke infrastructure to combine NMR with novel therapies. This model aims to define ALS recovery, characterize recovery profiles, standardize NMR protocols, and establish a rehabilitation framework adaptable to future disease-stabilizing therapies.}, } @article {pmid42309005, year = {2026}, author = {Rugarli, EI and Langer, T}, title = {Limiting neurodegeneration in ALS: A phosphatase paves the way.}, journal = {Neuron}, volume = {114}, number = {12}, pages = {2073-2075}, doi = {10.1016/j.neuron.2026.04.030}, pmid = {42309005}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/enzymology/metabolism ; Animals ; Motor Neurons/metabolism ; *Nerve Degeneration ; Mitochondria/metabolism ; *Phosphoric Monoester Hydrolases/metabolism ; }, abstract = {Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.}, } @article {pmid42310298, year = {2026}, author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS}, title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {}, pmid = {42310298}, issn = {2041-4889}, support = {R35 GM141867/GM/NIGMS NIH HHS/United States ; 4R01AG068292//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; R01 AG068292/AG/NIA NIH HHS/United States ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; }, mesh = {*Neurons/metabolism/drug effects/pathology ; *DEAD-box RNA Helicases/metabolism/genetics ; Humans ; *G-Quadruplexes ; Animals ; Female ; Male ; DNA Damage ; }, abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in female and male neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.}, } @article {pmid42313307, year = {2026}, author = {Saini, K and Dhiman, P}, title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42313307}, issn = {1573-4978}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; }, abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.}, } @article {pmid42315356, year = {2026}, author = {Henders, AK and Ziser, L and Garton, FC and Adams, L and Ernst, K and Furlong, S and Heads, JA and Heggie, S and Krasniqi, R and Bhadravathi Lokeshappa, M and Mazumder, S and McNamara, E and MacShane, A and Mekhael, L and Nunn, L and Orden, B and Ryder, J and Thorpe, K and Toubia, M and Wallace, LM and Wickremeratne, D and Windebank, E and Benyamin, B and Ngo, S and Nicholson, G and Pamphlett, R and Steyn, FJ and Visscher, PM and Willams, KL and Henderson, R and Kiernan, MC and Laing, N and Mathers, S and McCombe, PA and Needham, M and Rowe, D and Schultz, D and Talman, P and Vucic, S and Blair, IP and McRae, AF and Wray, NR}, title = {Strategic Amyotrophic Lateral Sclerosis Australia-Systems Genomics Consortium (SALSA-SGC): cohort profile.}, journal = {BMJ open}, volume = {16}, number = {6}, pages = {e110906}, pmid = {42315356}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Australia ; *Genomics ; Female ; Male ; Middle Aged ; Aged ; Polymorphism, Single Nucleotide ; Adult ; Cohort Studies ; C9orf72 Protein/genetics ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative motor neuron disease (MND) with heterogeneity in disease onset, progression and treatment response. The Strategic ALS Australia-Systems Genomics Consortium (SALSA-SGC) was established in recognition of the need for large data sets of clinical data matched with biological samples to enable and foster ALS research and better understanding of aetiology and biological mechanisms. SALSA-SGC brought together the major Australian MND clinics to set up sustainable infrastructure that could facilitate long-term human ALS research and clinical trials nationally and internationally.

PARTICIPANTS: Between April 2016 and December 2024, SALSA-SGC recruited 1813 participants, including 1386 ALS/MND cases, 388 controls and 39 others (asymptomatic relatives and ALS mimics). Clinical data and biospecimens are available for 1333 and 1189 ALS cases, respectively, with longitudinal data spanning 4442 total clinic visits and 3201 samples. An open-access online data explorer showcases collected datasets.

FINDINGS TO DATE: Detailed clinical and questionnaire data allow an in-depth description of the cohort, informing clinical and health policy research. Screening for known ALS large-effect risk variants identified 125 mutation carriers (11.5% from N=1059), including 70 with C9orf72 expansions. Single Nucleotide Polymorphism (SNP)-array data (N=1088 cases; N=244 controls) have supported multiple published studies. SALSA-SGC resources are actively used by national and international researchers.

FUTURE PLANS: Ongoing efforts aim to expand recruitment into regional Australia and enhance sample processing for cell-based studies. The SALSA-SGC resource is accessible by researchers under agreements governed by participant consent, human ethics committee guidelines and agreed use of data and samples.}, } @article {pmid42317872, year = {2026}, author = {Singh, G and Singh, G and Shreya, and Kumari, A and Aran, KR}, title = {Nutrients and bioactive compounds as modifiers of neurodegenerative trajectories: molecular mechanisms, translational barriers, and precision nutrition.}, journal = {Frontiers in nutrition}, volume = {13}, number = {}, pages = {1819432}, pmid = {42317872}, issn = {2296-861X}, abstract = {The Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS) are a growing health burden across the world with minimal disease-modifying treatment and therapy. It is emerging that neurodegeneration is not only a progressive loss of neurons, but also a nutrient-sensitive systems-level dysfunction that takes the form of redox imbalance, chronic neuroinflammation, mitochondrial dysfunction, impaired proteostasis, and synaptic loss. The aging brain are more prone to metabolic vulnerability, and subclinical deficiencies in essential nutrients and bioactive dietary compounds may exacerbate cellular stress responses that contribute to disease progression. It summarizes the existing data on the effects of nutrients like vitamins, minerals, polyunsaturated fatty acids, and various phytochemicals in modulating neuronal homeostasis by regulating oxidative signaling, inflammatory cascades, mitochondrial resilience, autophagy, and synaptic plasticity. These nutrient-mediated effects collectively influence neuronal survival, synaptic integrity, and cognitive function by affecting disease susceptibility and progression. Additionally newer metabolites of the marine and microbiome act as new neuroactive agents. The evidence from in-vitro and preclinical models, translation to clinical benefit remains inconsistent due to heterogeneity in study design, bioavailability, blood- brain barrier penetration, dosing strategies and disease stage. This review highlights emerging potential of precision nutrition frameworks that integrate nutrigenomics, metabolomics, and microbiome interactions, and individualized metabolic profiling to enable context-dependent and stage-specific interventions. Moreover, conceptualizing neurodegeneration as a nutrient-sensitive, systems level disorder, propose a mechanistically informed and integrative approach that combine targeted nutritional strategies with pharmacological and lifestyle therapies to more effectively modify neurodegenerative trajectories.}, } @article {pmid42320366, year = {2026}, author = {Lee, BC and Tsai, JC and Chang, WZ and Wang, CC and Hour, AL and Wang, CC and Tsai, HJ}, title = {Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119674}, doi = {10.1016/j.biopha.2026.119674}, pmid = {42320366}, issn = {1950-6007}, mesh = {Animals ; Zebrafish/genetics ; *Phosphoglycerate Kinase/genetics/administration & dosage/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mutation, Missense/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Animals, Genetically Modified ; Humans ; Motor Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons (MNs) with few available therapeutic options. Previous ALS studies demonstrated a decrease in phosphoglycerate kinase 1 (Pgk1) secreted from NogoA-overexpressing muscle cells, thus reducing interaction between extracellular Pgk1 (ePgk1) and neural membranous Enolase 2 (Eno2) with consequent inhibition of neurite outgrowth of MNs (NOMN). The negatively charged 419th aspartic acid of receptor Eno2 (Eno2-D419) is a critical residue interacting with the positively charged 353rd lysine of ligand ePgk1-K353. To strengthen the charge attraction, we mutated ePgk1-K353 to arginine (ePgk1-K353R). Compared to wild-type Pgk1, supplementary mutant Pgk1-K353R proved more effective in increasing NOMN derived from NSC34 neural cells cultured in Sol8-vector condition medium. In vivo, Pgk1-K353R-immersed zebrafish embryos exhibited increased caudal primary MNs branching. Intravenous injection of Pgk1-K353R into ALS-mice exhibited more preservative in innervated neuromuscular junctions in gastrocnemius muscle and diaphragm, increased grip strength, higher rearing frequency, 1.6-fold greater locomotive distance and longer survival. For example, median survival days for the control, Pgk1 and Pgk1-K353R groups were 131, 137.5 and 148, respectively. Collectively, we found a single-amino-acid mutant Pgk1-K353R that exhibits higher efficacy to ameliorate neurodegeneration in ALS-mice by delaying disease progression compared to that driven by wild-type Pgk1. We suggest this outcome might be due to more electrostatic attraction between ePgk1-K353R and Eno2-D419 region predicted by in silico analysis. Therefore, mutant Pgk1-K353R protein should be considered a promising neuroprotective drug for ALS treatment.}, } @article {pmid42324839, year = {2026}, author = {Felice, KJ and Leighton, DB and Daniel, AS and Cartwright, NI and Benchaya, LM}, title = {The Impact of Sponsored Genetic Testing in 170 Consecutive Consenting Patients With Amyotrophic Lateral Sclerosis: A Single-Site Retrospective Review.}, journal = {Muscle & nerve}, volume = {74}, number = {3}, pages = {698-701}, pmid = {42324839}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/economics ; Retrospective Studies ; Female ; Male ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Adult ; Genetic Predisposition to Disease ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is often categorized as sporadic (sALS) or familial (fALS) based on the family history. Several recent genetic studies have found disease-causing variants in 50%-85% of patients with fALS and 10%-15% of those with sALS. The aim of our study is to review our clinical experience with sponsored genetic testing (i.e., pharmaceutical company-sponsored and cost-free to patient) since its inception.

METHODS: We reviewed the medical records on all ALS patients seen at our Center who consented to sponsored genetic testing from August 2021 through October 2025.

RESULTS: Of the 170 medical records reviewed, 22 patients (12.9%) tested positive for a disease-causing variant in a known autosomal dominant disorder. Thirteen of 35 patients with fALS (37.1%) were found to have a disease-causing variant, in contrast to 9 of 135 patients (6.7%) with sALS. Of the 22 disease-causing variants found, the following genes were involved in decreasing frequency: C9orf72 11 (50%), SOD1 6 (27.3%), FUS 2 (9.1%), and one each (4.5%) of SQSTM1, TARDBP, and TBK1. Twenty-eight patients (16.5%) harbored 29 variants of uncertain significance (VUS).

DISCUSSION: Results of testing led to medically actionable activities including genetic counseling for patients and at-risk family members with positive results, and treatment (i.e., intrathecal tofersen) for the two patients harboring pathogenic SOD1 variants. The lower diagnostic yields than previously published for fALS and sALS patients likely are related to lower numbers of genes tested in the sponsored genetic panels, and these are expected to improve as more genes are added.}, } @article {pmid42328245, year = {2026}, author = {Dong, J and Lu, M and Chen, Y and Zisman-Ilani, Y and Feng, Y and Zhang, S and Huang, H and Zhou, Y}, title = {Bridging the Gap Between Efficacy and Practice: A Systematic Review of Shared Decision-Making in Severe Mental Illness.}, journal = {Journal of multidisciplinary healthcare}, volume = {19}, number = {}, pages = {610845}, pmid = {42328245}, issn = {1178-2390}, abstract = {Shared decision-making (SDM) is recommended for preference-sensitive treatment decisions in severe mental illness, but its routine use in psychiatric services remains inconsistent. This systematic review synthesized evidence published between 2014 and 2024 and examined clinical, cultural, and organizational factors associated with SDM implementation. We searched PubMed, Embase, CINAHL, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP for studies published from January 2014 to November 2024. Forty-two studies involving 8798 participants were included. Reporting followed PRISMA 2020 and SWiM guidance. Study quality was assessed with design-specific Joanna Briggs Institute tools, and certainty of key findings was appraised using a combined GRADE-CERQual approach. Because of heterogeneity in study design, interventions, outcomes, and settings, findings were synthesized narratively using Popay et al's framework. Patient decision aids were generally associated with lower decisional conflict, greater readiness, satisfaction, involvement, or autonomy, with little evidence of meaningful consultation-time extension. Clinician training and SDM interventions improved short-term engagement and information sharing, but evidence for sustained improvements in adherence, decisional conflict, and clinician behavior was mixed or low certainty. Family-mediated or triadic decision-making was prominent in East and Southeast Asian studies and may support adherence and participation, although it can also create tension between patient autonomy and family preferences. Across studies, clinicians and patients often emphasized different treatment priorities, particularly symptom control versus side-effect tolerability. Evidence was concentrated in Europe and East Asia, with limited data from low-resource regions. SDM in psychiatric care appears most reliable for improving immediate decision processes rather than long-term outcomes. Future implementation should test culturally adapted triadic decision aids, workflow-integrated prompts, and interprofessional decision coaching while using cautious, context-sensitive outcome evaluation.}, } @article {pmid42333562, year = {2026}, author = {Srivastava, V and Chakraborty, S and Srivastava, R}, title = {Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0127724328415188260605204430}, pmid = {42333562}, issn = {2772-4336}, abstract = {Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.}, } @article {pmid42339807, year = {2026}, author = {Jewer, M and Snyder, J and Caulfield, T and Zenone, M}, title = {The connection between unproven stem cell-based interventions and complementary and alternative medicine in crowdfunding for Amyotrophic Lateral Sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2026.2685157}, pmid = {42339807}, issn = {2167-9223}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease associated with substantial medical and non‑medical costs. In the absence of effective treatments, patients and families may turn to crowdfunding to finance care, including unproven stem cell‑based interventions (SCBIs) that are frequently marketed directly to consumers.

OBJECTIVE: conduct content analysis of English‑language GoFundMe campaigns seeking funds for SCBIs for ALS to better understand the market for unproven direct‑to‑consumer SCBIs.

METHODS: 247 campaigns were identified, and their data were collected and analyzed to determine the characteristics of the campaigns, campaigners, and their desired treatments.

RESULTS: ALS crowdfunding campaigns that collectively requested over $16 million USD. In addition to SCBIs, campaigns frequently requested funding for international travel to access these treatments. Campaigners express relatively high confidence that stem cell treatments would slow disease progression, improve symptoms, or, in some cases, cure or reverse ALS; conclusions that exceed the scientific evidence. Confidence in SCBIs is linked to requests for other alternative therapies and unsupported causes of ALS, supporting an emerging link between proponents of alternative medicines and unproven stem cell therapies.

CONCLUSION: Crowdfunding for unproven stem cell interventions exposes ALS patients and donors to financial risk, misinformation, and medical exploitation. The frequent linkage between SCBIs, CAM, and exaggerated claims highlights gaps in regulation, patient protection, and access to credible treatment options. These findings underscore the need for stronger oversight of direct‑to‑consumer stem cell markets and greater support for patients facing catastrophic illness.}, } @article {pmid42348198, year = {2026}, author = {Walter, KL}, title = {Amyotrophic Lateral Sclerosis.}, journal = {JAMA}, volume = {336}, number = {6}, pages = {528}, doi = {10.1001/jama.2026.9755}, pmid = {42348198}, issn = {1538-3598}, } @article {pmid42350385, year = {2026}, author = {Wan, F and He, J and Ma, H and PiresFerreira, D and Kumanan, V and Lee, JS and Chen, X and He, R and Su, Q and Gallagher, TL and Zhu, S and Cabrera, GT and Zhao, L and Shen, J and Gruntman, A and Brown, RH and Xu, Z and Gao, G and Xie, J}, title = {Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42350385}, issn = {2041-1723}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; AL240123//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Dependovirus/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Models, Animal ; *Genetic Vectors/administration & dosage/genetics ; Mice ; Motor Neurons/metabolism/pathology ; *Genetic Therapy/methods ; *Gene Silencing ; Mice, Transgenic ; Administration, Intravenous ; MicroRNAs/genetics ; Neuromuscular Junction/metabolism ; Female ; Gene Therapy Agents ; Male ; }, abstract = {Adeno-associated virus (AAV)-mediated gene silencing offers a promising strategy for achieving durable therapeutic effects with a single administration. Mutations in the human superoxide dismutase 1 (hSOD1) gene, inherited in an autosomal dominant manner, lead to motor neuron degeneration in amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease with no effective treatment. In this study, we employed AAV9 to deliver to the SOD1[G93A] ALS mouse model artificial microRNAs targeting SOD1, embedded in dual miR-33 scaffolds driven by the promoter of the human survival motor neuron 1 (hSMN1) gene. A single intravenous injection achieved widespread and sustained suppression of SOD1, preserved α-motor neurons, maintained neuromuscular junctions (NMJs), and improved muscle function. These benefits are translated into significantly improved respiratory function, motor performance, and survival. Therapeutic efficacy was observed both when the treatment was administered pre-symptomatically and during symptomatic stages. Compared with previous AAV-based interventions, the survival benefit achieved in this IV delivery approach is unprecedented, supporting its potential for clinical translation in SOD1-linked ALS and other central nervous system (CNS) diseases caused by gain-of-toxicity gene mutations.}, } @article {pmid42351313, year = {2026}, author = {Brenner, D and Ponomarenko, A and Petrut, I and Beyrle, S and Contardo, M and Loss, I and Radke, C and Frank, J and Zimmer, E and Schlesner, M and Achenbach, P and Scheveneels, W and Aly, A and Nazlican, H and Hesebeck-Brinkmann, J and Oeckl, P and Müller, K and Siebert, R and Böckers, T and van Eijk, K and Veldink, J and Kleger, A and Mulaw, M and Andersen, PM and Forsberg, K and Weishaupt, JH and Loghmani, SB and Grehl, T and van Damme, P and Weis, J and Catanese, A}, title = {A rare missense variant impacting NEK1 kinase function is associated with ALS.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {}, pmid = {42351313}, issn = {2051-5960}, mesh = {*NIMA-Related Kinase 1/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mutation, Missense/genetics ; Female ; Motor Neurons/pathology/metabolism ; Male ; Pedigree ; Animals ; }, abstract = {Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.}, } @article {pmid42352358, year = {2026}, author = {Lee, BC and Hwang, JJ and Tsai, HJ}, title = {Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.}, journal = {Biomolecules}, volume = {16}, number = {6}, pages = {}, pmid = {42352358}, issn = {2218-273X}, support = {NSTC-114-2313-B-030-001//National Science and Technology Council/ ; F630410//USA FJCU Alumni Foundation/ ; CPL-202508003//Collaborative Research Project between FJUH and FJU/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; *Phosphopyruvate Hydratase/metabolism ; Animals ; *Phosphoglycerate Kinase/metabolism ; *Motor Neurons/metabolism/pathology/drug effects ; *Peptides/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP/p-Pak1-T423/p-P38-T180/pMK2-T334/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1/-2 as promising protein/peptide drugs for ALS treatment.}, } @article {pmid42353064, year = {2026}, author = {Reedich, EJ and Chen, YT and Imhoff-Manuel, R and Li, D and Manuel, M}, title = {Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1[G93A] Mouse Spinal Motoneurons.}, journal = {International journal of molecular sciences}, volume = {27}, number = {12}, pages = {}, pmid = {42353064}, issn = {1422-0067}, support = {1R01NS110953-05/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/drug effects/metabolism/physiology ; *Diazepam/pharmacology ; Mice ; *Homeostasis/drug effects ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism/physiopathology/pathology ; *Spinal Cord/drug effects/metabolism ; *Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Action Potentials/drug effects ; Disease Models, Animal ; Synaptic Transmission/drug effects ; }, abstract = {Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1[G93A] mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild-type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1[G93A] mice modulate excitability differently than wild-type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1[G93A] versus wild-type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1[G93A] motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.}, } @article {pmid42357346, year = {2026}, author = {Costanzi, E and Fontana, L and Giroldo, F and Coco, S}, title = {Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.}, journal = {Pharmaceutics}, volume = {18}, number = {6}, pages = {}, pmid = {42357346}, issn = {1999-4923}, support = {P2022LR49L//Ministry of Universities and Research/ ; 202229X8HW//Ministry of Universities and Research/ ; }, abstract = {Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.}, } @article {pmid42359165, year = {2026}, author = {Morimoto, S and Kato, C and Takahashi, S and Okano, H}, title = {Therapeutic frontiers in ALS: iPSC-based drug discovery, cell therapy, and gene therapy-Advances through 2026.}, journal = {Regenerative therapy}, volume = {33}, number = {}, pages = {101150}, pmid = {42359165}, issn = {2352-3204}, abstract = {Three converging therapeutic paradigms-iPSC-based drug discovery, cell transplantation, and gene therapy-have substantially expanded the therapeutic pipeline for amyotrophic lateral sclerosis (ALS) between 2020 and 2026. The FDA's accelerated approval of tofersen (Qalsody) in April 2023 marked the first treatment targeting a genetic cause of ALS. iPSC-derived drug candidates, including ropinirole and bosutinib, have completed early-phase clinical trials led by Japanese institutions. Cell therapies targeting neuroinflammation through regulatory T cells are being actively explored as immunomodulatory strategies, although efficacy remains to be established in adequately powered trials. Next-generation gene-silencing approaches-including RNA interference (RNAi) therapeutics and AAV-delivered microRNA-entered first-in-human trials in 2024-2025. The identification of STMN2 as a downstream target of TDP-43 dysfunction has opened a potential TDP-43-downstream nucleic acid therapeutic avenue for sporadic ALS, which constitutes approximately 90% of all cases, with company-reported interim data suggesting target engagement in the ongoing Phase 1/2 ANQUR trial (QRL-201). This review synthesizes the latest evidence across all three therapeutic domains, with attention to the hierarchy of evidence, regulatory milestones, and the pioneering contributions of Japanese research groups.}, } @article {pmid42361623, year = {2026}, author = {Deptuła, P and Chmielewska-Deptuła, S and Spałek, J and Kaliniak, S and Okła, S and Bucki, R}, title = {Decoding the pathogenesis of Candida albicans infection and evaluating the efficacy of antifungal drugs using atomic force microscopy.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {201}, number = {}, pages = {119705}, doi = {10.1016/j.biopha.2026.119705}, pmid = {42361623}, issn = {1950-6007}, mesh = {*Microscopy, Atomic Force/methods ; *Candida albicans/drug effects/pathogenicity ; *Antifungal Agents/pharmacology/therapeutic use ; Biofilms/drug effects ; Humans ; *Candidiasis/drug therapy/microbiology/pathology ; Cell Wall/drug effects/metabolism ; Animals ; }, abstract = {Atomic force microscopy (AFM) has emerged as a pivotal method enabling multidimensional characterization of Candida albicans (C. albicans) by simultaneously providing topographical imaging, mechanical profiling, and quantitative measurements of adhesion forces under near-physiological conditions. AFM-derived data demonstrate that nanoscale surface alterations, including wrinkling, indentations, increased roughness, and perforations correlate closely with modulation of the Young's modulus and with the reorganization of mannoproteins and adhesins, particularly those of the Als family. The co-occurrence of structural, mechanical, and adhesive changes reflects the dynamic remodeling of the fungal cell wall that governs morphogenesis, virulence, and biofilm formation. AFM offers high resolution insight into the mechanisms of action of antifungal drugs, antimicrobial peptides, nanomaterials, and physical treatments that destabilize the cell wall, reduce its stiffness, or conversely induce compensatory stiffening and adhesin exposure. As a result, the technique enables the identification of critical steps in stress responses and hyperadhesive phenotypes that contribute to fungal invasion and treatment resistance. Integration of AFM with spectroscopic and microfluidic approaches further enhances its potential to reveal new therapeutic targets. Collectively, evidence from numerous studies underscores AFM as a foundational tool in the rational design of modern, multimodal antifungal strategies aimed at the cell wall and biofilm of C. albicans.}, } @article {pmid42363583, year = {2026}, author = {Ludwig, TD and Rabelo-Araujo, JVDS and Munhoz Pedroso, R}, title = {Enhanced weed control in flooded rice through diversified pre-emergence programs integrating PROTOX-inhibiting herbicides.}, journal = {Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes}, volume = {61}, number = {10}, pages = {733-739}, doi = {10.1080/03601234.2026.2694270}, pmid = {42363583}, issn = {1532-4109}, mesh = {*Herbicides/pharmacology ; *Oryza/growth & development/drug effects ; *Weed Control/methods ; *Protoporphyrinogen Oxidase/antagonists & inhibitors ; *Plant Weeds/drug effects ; Brazil ; Acetolactate Synthase/antagonists & inhibitors ; Echinochloa/drug effects ; Benzoxazines/pharmacology ; Floods ; Phthalimides ; }, abstract = {Rice (Oryza sativa L.) productivity in Brazil is increasingly threatened by herbicide-resistant weeds. We evaluated diversified pre-emergence programs in flooded Clearfield rice (Puitá INTA CL) through two field experiments conducted in southern Brazil during the 2016/2017 season. Programs were based on acetolactate synthase (ALS) inhibitors alone or combined with alternative modes of action, including protoporphyrinogen oxidase (PROTOX) inhibitors (saflufenacil and flumioxazin). Weed control of Aeschynomene spp. and Echinochloa spp. was high (≥80%) at 14 days after application (DAA) and remained satisfactory up to 21 DAA in most programs. Crop injury was treatment-dependent, with higher early phytotoxicity observed in mixtures containing mesotrione, but visual symptoms declined over time and did not compromise grain yield. All herbicide programs significantly increased productivity compared to the untreated control. These findings indicate that integrating PROTOX inhibitors into Clearfield-based pre-emergence programs is a feasible strategy to diversify modes of action while maintaining effective weed control and yield stability under flooded conditions.}, } @article {pmid42367645, year = {2025}, author = {Toussirot, E and Tatu, L and Bereau, M}, title = {Occurrence of amyotrophic lateral sclerosis during TNF inhibitor treatment in inflammatory rheumatic disease. What are the relationships?.}, journal = {EULAR rheumatology open}, volume = {1}, number = {4}, pages = {475-477}, pmid = {42367645}, issn = {3050-7081}, abstract = {Neurological adverse events have been reported in patients receiving tumor necrosis factor inhibitors (TNFi) for the treatment of inflammatory rheumatic diseases. The occurrence of amyotrophic lateral sclerosis (ALS) during TNFi therapy is rare but raises the question of a possible relationship. We report 2 cases of ALS diagnosed during TNFi treatment: the first in a patient with spondyloarthritis treated with adalimumab and the second in a patient with seronegative polyarthritis treated with infliximab. Tumor necrosis factor alpha (TNFα) has been implicated in ALS pathogenesis and is considered to exert both neuroprotective and neurotoxic effects, depending on the differential expression of its receptors in distinct regions of the central nervous system. We also review data from pharmacovigilance databases and discuss the potential influence of TNFα inhibition on ALS development.}, } @article {pmid42369121, year = {2026}, author = {Cao, G and Yang, X and Wang, X and Shi, X and Yang, L and Wang, P and Tan, H}, title = {Meniscal repair and partial meniscectomy demonstrated similar clinical outcomes with simultaneous combined anterior cruciate ligament and anterolateral structure reconstruction.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1847295}, pmid = {42369121}, issn = {2296-858X}, abstract = {PURPOSE: The clinical outcomes of patients after combined anterior cruciate ligament (ACL) and anterolateral structure (ALS) reconstruction with or without concomitant meniscal treatment were limited. The purpose of this study was to evaluate clinical outcomes and investigate the effect of concomitant treatment of meniscal injury on these outcomes following combined ACL and ALS reconstruction.

METHODS: A total of 86 patients with combined ACL and ALS reconstruction were eligible for inclusion, from August 2018 to November 2022, with at least 1-year follow-up. The patients were assigned to three groups based on meniscal status, including the no injury group (n = 26), the partial meniscectomy group (the meniscus was resected partially, n = 24), and the repair group (the meniscus was sutured, n = 36). Outcome measurements consisted of function, stability, and safety evaluation. Functional evaluation included Lysholm score, Tegner score, and International Knee Documentation Committee (IKDC) score.

RESULTS: At the last follow-up, the Lysholm, Tegner, and IKDC scores were significantly improved compared with preoperative status (p < 0.05). Functional scores in the no injury group were much higher than those in the partial meniscectomy and repair groups. In addition, the expense was significantly higher in the repair group (43840.9 ± 10804.9) than that in the no injury (37767.7 ± 4537.4, p = 0.003) and partial meniscectomy (37738.7 ± 3794.4, p = 0.004) groups. The stability and safety indices did not differ significantly among the three groups (p > 0.05).

CONCLUSION: Among patients following simultaneous ACL and ALS reconstruction with concomitant meniscal injury, meniscal repair and partial meniscectomy could demonstrate comparable functional outcomes.}, } @article {pmid42372734, year = {2026}, author = {Pena, C and Barker, C and Grossberg, AN and Mian, I and Williams, S and MacAllister, T and Vu, T and Linseman, DA}, title = {An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2026.2694507}, pmid = {42372734}, issn = {2167-9223}, abstract = {OBJECTIVES: The primary objective was to assess the safety of oral fasudil in amyotrophic lateral sclerosis (ALS) patients. Changes in serum neurofilament light (NfL) levels and the ratio of phosphorylated to total AKT (pAKT/tAKT) were exploratory endpoints.

METHODS: This was a multicenter, open-label study. Two 31-patient cohorts were sequentially enrolled and treated with either 180 mg or 300 mg per day of oral fasudil for 24 weeks. The primary endpoint was safety. Secondary endpoints evaluated changes in the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity, and muscle strength. We also assessed changes in serum NfL and pAKT/tAKT ratios in plasma (neuron-derived) and CSF (total) extracellular vesicles (EVs).

RESULTS: Eighty-one percent (25/31) and 71% (22/31) of patients completed 24 weeks of treatment in the 180 and 300 mg cohort, respectively. Fasudil was safe and well tolerated, with predominantly mild drug-related adverse events. Secondary endpoints, though not statistically significant, were directionally consistent with a treatment effect. Exploratory analyses showed a 15.4% reduction in serum NfL at 24 weeks (p = 0.001) in the 180 mg cohort, with no change in the 300 mg cohort (-0.4%, p = 0.990). The NfL reduction was inversely correlated with ALSFRS-R decline (Spearman = -0.45, p = 0.028). Ratios of pAKT/tAKT, a pharmacodynamic marker of rho kinase (ROCK) inhibition, were significantly increased at 24 weeks in plasma (neuron-derived) and CSF EVs.

CONCLUSIONS: Oral fasudil is safe and well-tolerated in ALS patients. The reduction in NfL and demonstration of CNS target engagement, supports studying the 180 mg dose in a double-blind placebo-controlled study.}, } @article {pmid42374626, year = {2026}, author = {Walton, EI and Sun, J}, title = {Microbiome and metabolites impact enteric and central nervous systems in ALS.}, journal = {Gut microbes}, volume = {18}, number = {1}, pages = {2692737}, pmid = {42374626}, issn = {1949-0984}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/physiopathology ; Humans ; *Central Nervous System/metabolism/microbiology/physiopathology ; *Enteric Nervous System/metabolism/physiopathology/microbiology ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis/microbiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to gastrointestinal symptoms and alterations in the gut microbiota. The enteric nervous system (ENS) coordinates intestinal function and sits at the host-microbe interface. The mechanisms by which luminal changes relay to the central nervous system (CNS), where motor neurons reside, have yet to be completely defined. In this narrative review, we first present evidence from ALS patient cohorts and preclinical models alongside mechanistic studies of infection, dysbiosis, and related neurodegenerative diseases to discuss how the microbiota and its metabolites may affect the ENS and CNS in ALS. Next, we propose a plausible mechanism of ALS pathogenesis through the gut-microbiome-brain axis. We further offer a summary of clinical trials that have studied the impacts of the microbiota on human ALS. Finally, we discuss future directions for studies of microbiota-ENS-CNS interactions in ALS. Better understanding of the dynamic interactions among the microbiota, microbial metabolites, neuroactive metabolites, and inflammation through the ENS/CNS in ALS will provide innovative insights into ALS prevention and treatment.}, } @article {pmid42377311, year = {2026}, author = {Price, TR and Chang, CY and Skinner, K and Dinneny, M and Nafezi, P and Kuramoto, L and De Vera, MA and Cashman, NR and Cragg, JJ}, title = {Could anticholinergics accelerate ALS progression? A critical perspective on drug safety and disease vulnerability.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/14740338.2026.2687628}, pmid = {42377311}, issn = {1744-764X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited treatment options and diverse symptoms necessitating active management. Anticholinergic medications are frequently used in ALS care, particularly for sialorrhea and mood disturbances. Their cumulative effects, termed anticholinergic burden, may pose underrecognized risks in this neurologically vulnerable population. This review highlights a plausible safety signal and outlines priorities for future research.

AREAS COVERED: This narrative review synthesizes evidence from non-ALS populations reporting associations between higher anticholinergic burden and cognitive decline, respiratory complications, functional deterioration, and mortality. Evidence was identified through targeted PubMed/MEDLINE and Embase searches with reference chaining, emphasizing recent and seminal studies. Mechanistic overlap with ALS pathophysiology, including neuromuscular junction disruption, impaired cholinergic signaling, and neuroinflammation, supports biological plausibility for harm. Current ALS guidelines do not address cumulative anticholinergic exposure, leaving clinicians without a framework for evaluating risk or deprescribing.

EXPERT OPINION: This article proposes a testable hypothesis that anticholinergic burden may represent a clinically relevant yet unmeasured risk factor in ALS. Emerging pharmacoepidemiologic methods and validated burden tools offer approaches to quantify exposure and evaluate relationships with ALS outcomes, supporting safer symptomatic management. Prioritizing longitudinal studies and integrating burden assessment into multidisciplinary care may help clarify risk.}, } @article {pmid42394935, year = {2026}, author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS}, title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1824840}, pmid = {42394935}, issn = {1664-2295}, abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.}, } @article {pmid42398690, year = {2026}, author = {Sun, Y and Wang, Y and He, Q and Zhao, M and Guo, J and Xu, C and Yan, Q and Chen, Y and Zhang, B and Du, H and Huo, J and Zhang, Y and Zhang, H and Guan, Y and He, Q}, title = {Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress-neuroinflammation crosstalk.}, journal = {Acta biomaterialia}, volume = {219}, number = {}, pages = {663-678}, doi = {10.1016/j.actbio.2026.07.004}, pmid = {42398690}, issn = {1878-7568}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; *Oxidative Stress/drug effects ; *Hydrogen/therapeutic use/pharmacology/chemistry ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/pathology/genetics ; Humans ; *Mutation ; Spinal Cord/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of ·OH and a hydrogenation catalyst for H2 scavenging reactive oxygen species. To enhance the bioavailability of H2, we develop an orally administered Mg2Si nanosheets based feed for sustained release of high-amount H2. On an ALS model of hSOD1[G93A] transgenic mice, Mg2Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg2Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H2-mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. STATEMENT OF SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H2) exhibits promising neuroprotective potential, conventional H2 therapy is severely limited by unstable and transient H2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg2Si nanosheets that enable sustained H2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo. Mechanistically, Mg2Si-derived H2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg2Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg2Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders.}, } @article {pmid42399152, year = {2026}, author = {Demeret, R and Vieles Marais, D and Treiner, E and Acket, B and Fabry, V and Levade, T and Nogueira, L and Pages, JC and Cintas, P}, title = {Macrophage inclusions in patients undergoing antisense oligonucleotide therapy for ALS or SMA: A retrospective and transversal study.}, journal = {Revue neurologique}, volume = {182}, number = {7}, pages = {652-659}, doi = {10.1016/j.neurol.2026.05.005}, pmid = {42399152}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/cerebrospinal fluid ; Retrospective Studies ; *Oligonucleotides, Antisense/therapeutic use ; *Muscular Atrophy, Spinal/drug therapy/pathology/cerebrospinal fluid ; Female ; Male ; Oligonucleotides/therapeutic use ; *Macrophages/pathology ; Middle Aged ; *Inclusion Bodies/pathology ; Adult ; Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: Intrathecal antisense oligonucleotides (ASOs) have revolutionized the management of genetic motor neuron diseases. Nusinersen is approved for spinal muscular atrophy (SMA) caused by SMN1 mutations, and tofersen for amyotrophic lateral sclerosis (ALS) linked to SOD1 mutations. Since their approval, some studies reported the presence of macrophagic inclusions in cerebrospinal fluid (CSF) of patients treated with ASOs, first in nusinersen-treated patients and more recently in those receiving tofersen. These findings remain poorly characterized, and their clinical significance is unclear.

METHODS: We first conducted a retrospective study in 21 patients (132 CSF samples): six treated with tofersen (every 4 weeks) and 15 with nusinersen (every 4 months). CSF samples were analyzed for macrophagic inclusions, their time of onset, and persistence over time. To assess clinical and inflammatory correlates of macrophagic inclusions, we then performed an analysis of CSF inflammatory biomarkers and serum ferritin and neurofilament light chain tests in 18 of these patients still under treatment.

RESULTS: In tofersen-treated patients, macrophagic inclusions were consistently observed and persisted over time, except in one case. In nusinersen-treated patients, inclusions were rare and transient. An inflammatory CSF profile was associated with the presence of inclusions, but their cellular nature remained undetermined. Notably, tofersen-treated patients with "tofersenophages" exhibited favorable clinical responses.

DISCUSSION: Macrophagic inclusions appear more frequent in the CSF of tofersen-treated patients than previously reported. While their origin remains unclear, they seem linked to CSF inflammation without precluding a beneficial therapeutic response.}, } @article {pmid42400371, year = {2026}, author = {Harrington, EA and Dratch, L and Jones, TA and Fong, JC and Kinnamon, DD and Goldman, J and Uhlmann, WR and Roggenbuck, J}, title = {Reduced penetrance in genetic ALS/FTD spectrum disorders: implications for genetic counseling, predictive testing and treatment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2026.2696378}, pmid = {42400371}, issn = {2167-9223}, abstract = {As the offer of genetic testing for people with ALS/FTD becomes standard of care, clinicians and affected individuals should have accurate and balanced information regarding the clinical and familial implications of test results, including the penetrance of identified variants. Published estimates of the penetrance of specific ALS/FTD variants, including the C9orf72 repeat expansion, have varied widely. However, it is now apparent that most pathogenic variants identified in clinical testing exhibit reduced penetrance. Although data on the disease risk of many variants is limited and likely to evolve in the coming years, the challenges of estimating penetrance should not preclude transparent discussion of these issues with affected individuals and their families. Here, we review published penetrance data and highlight genetic counseling considerations to support the clinician in discussing disease risk and facilitating decision-making in genetic testing and patient care.}, } @article {pmid42400730, year = {2026}, author = {Shahsavari, K and Yazarlu, O and Ahmadnia, H and Ardakani, MT and Khanavi, M and Esfahani, HM and Abdollahzadeh, R and Sajedi, A and Kazemizadeh, H and Hasanpour, M}, title = {Neuroprotective potential of resveratrol in Parkinson, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis: a comprehensive review.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {}, pmid = {42400730}, issn = {1573-4978}, mesh = {*Resveratrol/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Multiple Sclerosis/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Huntington Disease/drug therapy/metabolism ; Mitochondria/drug effects/metabolism ; Sirtuin 1/metabolism ; }, abstract = {Resveratrol shows neuroprotective effects in preclinical studies across a number of neurodegenerative illnesses, including Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's disease (HD), and it enhances mitochondrial function through stimulation of the AMPK/SIRT1/PGC-1α pathway, thereby improving mitochondrial oxidative capacity and ATP generation. The natural polyphenol lowers α-synuclein accumulation and affects autophagy; both markers of PD. Combining nano‑resveratrol formulations with L‑DOPA has shown greater therapeutic efficacy in animal models (MPTP mouse), while co‑administration with EGCG has shown synergistic neuroprotection in vitro (SH‑SY5Y cells). These combination strategies offer potential advantages in neuroprotection and symptom alleviation while minimizing adverse drug effects. Resveratrol activates SIRT1 and AMPK signaling in preclinical models, enhancing mitochondrial biogenesis, lowering apoptosis, and restoring cellular resilience. The effectiveness of various models and dosages varies. The primary mechanism by which resveratrol promotes neuronal survival and remyelination in multiple sclerosis is through SIRT1 activation, which does not directly reduce inflammation. As innovative delivery systems, intranasal nanoparticles and exosomes produced from macrophages have shown improved CNS targeting accuracy. Resveratrol slows down neurodegeneration and improves the prognosis of HD by improving motor function and stimulating mitochondrial biogenesis in addition to activating neuroprotective ERK signaling. All of these results point to resveratrol's several pathways as a strong contender for neurodegenerative disease adjunctive treatment. The current evidence base is insufficient to support clinical use of resveratrol for any of the four diseases. Further rigorous preclinical studies (including TDP-43 models for ALS, SIRT1 knockout studies, and human-feasible dosing) and well-designed clinical trials with pharmacokinetic endpoints are required before any clinical recommendations can be made.}, } @article {pmid42404435, year = {2026}, author = {Hobin, F and Das, S and Lambrechts, C and De Rocker, C and Dubin, J and Ombelet, F and De Vocht, J and Lamaire, N and Vanmechelen, E and Poesen, K and Van Damme, P}, title = {Value of synaptic proteins as biomarkers in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {8}, number = {4}, pages = {fcag247}, pmid = {42404435}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a heterogeneous and rapidly progressing neurodegenerative disorder with limited treatment options. Therefore, there is a critical need for biomarkers that capture the diverse pathophysiological mechanisms underlying disease onset and progression. Emerging evidence suggests that synaptic dysfunction is an early disease mechanism in amyotrophic lateral sclerosis. Using homebrew immunoassays, we explored a panel of pre- and post-synaptic proteins in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (N = 57) and controls (N = 36). The potential value as a biomarker was explored by correlating cerebrospinal fluid levels with clinical parameters and established biomarkers for amyotrophic lateral sclerosis. Higher levels of Neurogranin (NRGN) (P = 0.003) and Vesicle-associated membrane protein 2 (VAMP2) (P = 0.014) were observed in patients with amyotrophic lateral sclerosis compared with controls. VAMP2, Synaptosome-associated protein 25 kDa (SNAP25) and β-synuclein (SNCB) correlated with individual relative disease stage, but none of the biomarkers correlated with disease progression rate. High levels of SNAP25 predicted worse survival in a univariate and stepwise multivariable analysis, but significance did not persist upon including Neurofilament light chain (NfL) levels. Synaptic proteins did not correlate with cerebrospinal fluid levels of neurofilaments or biomarkers of neuroinflammation, suggesting that they reflect different pathological mechanisms in amyotrophic lateral sclerosis. Our findings warrant further investigation to determine whether increased cerebrospinal fluid levels of synaptic proteins reflect synaptic breakdown or active release of synaptic proteins. This will help elucidate how synaptic dysfunction or damage contributes to elevated levels of synaptic markers in amyotrophic lateral sclerosis, and its underlying value as biomarker.}, } @article {pmid42414029, year = {2026}, author = {Hata, T and Ogawa, N and Yabata, H and Kobashi, S and Nakayama, M and Ishigaki, H and Yamakawa, I and Itoh, Y and Nishino, I and Urushitani, M}, title = {Case of concurrent ALS and human T-cell leukaemia virus type 1-associated myositis.}, journal = {BMJ case reports}, volume = {19}, number = {7}, pages = {}, pmid = {42414029}, issn = {1757-790X}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/pathology ; *Human T-lymphotropic virus 1 ; Aged ; Fatal Outcome ; *HTLV-I Infections/complications ; *Myositis/virology/complications/diagnosis ; Muscle, Skeletal/pathology ; Immunoglobulins, Intravenous/therapeutic use ; Magnetic Resonance Imaging ; }, abstract = {A woman in her late 70s presented with progressive limb weakness, muscle atrophy and hyper-reflexia. Laboratory findings revealed elevated creatine kinase and positive serum human T-cell leukaemia virus type 1 (HTLV-1) antibody. Clinical and electrophysiological findings met revised El Escorial criteria for amyotrophic lateral sclerosis (ALS), but muscle MRI showed inflammatory changes. Muscle biopsy revealed both neurogenic and inflammatory features. While methylprednisolone showed no benefit, intravenous immunoglobulin therapy produced transient improvement in weakness with normalisation of creatine kinase levels. The patient died from respiratory failure 3 years after symptom onset. Autopsy confirmed typical ALS-TDP pathology with phosphorylated TDP-43 inclusions in motor neurons. HTLV-1 Tax-positive lymphocytes infiltrated skeletal muscles but not the central nervous system, establishing dual pathology of ALS-TDP with HTLV-1-associated myositis. The improvement most likely reflected treatment of the HTLV-1-associated myositis rather than the underlying motor neuron disease. This case highlights the importance of evaluating treatable conditions in HTLV-1-seropositive ALS patients.}, } @article {pmid42414949, year = {2026}, author = {Njohjam, MN and Ngoule, MO and Niakam, TF}, title = {Biological sex differences in neurodegenerative diseases in Africa: a scoping review of evidence and research gaps.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-026-05123-w}, pmid = {42414949}, issn = {1471-2377}, abstract = {BACKGROUND: Biological sex is a well-established determinant of risk, progression, and therapeutic response in neurodegenerative diseases (NDs). However, current evidence on sex differences in NDs is from high-income Western populations. This review aims to map and synthesize evidence on biological sex differences in NDs in Africa, and to identify key research gaps.

METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute methodology and reported in accordance with the PRISMA-ScR guidelines. A literature search was conducted on PubMed, African Journals Online, Sabinet Journals, ScienceDirect, and Google Scholar. We included studies conducted in African countries that reported sex disaggregated data or examined biological sex differences in at least one ND. Data were synthesized descriptively.

RESULTS: All included studies reported sex distribution, but most (about 84%) did so only descriptively. Approximately 17% conducted sex-stratified analyses beyond prevalence. Similar to global epidemiological trends, several studies suggested a higher prevalence or odds of dementia and multiple sclerosis among females, while male predominance was observed in Parkinson's disease and Amyotrophic lateral sclerosis studies. An earlier onset and a higher mutation frequency in LRRK2-G2019S were reported in females with Parkinson's disease in some studies, while another study reported a higher mortality rate in females with dementia. No study evaluated sex specific biomarker profiles, disease progression, or treatment response.

CONCLUSIONS: Evidence on biological sex differences in NDs in Africa remains limited and is largely descriptive. Mechanistic, longitudinal, and biomarker-based investigations are largely absent.}, } @article {pmid42432671, year = {2026}, author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N}, title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.}, journal = {Journal of nanobiotechnology}, volume = {24}, number = {1}, pages = {}, pmid = {42432671}, issn = {1477-3155}, mesh = {*Drug Repositioning/methods ; Humans ; *Nervous System Diseases/drug therapy ; Animals ; *Artificial Intelligence ; Blood-Brain Barrier/metabolism ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.}, } @article {pmid42436372, year = {2026}, author = {Roy, T and Ramesh, M and Nizam, NAA and Tandiono, S and Al-Jamal, KT and Al-Chalabi, A and Iacoangeli, A and Al Khleifat, A}, title = {Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.}, journal = {BMC neuroscience}, volume = {27}, number = {1}, pages = {}, pmid = {42436372}, issn = {1471-2202}, support = {303476//National Institute for Health and Care Research/ ; MRC (MR/Z505705/1)//South London and Maudsley NHS Foundation Trust/ ; LS Association Milton Safenowitz Research Fellowship (RE19765)//NIHR Maudsley Biomedical Research Centre/ ; RE23378//LifeArc/ ; 1819242//Dementia Consortium/ ; 1122462/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/Z505705/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/virology ; *Exosomes/metabolism/virology ; *Endogenous Retroviruses/genetics ; Female ; Male ; Middle Aged ; Aged ; Biomarkers/blood ; Gene Products, env/blood ; }, abstract = {Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.}, } @article {pmid42447123, year = {2026}, author = {Wohnrade, C and Thau-Habermann, N and Gschwendtberger, T and Rückoldt, J and Huang, Z and Schreiber, S and Haastert-Talini, K and Petri, S}, title = {Neuromuscular ultrasound as a biomarker in the SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0353397}, pmid = {42447123}, issn = {1932-6203}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/genetics/physiopathology ; Mice ; *Superoxide Dismutase/genetics ; Disease Models, Animal ; Superoxide Dismutase-1 ; Biomarkers/metabolism ; Ultrasonography ; Mice, Transgenic ; Humans ; Sciatic Nerve/diagnostic imaging/pathology ; Muscle, Skeletal/diagnostic imaging/pathology ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {A progression marker that indicates early disease-related changes and treatment responses in the to date incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS) is highly desirable. Translation of therapeutics that have been successful in in vivo models into trials in human patients has proven difficult in recent decades. This failure can be attributed, at least in part, to the lack of specific biomarkers for ALS diagnosis and progression in human ALS patients as well as in in vivo models. Neuromuscular ultrasound is an easily accessible, non-invasive tool to support diagnosis of ALS in humans. Our current study shows for the first time that the disease can be detected in an ALS mouse model with the help of neuromuscular ultrasound. We characterized disease progression regarding changes in the peripheral nerves and muscles of the hind limb in the SOD1G93A mouse model of ALS using different techniques (neuromuscular ultrasound, electroneurography, motor function tests, phenotypic assessments and histology). By neuromuscular ultrasound, we measured the cross-sectional area and diameter of the sciatic nerve and analyzed hind limb muscle texture and thickness. Our results show that motor neuron loss and muscle atrophy - analogous to ALS in humans - can be measured by ultrasound in the SOD1G93A mouse model. Changes in nerve and muscle morphology appear at the same time or even before changes in the established tests (including electroneurographic measurements) performed in vivo in this model. Correlations with histologic features of disease progression make neuromuscular ultrasound a sensitive, non-invasive outcome marker for preclinical studies.}, } @article {pmid42451691, year = {2026}, author = {Singh, AA and Arukha, AP and Song, M}, title = {Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {13}, pages = {}, pmid = {42451691}, issn = {1420-3049}, mesh = {Humans ; *Antioxidants/pharmacology/chemistry ; *Indoles/chemistry/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Oxidation-Reduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.}, } @article {pmid42453524, year = {2026}, author = {Yang, HI and Hsueh, KW and Ding, DC and Harn, HJ and Lin, YC and Chang, CY and Tsai, ST and Lin, SZ}, title = {Therapeutic potential of adipose-derived stem cell transplantation in amyotrophic lateral sclerosis: A combined clinical case and preclinical study.}, journal = {Tzu chi medical journal}, volume = {38}, number = {3}, pages = {332-339}, pmid = {42453524}, issn = {2223-8956}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal neurodegenerative disease with no adequate treatment. Transplantation of adipose-derived stem cells (ADSCs) may be an effective therapeutic strategy for delaying progression or restoring neurological function in ALS.

MATERIALS AND METHODS: We evaluated the safety and therapeutic efficacy of intravenous (i.v.) and intracerebral (i.c.) ADSC injection in a late-stage ALS patient and in a SOD1 transgenic (Tg) mouse model. Magnetic resonance imaging (MRI) and computed tomography (CT) were conducted to examine potential cerebral hemorrhage and tumor generation in the treated patient. In addition, maximal inspiratory pressure, maximal expiratory pressure, tidal volume, and respiratory rate were measured as indices of respiratory function.

RESULTS: ADSC transplantation was safe, with MRI and CT showing no hemorrhage or tumorigenesis up to 12 months. The patient's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score improved from 7 to 9 at 3 months and remained above baseline for 6 months. Respiratory function was preserved during this period. In SOD1 Tg mice, i.c. and i.v. ADSC infusion significantly prolonged survival (165.0 ± 10.4 and 147.3 ± 4.5 days vs. 129.7 ± 3.9 days) and improved motor scores (P < 0.01).

CONCLUSION: This preliminary finding suggests potential therapeutic feasibility, but further studies with larger cohorts are needed to confirm its safety and efficacy.}, } @article {pmid42458007, year = {2026}, author = {Chen, W and Jiang, L and Duan, C and Kang, M and Ye, J and Wang, L and Pan, Y and Qu, H and Liao, X and Zhou, X and Li, Y and Gan, Z and Chen, J and Schacht, I and Place, RF and Li, LC and Wang, Y}, title = {Oligonucleotide-siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial.}, journal = {Nature medicine}, volume = {32}, number = {7}, pages = {2619-2628}, pmid = {42458007}, issn = {1546-170X}, support = {No.Z231100004823036//Beijing Municipal Science and Technology Commission/ ; 20230484245//Beijing Nova Program/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy/pathology ; Humans ; Animals ; *Superoxide Dismutase-1/genetics/cerebrospinal fluid ; Female ; Male ; *RNA, Small Interfering/administration & dosage/genetics/therapeutic use ; *Oligonucleotides/administration & dosage/therapeutic use/genetics ; Macaca fascicularis ; Middle Aged ; Aged ; Adult ; Motor Neurons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease partly caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Here we developed RAG-17, an siRNA-targeting SOD1, using an accessory oligonucleotide conjugate platform for enhanced central nervous system (CNS) delivery. Preclinically, RAG-17 rescued motor neuron degeneration, delayed disease progression, preserved motor function and extended survival in SOD1[G93A] ALS rodents, even with advanced-stage treatment. In cynomolgus monkeys, intrathecal RAG-17 led to dose-dependent, durable reductions in SOD1 mRNA (CNS) and protein (cerebrospinal fluid (CSF)). In a first-in-human trial in patients with SOD1-ALS (n = 6), participants were assigned to two cohorts-cohort 1 (n = 3) received an initial 60 mg dose (seven doses total) and cohort 2 (n = 3) received an initial 90 mg dose (six doses total). The dose was escalated in 30 mg steps to maintenance doses of 150 mg (n = 5) or 180 mg (n = 1). Thus, the primary safety endpoint was met, showing acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) occurred in 33% of participants (two of six). All TEAEs were mild to moderate, including muscle tremor (two patients) and elevated alanine aminotransferase (one patient), all of which resolved. No serious adverse events were reported. Furthermore, no other clinically meaningful changes were observed in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, physical or neurological examinations or ECG. The key secondary endpoints showed CSF SOD1 reductions of 69% (cohort 1, day 240) and 56% (cohort 2, day 210), and plasma neurofilament light chain reductions of 62% (cohort 1) and 52% (cohort 2), from baseline; no patient required invasive mechanical ventilation or died by the end of the study. These results demonstrate a favorable safety outcome, supporting the continued clinical evaluation of RAG-17 for SOD1-ALS. ClinicalTrials.gov registration: NCT05903690 .}, } @article {pmid42458512, year = {2026}, author = {Jo, M and Kim, S and Woo, J and Park, JS and Kim, SH and Nahm, M and Kim, SR and Lee, S and Kim, HJ}, title = {Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.}, journal = {Cell communication and signaling : CCS}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12964-026-03082-w}, pmid = {42458512}, issn = {1478-811X}, support = {RS-2024-00454715//National Research Foundation of Korea/ ; RS-2024-00343239//National Research Foundation of Korea/ ; 26-BR-02-03//Korea Brain Research Institute/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD.

METHODS: The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-κB) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS.

RESULTS: DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-κB-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE.

CONCLUSION: DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.}, } @article {pmid42459857, year = {2026}, author = {Hu, M and You, L and Zhang, X and Xuan, Z and Ma, S and Wu, X}, title = {Experimental evidence of electroacupuncture in ALS mouse models: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1780176}, pmid = {42459857}, issn = {1664-2295}, abstract = {OBJECTIVE: This study aimed to systematically evaluate the therapeutic efficacy of electroacupuncture (EA) in amyotrophic lateral sclerosis (ALS) and to elucidate the underlying neurobiological mechanisms by synthesizing preclinical evidence.

METHODS: According to the PICOS principle, relevant studies were searched in the following databases: PubMed, Web of Science, Embase, Cochrane Library, Scopus, and CNKI. Search terms and strategies were determined based on MeSH terms. The methodological quality of the included studies was assessed using the SYRCLE's Risk of Bias tool and the CAMARADES checklist. Meta-analysis was performed using Stata 15.0 and Rstudio software.

RESULTS: Seventeen studies involving 372 animals were included. The quality scores of the included studies ranged from 5 to 8, with an average score of 7. The meta-analysis of the primary outcome, the rotarod test score, showed a significant improvement in the EA group compared to the control group [SMD = 3.31, 95% CI (2.05, 4.57), Z = 5.151, p < 0.001], indicating that EA can enhance motor function in ALS mice. Regarding secondary outcomes, EA intervention alleviated neuroinflammation, promoted neuronal survival, improved axonal regeneration inhibition, and stabilized RNA metabolism homeostasis. Consequently, it slowed disease progression, improved motor performance, prolonged survival time, and effectively protected motor neurons at the histopathological level (p < 0.05). These findings underscore the potential of EA as a promising multimodal therapeutic strategy for ALS. For the heterogeneity observed in the rotarod test, sensitivity analysis, subgroup analysis, and meta-regression did not identify its source. However, potential publication bias was detected, which might contribute to the heterogeneity. The heterogeneity for other outcome measures might originate from differences in stimulation parameters (e.g., waveform), acupoint selection, or treatment duration.

CONCLUSION: This meta-analysis demonstrates that EA confers significant neuroprotective benefits in preclinical ALS models, primarily through multi-target modulation of key pathological processes such as neuroinflammation, aberrant cell death signaling, and RNA metabolism. These preclinical findings underscore the potential of electroacupuncture as a complementary neuroprotective strategy and warrant further investigation in rigorous clinical trials.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251229183.}, } @article {pmid42461162, year = {2026}, author = {Zhang, R and Zhang, N and Li, B and Liu, Q and Xu, C and Li, B and Zhang, J}, title = {Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.}, journal = {Nursing in critical care}, volume = {31}, number = {4}, pages = {e70573}, pmid = {42461162}, issn = {1478-5153}, support = {25ZZJJLW-015//Medical Research Council Foundation of the 305 Hospital of the PLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/complications ; *Epilepsy/nursing/complications ; Male ; Intensive Care Units ; *Critical Care Nursing/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34 days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.}, } @article {pmid42461445, year = {2026}, author = {Mitsumoto, H and Cheung, K and Matsumoto, T and Lanza, I and Oskarsson, B and Johnson, S and Petterson, XT and Jang, GE and Andrews, HF}, title = {Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {22}, number = {4}, pages = {}, pmid = {42461445}, issn = {1573-3890}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/blood ; *Muscle Cramp/drug therapy/metabolism/blood ; *Metabolomics/methods ; Female ; Male ; Middle Aged ; Aged ; Cross-Over Studies ; Medicine, Kampo ; *Drugs, Chinese Herbal/therapeutic use ; }, abstract = {INTRODUCTION: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS.

OBJECTIVES: This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68.

METHODS: Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68.

RESULTS: Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, β-aminoisobutyric acid, α-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68.

CONCLUSION: This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.}, } @article {pmid42465739, year = {2026}, author = {You, Y and Zhu, H and Zhang, Q and Wang, J and Dong, C and Yang, Z and Zhang, J and Zhang, Y and Zhang, M and Lu, M and Du, C}, title = {Development and efficacy of ex vivo expanded autologous regulatory T cells for the treatment of amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1854252}, pmid = {42465739}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology/genetics ; *T-Lymphocytes, Regulatory/immunology/transplantation/metabolism ; Animals ; Humans ; Mice ; Disease Models, Animal ; Female ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options, in which neuroinflammation critically drives disease progression. Regulatory T cells (Tregs) exert potent immunosuppressive and neuroprotective effects, offering great potential for ALS treatment. However, clinical application of Treg therapy is hampered by low peripheral cell abundance and unstable expansion quality. Here, we established and optimized a GMP-grade protocol for sorting and expanding peripheral blood-derived Tregs, and validated cryopreserved apheresis products as feasikble starting materials. Although ALS patient-derived Tregs showed reduced expansion capacity compared with healthy donor counterparts, they maintained comparable purity, stable regulatory phenotypes, and robust immunosuppressive function. Transcriptomic analysis confirmed the lineage fidelity and low pro-inflammatory characteristics of expanded Tregs. Therapeutic efficacy was verified in SOD1G93A ALS and GvHD mouse models with delayed disease progression and relieved inflammation. This study provides standardized GMP manufacturing strategies and solid preclinical evidence to support the ongoing clinical trial (NCT06671236) and facilitate Treg immunotherapy translation for ALS.}, } @article {pmid42467293, year = {2026}, author = {Hassan, MA and Al Amin, M and Sweilam, SH and Abohassan, M and Krishnan, K and Gupta, JK and Jahnavi, P and Vodeti, R and Radha, R and Gupta, PS and Reddy, KTK}, title = {Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.}, journal = {Inflammopharmacology}, volume = {34}, number = {8}, pages = {5093-5117}, pmid = {42467293}, issn = {1568-5608}, mesh = {*Resveratrol/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology ; *Signal Transduction/drug effects ; Oxidative Stress/drug effects ; *Neuroprotection/drug effects ; Neurons/drug effects/metabolism ; }, abstract = {Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.}, } @article {pmid42467750, year = {2026}, author = {Deressa, JD and Behaksra, SW and Molla, E and Letebo, A and Shumie, G and Adnew, B and Alemayehu, DH and Kassa, FA and Seyoum, T and Tafa, EB and Woldekidan, K and Ejigu, LA and Huwe, T and Keffale, M and Bayissa, GA and Koepfli, C and Chala, B and Asmamaw, Y and Tadesse, FG and Gadisa, E}, title = {Therapeutic efficacy of artemether-lumefantrine plus single low dose primaquine for the treatment of uncomplicated Plasmodium falciparum malaria in a high transmission setting, Western Ethiopia.}, journal = {PloS one}, volume = {21}, number = {7}, pages = {e0335833}, pmid = {42467750}, issn = {1932-6203}, mesh = {Humans ; *Primaquine/therapeutic use/administration & dosage ; *Artemether, Lumefantrine Drug Combination/therapeutic use/administration & dosage ; *Malaria, Falciparum/drug therapy/transmission/epidemiology/parasitology ; *Antimalarials/therapeutic use/administration & dosage ; Female ; Male ; Ethiopia/epidemiology ; Plasmodium falciparum/drug effects/genetics ; Child, Preschool ; Adolescent ; Treatment Outcome ; Child ; Adult ; Drug Therapy, Combination ; Young Adult ; }, abstract = {BACKGROUND: The development and spread of drug-resistant parasites continue to threaten progress toward malaria elimination. Therapeutic efficacy and molecular resistance marker studies are needed to guide national control programs. In African settings, evidence of partial resistance to artemisinin-based combination therapies (ACTs) associated with Pfkelch13 mutations is accumulating, and World Health Organization (WHO) recommends regular monitoring of first line antimalarial drugs for early detection of resistant parasites. In this study, we evaluated the efficacy of artemether-lumefantrine (AL) combined with a single low dose of primaquine (PQ) for treating uncomplicated Plasmodium falciparum malaria in a co-endemic area where P. falciparum predominates.

METHODS AND FINDINGS: One hundred twenty-three patients with P. falciparum mono-infection were enrolled between November 2020 to March 2021 and treated with artemether-lumefantrine (AL) plus a single low dose of primaquine (PQ) as per the national malaria treatment guideline and followed up for 28 days. Ethical approval was obtained from the AHRI/ALERT ethics committee (Po/23/19), and the study was registered at Pan-African clinical trials registry (PACTR) with unique identification number of PACTR202509595696440. Pfmsp2 capillary electrophoresis (CE) genotyping was used to differentiate recrudescence from new infections. More than half (56.1%) of the participants had high parasitemia (>10,000 parasites/μL) at enrollment. On day 3, 16.9% (20/118) remained parasitemic, and of the 10 individuals with detectable gametocytes at enrollment, only 3.4% remained gametocytemic on day 3, and 100% parasite clearance was observed on day 7, respectively. Multiplicity of infection was 3.8 at enrollment and 1.7 at the time of recurrence. The adequate clinical and parasitological responses at 28-day (ACPR) of per protocol analysis (PPA) was 73.7% for PCR-uncorrected and 91.3% for PCR-corrected, respectively and while, the intention-to-treat analysis (ITA), the Kaplan-Meier estimated treatment success at day 28 was 93.2% (95% CI: 88.5-98.2) after PCR correction, compared with 78.3% (95% CI: 71.0-86.4) in the PCR-uncorrected analysis. In our study assessment, no cases of severe malaria or serious adverse events occurred.

CONCLUSIONS: The efficacy observed in this study, although remaining above the WHO policy change threshold after PCR correction, may indicate a potential decline in AL's effectiveness in this high transmission setting. However, because antimalarial drug concentrations were not measured and evening doses were not fully directly observed, reduced drug exposure or imperfect adherence cannot be excluded as possible contributors to the observed treatment outcomes Therefore, we suggest regular therapeutic efficacy monitoring and further investigation using advanced molecular techniques, such as next-generation sequencing (NGS), to enable early detection of resistance-associated parasite variants that may compromise treatment efficacy.}, } @article {pmid42471754, year = {2026}, author = {Xia, CA and Salarian, M and Gartshore, CJ and Scaglione, A and Hayes, T and Liu, S and Tsai, HM and Echavarren, J and Cid, JM and Matzeu, A and Szardenings, AK}, title = {Development and characterization of a novel TDP-43 positron emission tomography tracer: [[18]F]JNJ-TDP43-1.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {7}, pages = {e71675}, pmid = {42471754}, issn = {1552-5279}, support = {//Johnson & Johnson/ ; }, mesh = {Animals ; *Positron-Emission Tomography/methods ; *DNA-Binding Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Rats ; Mice ; Humans ; Male ; Disease Models, Animal ; TDP-43 Proteinopathies/diagnostic imaging ; *Radiopharmaceuticals/pharmacokinetics ; Fluorine Radioisotopes ; }, abstract = {INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.

METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.

RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.

DISCUSSION: [[18]F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.}, } @article {pmid42473218, year = {2026}, author = {Keskin, A and Mogulkoc, R and Baltaci, AK}, title = {Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575484348260702044851}, pmid = {42473218}, issn = {1875-5607}, abstract = {The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).}, } @article {pmid42473814, year = {2026}, author = {Shao, D and Wen, X and Xu, X and Liu, X and Guo, B and Li, B and Wang, G and Liu, X and Men, S}, title = {Cyprosulfamide mitigates nicosulfuron phytotoxicity in maize through activation of GST-associated phase II detoxification involving ZmGST24.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71142}, pmid = {42473814}, issn = {1526-4998}, support = {32370271//National Natural Science Foundation of China/ ; 2026KJCXZX-LYS-14//HAAFS Agriculture Science and Technology Innovation Project/ ; 254Z6303G//Project of Central Guidance for Local Science and Technology Development Funds/ ; 23JCYBJC01180//Natural Science Foundation of Tianjin/ ; 24YFXTHZ00050//Key Research and Development Program of Tianjin/ ; }, abstract = {BACKGROUND: Nicosulfuron is an acetolactate synthase (ALS)-inhibiting herbicide widely used in maize production. However, under unfavorable environmental conditions, its phytotoxicity to maize remains a practical concern. Cyprosulfamide (CSA) is an effective safener for maize, yet the contribution of glutathione S-transferases (GST)-associated phase II detoxification to CSA-conferred protection against nicosulfuron injury remains poorly understood.

RESULTS: CSA markedly alleviated nicosulfuron-induced growth inhibition in maize seedlings and effectively reduced herbicide injury under field conditions. Inhibitor assays showed that both cytochrome P450-mediated phase I metabolism and GST-associated phase II detoxification contribute to maize tolerance to nicosulfuron. Proteomic analysis further revealed that, relative to nicosulfuron treatment alone, co-application of nicosulfuron and CSA significantly enriched the glutathione metabolism pathway in maize leaves. Among the induced GST candidate genes, ZmGST24 showed the strongest transcriptional response. Phylogenetic and conserved motif analyses supported its functional similarity to previously reported GSTs involved in herbicide detoxification. Molecular docking suggested favorable binding of ZmGST24 to nicosulfuron, and heterologous expression in yeast demonstrated that ZmGST24 not only enhanced tolerance to nicosulfuron, but also increased tolerance to several herbicides commonly used in maize fields.

CONCLUSION: These findings indicate that the protective effect of CSA against nicosulfuron phytotoxicity in maize is associated with activation of GST-associated phase II detoxification. The pronounced response of the glutathione metabolism pathway, together with the functional characterization of ZmGST24, identifies this gene as a promising candidate involved in CSA-induced herbicide tolerance and as a potential target for improving herbicide safety in maize. © 2026 Society of Chemical Industry.}, } @article {pmid42474734, year = {2026}, author = {Zheng, Y and Bhalala, OG and Chin, KS and Watson, R and Yassi, N}, title = {Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42474734}, issn = {1432-1459}, mesh = {Humans ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Biomarkers/blood ; *Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.

METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.

RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.

CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.}, } @article {pmid42484074, year = {2026}, author = {Carberry, N and Wuu, J and Benatar, M}, title = {SOD1-lowering therapy for patients with wildtype SOD1-ALS: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2026.2705142}, pmid = {42484074}, issn = {2167-9223}, abstract = {Background and Objectives: To describe clinical and biomarker experience using an SOD1 antisense oligonucleotide (ASO) in a patient with non-SOD1 amyotrophic lateral sclerosis (ALS). Methods: Case report. Results: In a 72-year-old male with non-SOD1 ALS, rapid decline on the ALS functional rating scale revised (ALSFRS-R) and a rise in serum neurofilament light chain (NfL) concentration were observed following 3 loading doses of an SOD1 ASO before the patient succumbed to disease. The time from symptom onset to death was 9 months. Discussion: While treatment was initiated relatively late (∼7 months) after symptom onset and follow-up duration was short, the observed increase (as opposed to a reduction) in serum NfL and accompanying rapid functional decline, suggest the lack of a therapeutic effect in someone with fast progressing non-SOD1 ALS.}, } @article {pmid42492371, year = {2026}, author = {Majumder, M and Borucki, DM and Chowdhury, N and Mallah, K and Tomlinson, S}, title = {Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00969}, pmid = {42492371}, issn = {1878-7479}, support = {S10 OD018113/OD/NIH HHS/United States ; P30 DK123704/DK/NIDDK NIH HHS/United States ; I01 BX004256/BX/BLRD VA/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P20 GM130457/GM/NIGMS NIH HHS/United States ; I21 BX005853/BX/BLRD VA/United States ; IK6 BX005235/BX/BLRD VA/United States ; I01 RX003958/RX/RRD VA/United States ; S10 OD028663/OD/NIH HHS/United States ; P20 GM148302/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; Mice ; Disease Models, Animal ; *Complement C3/antagonists & inhibitors/metabolism ; Mice, Transgenic ; *Complement C5/antagonists & inhibitors/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; *Nerve Degeneration/pathology/drug therapy/metabolism ; }, abstract = {Complement activation contributes to amyotrophic lateral sclerosis (ALS) neuropathology, but whether motor neuron degeneration is driven by proximal or terminal activation products remains unresolved. Failed trials of C5 inhibition - ravulizumab (CHAMPION-ALS) and zilucoplan (ATHLEET/HEALEY ALS Trial), and of systemic C3 inhibition (pegcetacoplan, MERIDIAN) underscore this mechanistic gap. We compared two pharmacologically distinct inhibitors in hSOD1[G93A] mice. CR2Crry blocks complement at C3 and localizes to sites of active deposition. BB5.1, functionally equivalent to ravulizumab, selectively blocks C5a generation and membrane attack complex (MAC) assembly. Treatment began at symptom onset and continued to humane endpoint. Both agents achieved robust target engagement across spinal cord, sciatic nerve, and neuromuscular junction (NMJ). Only CR2Crry extended survival, preserved motor function, and attenuated weight loss. CR2Crry reduced microglial activation and C3 opsonization in the ventral horn, diminished macrophage infiltration, preserved sciatic nerve axonal integrity, and maintained NMJ innervation. BB5.1 failed to modify any functional or neurodegenerative pathology despite confirmed MAC suppression. Proximal C3 activation products, not C5a or MAC, are the dominant drivers of complement-mediated neurodegeneration in the hSOD1[G93A] model of ALS. Site-targeted C3 inhibition may address the mechanistic limitation underlying recent clinical trial failures and represents a translationally justified therapeutic strategy.}, } @article {pmid42498658, year = {2026}, author = {Palm, A and Ekström, M and Einarsson, J and Ersson, K and Ingre, C and Kläppe, U and Lindberg, E and Ljunggren, M and Nygren, I and Sundh, J and Grote, L}, title = {Home mechanical ventilation for amyotrophic lateral sclerosis-a national study of survival and treatment trends across 27 years.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/annalsats/aaoag219}, pmid = {42498658}, issn = {2325-6621}, abstract = {RATIONALE: Home mechanical ventilation (HMV) improves survival in Amyotrophic lateral sclerosis (ALS) and may be provided non-invasively (NIV) or invasively (IV). While NIV is guideline-recommended, the role of IV remains controversial, and data on long-term outcomes and NIV-to-IV transitions are limited.

OBJECTIVES: To examine survival across HMV strategies in people with ALS (pwALS) in Sweden over 27 years, factors associated with IV initiation, temporal trends in IV use and survival, and regional variation in IV utilisation.

METHODS: A longitudinal cohort study of pwALS in the Swedish National Registry of Ventilatory Failure (Swedevox) 1996-2022, cross-linked with national registries. Factors associated with mortality and treatment patterns were assessed using multivariable regression models.

RESULTS: Among 1,360 pwALS, initial NIV was most common (92%), followed by IV (5%) and NIV-to-IV transitions (3%). Most IV initiations were non-elective (77% vs. 18% NIV, p < 0.001). NIV-to-IV transitions occurred mainly in metropolitan areas (OR 5.11; 95% CI 2.30-11.4). Median survival differed across observed treatment pathways (p < 0.001): 1.7 years with NIV, 4.9 years with IV, and 6.5 years with NIV-to-IV. Mortality was associated with higher age (aHR 1.33 per decade; 95% CI 1.26-1.41), female sex (aHR 1.15; 95% CI 1.02-1.29), and acute initiation (aHR 1.26; 95% CI 1.08-1.47). Longer time from diagnosis to NIV initiation was associated with reduced mortality risk (aHR 0.58 per year; 95% CI 0.55-0.62). Over time, patients initiated HMV at older age with better lung function and lower PaCO2 values among those with available measurements, whereas overall survival remained unchanged.

CONCLUSION: Patients receiving IV had longer observed survival, likely reflecting the benefits of a secured airway as well as patient selection and underlying disease trajectory. Most IV initiations were unplanned. Over three decades, HMV was initiated in older patients at an earlier stage of respiratory decline, but overall survival remained unchanged. IV use increased with marked regional variation.}, } @article {pmid42501325, year = {2026}, author = {Jia, Y and Cui, B and Liang, Y and Zhang, M and Wang, S and Wang, Y and Chen, H}, title = {Focal epilepsy expands the phenotype of FUS-associated amyotrophic lateral sclerosis.}, journal = {Epilepsia}, volume = {67}, number = {9}, pages = {e157-e162}, doi = {10.1002/epi.70409}, pmid = {42501325}, issn = {1528-1167}, support = {82401705//National Natural Science Foundation of China/ ; 82371461//National Natural Science Foundation of China/ ; 2022YFC2503802//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; *RNA-Binding Protein FUS/genetics ; Male ; Phenotype ; Adult ; *Epilepsies, Partial/genetics/complications/physiopathology/drug therapy ; Anticonvulsants/therapeutic use ; Electroencephalography ; Mutation ; }, abstract = {Epileptic seizures are an exceedingly rare manifestation in classic amyotrophic lateral sclerosis (ALS). Emerging case reports suggest a potential link between ALS associated with FUS gene mutations (FUS-ALS) and seizures, expanding the disease's phenotypic spectrum. A 25-year-old man presented with a 5-month history of rapidly progressive limb weakness, atrophy, and both upper and lower motor neuron signs, consistent with ALS. Notably, he developed two types of epileptic seizures during the disease course, including focal motor seizures and focal seizures evolving to bilateral tonic-clonic seizures. Electroencephalography revealed epileptiform discharges over the right frontotemporal region. Brain [18]F-fluorodeoxyglucose positron emission tomography-computed tomography showed focal hypometabolism in the right frontal cortex. Genetic testing identified a de novo pathogenic FUS variant (c.1574C>T, p.Pro525Leu). The patient was diagnosed with FUS-ALS with comorbid focal epilepsy. Treatment with levetiracetam partially controlled the seizures, but motor function continued to deteriorate. This case highlights focal epilepsy as a comorbid feature in FUS-ALS, broadening the recognized phenotypic spectrum. Genetic testing for FUS mutations should be considered in young-onset ALS patients presenting with seizures.}, } @article {pmid42503607, year = {2026}, author = {Sanghai, N and Kelley, R and Lao, Y and Madlangsakay, MIR and Paul, P and Llanes-Cuesta, MA and Wang, JF and Zahedi, RP and Kong, J and Tranmer, GK}, title = {Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e76432}, pmid = {42503607}, issn = {2198-3844}, support = {//Research Manitoba 2017 Health Research New Investigator Operating Grant/ ; //Natural Sciences and Engineering Research Council of Canada/ ; /CAPMC/CIHR/Canada ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered a highly complex, heterogeneous, fatal disease with a high unmet medical need that affects multiple pathophysiological pathways and has no known singular cause. Oxidative stress, however, is implicated as a central player in the progression of ALS and other neurodegenerative diseases. To date, only two FDA-approved drugs, Edaravone, an antioxidant, and Riluzole, an antiglutamatergic, have been widely used clinically, albeit with modest effects on the clinical course of ALS disease progression. Additionally, preclinical studies of both drugs in ALS mouse models have not shown any significant survival benefit, although some abatement in disease progression is observed and translated from preclinical animal models to clinical human studies.

METHODS: Using a trifunctional boron-based drug design strategy, we have synthesized a pyrazole small molecule called Borsantrazole (BSZ) and evaluated BSZ in cell-based experiments, acute and chronic toxicity models, and the SOD1-G37R ALS mouse model. We have also evaluated untargeted global proteomic and phosphoproteomic changes induced by BSZ.

RESULTS: Borsantrazole (a small molecule that can selectively target oxidative stress) with favorable CNS drug like properties (low ER values of 0.9 and 1.0 at 1 and 10 µm, respectively, suggesting lower Pgp efflux liability and the LogD at pH 7.4 was within the range of 1.2 to 3.1, suggesting BSZ is lipophilic at pH 7.4.) shows no signs of treatment associated toxicity (acute or chronic (120 days)), significantly increases survival (whole animals, 15.1 days (p = 0.0326); males, 16.5 days; females, 13.7 days), rescued weight loss (27.1% control, 18.3% BSZ, p < 0.0001), delays symptom onset (whole animals, 24.9 days (p = 0.0011); males, 23.3 days; females, 26.4 days), delays disease onset (whole animals, 25.5 days (p = 0.0001); males, 21.1 days; females, 29.8 days) and affects global proteomic changes in the SOD1-G37R mouse model of ALS. In total, 51 proteins were found to be significantly differentially expressed (p < 0.05), including Ca3, Gan, Cplx2, Lrp4, Sqstm1, and 29 phosphorylation sites were differentially expressed and considered statistically significant, including T317 and T72 for neurofilaments light and heavy chain, respectively.

CONCLUSIONS: Herein, we report that BSZ has demonstrated a favorable safety profile and compelling proof-of-concept efficacy in a ALS mouse model and has the potential to become a disease-modifying ALS therapeutic following further clinical development. Within a broader perspective of treatments for neurodegenerative diseases, BSZ offers a new paradigm for trifunctional small molecule targeting of oxidative stress that can mitigate neuronal deterioration and serve as a potential treatment.}, } @article {pmid42508294, year = {2026}, author = {Liu, X and Fu, W and Cui, X and Feng, Y and Wen, B and Shan, L and Xu, X and Yang, J and Zhang, J and He, L and Zang, Y and Zhao, S and Yao, X and Liu, Y and Ma, M and Du, B and Dang, J and Zou, Z and Feng, H and Lu, Z and Zhang, Y and Wu, Z and Shang, H and Yin, P and Fan, D}, title = {Huoling Shengji granule in amyotrophic lateral sclerosis: A multicenter, randomized, double-blind, riluzole-controlled trial.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e00953}, pmid = {42508294}, issn = {1878-7479}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Riluzole/therapeutic use ; Double-Blind Method ; *Drugs, Chinese Herbal/therapeutic use ; Female ; *Neuroprotective Agents/therapeutic use ; Male ; Middle Aged ; Treatment Outcome ; Aged ; Adult ; }, abstract = {Currently, no curative therapies exist for Amyotrophic Lateral Sclerosis (ALS). This study aimed to evaluate the efficacy and safety of Huoling Shengji granules (HLSJ), a traditional Chinese medicine (TCM), compared to the standard treatment riluzole. A multicenter, randomized, double-blind, double-dummy, active-controlled Phase II clinical trial was conducted across 11 centers in China. A total of 140 ALS patients were randomly assigned (1:1) to receive either HLSJ or riluzole for 48 weeks. The primary endpoint, analyzed in the full analysis set (FAS), was the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from baseline to Week 48. Safety profiles were comparable between groups, with no significant difference in adverse events (80.28% vs. 80.56%, P = 0.9671). Analysis using the pre-specified Last Observation Carried Forward (LOCF) method showed a numerical advantage for HLSJ (1.07 points) but lacked statistical superiority. However, a more scientific analysis using the Mixed Model for Repeated Measures (MMRM), recommended for progressive diseases, indicated that HLSJ was significantly superior to riluzole in slowing ALSFRS-R score decline (Least Squares Mean Difference [LSMD]: 2.29 points; 95% confidence interval [CI]: 0.52 to 4.06; P = 0.0114). While the LOCF model showed no statistical difference, the MMRM analysis confirmed that HLSJ demonstrated significant efficacy superior to riluzole with a favorable safety profile. These findings provide a critical basis for conducting pivotal Phase III confirmatory trials of HLSJ for ALS treatment.}, } @article {pmid42510722, year = {2026}, author = {Avitabile, A and Rusciano, D and Amato, R and Cannizzaro, L and Gagliano, C}, title = {Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.}, journal = {Biology}, volume = {15}, number = {14}, pages = {}, pmid = {42510722}, issn = {2079-7737}, abstract = {Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.}, } @article {pmid42512450, year = {2026}, author = {Yogi, S and Singh, A}, title = {Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.}, journal = {Brain sciences}, volume = {16}, number = {7}, pages = {}, pmid = {42512450}, issn = {2076-3425}, support = {R01 EY032959/EY/NEI NIH HHS/United States ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.}, } @article {pmid42514481, year = {2026}, author = {Xie, P and Wang, J and Tong, B and Di, C and Zhou, F and Wang, W}, title = {Genome-Wide Characterization of the HaALS Gene Family Reveals Its Potential Roles in Imazethapyr Tolerance in Sunflower (Helianthus annuus L.).}, journal = {Plants (Basel, Switzerland)}, volume = {15}, number = {14}, pages = {}, pmid = {42514481}, issn = {2223-7747}, support = {CARS-14-1-06//Project of China Agriculture Research System/ ; CX25JC27//Heilongjiang Agricultural Science and Technology Innovation Leap Project/ ; }, abstract = {Acetolactate synthase (ALS; EC 2.2.1.6) catalyzes the first committed step in branched-chain amino acid (BCAA) biosynthesis and is the molecular target of multiple herbicide classes, including the imidazolinones. Here, we performed a genome-wide characterization of the HaALS gene family in sunflower (Helianthus annuus L.) and investigated genotype-dependent transcriptional responses to imazethapyr. A total of 11 HaALS genes were identified and classified into three phylogenetic clades (Groups A-C). All HaALS proteins contained the conserved TPP_enzyme domains (TPP_enzyme_N, TPP_enzyme_M, and TPP_enzyme_C), and purifying selection (Ka/Ks < 1) indicated strong evolutionary constraint on their core enzymatic function. Promoter analyses revealed abundant cis-regulatory elements associated with diverse stress and signaling inputs, supporting regulatory potential for herbicide-triggered transcriptional modulation. qRT-PCR analysis following imazethapyr application (0, 24, and 48 h) showed pronounced genotype-dependent expression reprogramming between the susceptible (S) and resistant (R) cultivars. In the R genotype, multiple HaALS members were strongly induced after treatment; specifically, HaALS4 reached a ~6-fold increase at 24 h and a >10-fold increase at 48 h, and HaALS11 increased to ~6-7-fold at 24 h while remaining above the baseline at 48 h; several additional paralogs exhibited intermediate induction (~3-8-fold by 48 h). In contrast, the S genotype showed limited changes (typically ~0.8-2-fold). Collectively, these findings define the evolutionary features of the sunflower HaALS family and identify herbicide-responsive paralogs that may contribute to imidazolinone tolerance, providing candidates for functional validation and molecular breeding.}, } @article {pmid42514807, year = {2026}, author = {Cazacu, G and Pamfil, D and Chirilă, O and Totolin, M and Ciolacu, D and Ghilan, A and Niţă, L and Niţă, T and Vasile, C}, title = {Chemical Treatment of Some Lignosulfonates Under DBD Plasma Conditions-II: Characterization of the Modified Lignosulfonates Microparticles.}, journal = {Polymers}, volume = {18}, number = {14}, pages = {}, pmid = {42514807}, issn = {2073-4360}, abstract = {The chemically modified ammonium lignosulfonate (ALS) powders with carboxylic acids such as, oleic (OA) and lactic acid (LA) and γ-butyrolactone (BL) under dielectric barrier plasma discharge (DBD) have been characterized by average molecular weight and particle size determinations, morphology examination by optical and electronic microscopy (SEM), the study of the thermal properties by thermogravimetry (TG/DTG), differential scanning calorimetry (DSC), differential thermal analysis (DTA) and antioxidant activity tests by DPPH method. The thermal characterization of the modified lignosulfonates reveals their improved thermal stability comparatively with ALS. It has been established that the obtained microparticles are aggregates of particles, covered by modified polymer and exhibit a particular behavior depending on the chemical structure of the used modifier, leading to multifunctional active lignin-based products with better homogeneity. By surface modification, the antioxidant capacity of modified lignosulfonate powders has been maintained.}, } @article {pmid42521811, year = {2026}, author = {Willemse, SW and Demaegd, KC and Koole, W and van Eijk, RPA and van Rheenen, W and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {42521811}, issn = {1476-5438}, support = {09150161810018//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; V0000319//ZonMw (Netherlands Organisation for Health Research and Development)/ ; }, abstract = {The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.}, } @article {pmid42523591, year = {2026}, author = {Balanis, T and Doulberis, M and Tutuian, R}, title = {EUS-guided transmural treatment of afferent loop syndrome: a systematic review and meta-analysis.}, journal = {Frontiers in gastroenterology (Lausanne, Switzerland)}, volume = {5}, number = {}, pages = {1853386}, pmid = {42523591}, issn = {2813-1169}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is an uncommon but clinically relevant complication after pancreaticobiliary or upper gastrointestinal reconstruction, most often in patients with recurrent malignant disease. Endoscopic ultrasound-guided creation of a transmural bypass, either as gastroenterostomy or enteroenterostomy, has emerged as a minimally invasive alternative to surgery or percutaneous drainage. We aimed to systematically review the available evidence and provide a pooled descriptive analysis of the efficacy and safety of EUS-guided treatment for ALS.

METHODS: A systematic review was performed in accordance with PRISMA principles. PubMed/MEDLINE, Embase and the Cochrane Library were searched up to 15 May 2025 for studies reporting EUS-guided gastroenterostomy or enteroenterostomy for ALS. Case reports, case series and observational studies with extractable outcome data were eligible. Data on study design, indication, stent type, technical success, clinical success, adverse events and follow-up were extracted and synthesized.

RESULTS: Twelve studies involving 134 patients were included. On crude analysis, technical success was achieved in 132/134 patients (98.5%), clinical success in 127/134 (94.8%), and adverse events were reported in 13/134 (9.7%). In the pooled random-effects analysis, the technical success rate was 93.5% (95% CI 87.1-96.8; I²=0%), the clinical success rate was 91.0% (95% CI 84.5-94.9; I²=0%), and the overall adverse-event rate was 14.6% (95% CI 9.1-22.5; I²=0%). Adverse events were mainly procedure-related pain, fever, stent misdeployment, peritonitis or intra-abdominal infection. Electrocautery-enhanced lumen-apposing metal stents were used in most studies, whereas fully covered self-expandable metal stents were used in a smaller subset. Reported follow-up ranged from 1 to 15 months.

CONCLUSIONS: EUS-guided transmural bypass represents a promising, minimally invasive, and technically feasible alternative for the management of ALS. However, given the retrospective nature and small sample sizes of the available evidence, larger comparative trials are warranted to define its definitive role.}, } @article {pmid42529685, year = {2026}, author = {Cheung, N}, title = {Cellular Logistics and Synaptic Vesicle Vulnerability in Major Depressive Disorder and Amyotrophic Lateral Sclerosis Comorbidity: Insights From Nicotinamide Mononucleotide Rescue and Transcriptome-Wide Association Study Integration.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e113549}, pmid = {42529685}, issn = {2168-8184}, abstract = {BACKGROUND: Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are usually treated as unrelated, yet depressive symptoms occur in a substantial minority of people with ALS and may appear early. These symptoms are heterogeneous and may reflect syndromal MDD, psychological and functional burden, fatigue, apathy, pseudobulbar affect, frontotemporal involvement, sleep or respiratory disturbance, medication effects, or shared affective vulnerability. A proposed pruning-continuum model suggests both disorders may share vulnerability in microglia-mediated synaptic pruning, with ALS amplified by autophagy and protein-quality-control failure and MDD by RNA-processing, stress, and immune dysregulation. We performed an exploratory secondary transcriptome-wide association study (TWAS)/pathway-integration analysis to test whether predefined nicotinamide mononucleotide (NMN)-nominated pathways map onto this vulnerability.

METHODS: We integrated precomputed S-PrediXcan outputs for MDD and ALS across available brain-relevant tissues. Ten Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predefined from a prior re-analysis of NMN-associated transcriptional programs in aged mouse metabolic tissues. Mouse-derived candidates were represented by human ortholog symbols before the human TWAS screen. The analysis tested nominated pathways rather than the 35-gene NMN-robust list as a standalone set. Cross-tissue screening used Stouffer Z aggregation, tissue-level Wilcoxon testing, competitive permutation testing, percentile bootstrap intervals, pairwise disease statistics, Levene variance tests, concordance measures, and leave-one-out sensitivity analysis. No analysis was treated as confirmatory or evidence of causal mediation.

RESULTS: MDD showed the strongest Stouffer-based exploratory signal in the synaptic vesicle cycle pathway, with a meta-across-tissue Stouffer Z of 3.41 and a wide bootstrap 95% confidence interval of -0.46 to 7.40. This signal did not survive competitive permutation testing (p = 0.1222) or Wilcoxon testing (p = 0.1926). The strongest tissue-level result occurred in the amygdala (Z = 4.057; nominal Wilcoxon p = 0.0093), although tissue-level permutation testing was not performed in the multi-gene-set run. ALS showed no significant meta-across-tissue enrichment among the 10 nominated pathways but displayed candidate gene-level signals in autophagy, endosomal, and vesicle-related genes, including TBK1 and C9orf72. Exploratory Levene tests indicated variance heterogeneity in the regulation of the actin cytoskeleton, endocytosis, and neuroactive ligand-receptor interaction; the actin cytoskeleton and endocytosis remained significant in pooled global false discovery rate (FDR) analysis. Fourteen genes were influential in at least two focus pathways, including EGF, KNG1, FGF8, RAC1, PAK1, PAK2, RAF1, MAPK1, and FGFR1.

CONCLUSIONS: These findings are hypothesis-generating. MDD and ALS may stress overlapping cellular logistics processes while engaging largely different genes. MDD showed the strongest exploratory pathway-level signal in synaptic vesicle biology, whereas ALS showed candidate gene-level coherence in autophagy and endosomal processes without significant meta-pathway enrichment. NMN/NAD+ repletion is not established as a treatment for MDD, ALS, or their comorbidity. These findings generate hypotheses about NAD+-linked cellular stress pathways for future preclinical and clinical studies.}, } @article {pmid42533344, year = {2026}, author = {Bublitz, SK and Becker, B and Demleitner, AF and Dietz-Laukemann, P and Lingor, P and Littger, B and Lorenzl, S and Feddersen, B}, title = {Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.}, journal = {Neurological research and practice}, volume = {8}, number = {1}, pages = {}, pmid = {42533344}, issn = {2524-3489}, abstract = {INTRODUCTION: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP).

METHODS: We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges.

RESULTS: Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences.

IMPLICATIONS: Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making.}, } @article {pmid42539252, year = {2026}, author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, E and Asher, MJ and Isaacs, A and Garner, AL and Todd, PK}, title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42539252}, issn = {2692-8205}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; F31 NS113513/NS/NINDS NIH HHS/United States ; R35 GM153185/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; }, abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks global cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global increase in start codon stringency in neurons as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with a cytoplasmic redistribution of eIF1 in neurons and is reversed with neuronal overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and selectively enhances cap-dependent RAN translation. Taken together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis and neuronal translational regulation.}, } @article {pmid42541567, year = {2026}, author = {Estevez-Fraga, C and Alvarez-Velasco, R and Afroz, T and Costa, MR and Jovičić, A and Yeh, FL and McColgan, P and Malaspina, A and McCampbell, A}, title = {Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {273}, number = {8}, pages = {}, pmid = {42541567}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by motor neuron degeneration leading to early mortality. Despite advances in understanding genetic and molecular contributors, effective disease-modifying therapies for sporadic ALS are of limited utility. The identification of the accumulation of TAR DNA-binding protein 43 (TDP-43) in 97% of total ALS cases represents a critical pathogenic hallmark. This review examines key biological mechanisms underlying TDP-43 pathology, emerging therapeutic strategies, and evolving approaches to clinical trial design and biomarker development. TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction. Therapeutic strategies targeting these pathways are currently under investigation. Additional approaches aim to ameliorate TDP-43 gain-of-function through cytoplasmic TDP-43 aggregation or modulating processes such as stress responses and RNA metabolism, although clinical translation has been challenging. Advances in biomarkers, including neurofilament light chain and cryptic exon-derived peptides, provide tools for developing efficient clinical trials. However, heterogeneity in disease progression and limitations of available clinical endpoints complicate trial design. Integration of biological insights with biomarker-driven patient stratification and optimized trial methodologies is essential to improve clinical trial outcomes. Emerging biomarkers may enable earlier diagnosis, monitoring of therapeutic response, and personalized treatment approaches. Continued alignment of biological discovery with innovative clinical trial design holds promise for advancing effective therapies and transforming the future of ALS.}, } @article {pmid42546549, year = {2026}, author = {Silvagi, R and Rodriguez-Fohn, E and Reece, RJ and Cranford, JA and Alangaden, K and Byrd, M and Klausner, H and Pravin, R and Li, J and Conn, C and Dunne, R and O'Neil, BJ}, title = {Advanced vs basic life support outcomes in treatment of out-of-hospital-cardiac-arrest: A registry-based cohort study.}, journal = {The American journal of emergency medicine}, volume = {109}, number = {}, pages = {263-267}, doi = {10.1016/j.ajem.2026.07.021}, pmid = {42546549}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Registries ; Retrospective Studies ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; Aged ; *Advanced Cardiac Life Support ; Emergency Medical Services ; Treatment Outcome ; Michigan ; Return of Spontaneous Circulation ; }, abstract = {IMPORTANCE: The absolute effect on outcomes with Advanced, (ALS) as compared to Basic Life Support, (BLS) care in Out of Hospital Cardiac Arrest, (OHCA) remains unclear.

OBJECTIVE: To assess the association of ALS compared to BLS alone prehospital care on return of spontaneous circulation, (ROSC), survival to hospital discharge, and neurological outcome in OHCA in Detroit, MI.

METHODS: Retrospective analysis of 6746 patients from the Cardiac Arrest Registry to Enhance Survival database from January 2016 to December 2021 who had non-traumatic OHCA and received cardiopulmonary resuscitation. Cohorts were grouped by ALS v BLS care then initial rhythm and then compared by chi-squared, multivariable logistic, and multinomial regression analysis for outcomes of sustained ROSC, survival to hospital discharge and favorable neurological outcome at hospital discharge. The BLS cohort is defined by units that provided manual CPR, automated rhythm and defibrillation, airway management, but no endotracheal intubation or parenteral medications. ALS care was defined as manual rhythm interpretation, manual defibrillation, intravenous or intraosseous drug administration or endotracheal intubation.

RESULTS: Mean age was 62.6 years (SD-16.7), with 56.3% male and 84.6% Black. Cohort breakdown: shockable ALS (S-ALS; n = 330, 4.9%); shockable BLS (S-BLS; n = 466, 6.9%); non-shockable ALS (NS-ALS; n = 2793, 41.4%); non-shockable BLS (NS-BLS; n = 3157, 46.8%). ROSC rates by cohort: S-ALS (37.9%); S-BLS (19.5%); NS-ALS (18.6%); NS-BLS (9.3%). ALS was associated with increased sustained ROSC for all initial rhythms (p < .001). S-ALS was associated with increased survival (p = .03), and neurologic outcome (p = .01) when compared to S-BLS.

CONCLUSION & RELEVANCE: Advanced Life Support, relative to Basic Life Support alone, was associated with improved sustained return of spontaneous circulation across all initial rhythms, and improved survival to discharge and favorable neurologic outcome in shockable initial rhythms.}, } @article {pmid42548517, year = {2024}, author = {Palm, A and Grote, L and Einarsson, J and Hansson, D and Ljunggren, M and Sundh, J and Ekström, M}, title = {Evolution of Home Mechanical Ventilation in Sweden Over 27 Years: Changing Trends in Incidence, Prevalence, and Patient Characteristics - The Population-Based the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) Study.}, journal = {CHEST pulmonary}, volume = {2}, number = {4}, pages = {100108}, pmid = {42548517}, issn = {2949-7892}, abstract = {BACKGROUND: Home mechanical ventilation (HMV), noninvasive ventilation and invasive ventilation outside a hospital setting, is a key treatment to improve outcomes in chronic hypoventilation.

RESEARCH QUESTION: What are the temporal trends observed over 27 years in Sweden regarding the incidence, prevalence, diagnostic spectrum, and patient characteristics associated with HMV?

STUDY DESIGN AND METHODS: This was a national population-based longitudinal analysis of the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) study of patients initiating HMV between 1996 and 2022. Time trends stratified by the underlying diagnosis group (lung disease, predominantly COPD, restrictive thoracal diseases, obesity hypoventilation syndrome [OHS], neuromuscular diseases, amyotrophic lateral sclerosis, and other neurologic disorders) were analyzed using linear regression models.

RESULTS: We included 10,555 patients aged ≥ 16 years (mean age 63 [SD, 15] years; 50% women). Between 1996 and 1998 and 2020 and 2022, the HMV incidence increased threefold to 7 per 100,000 people, and the prevalence increased sixfold to 33 per 100,000 people. The most common indication for incident HMV shifted from restrictive thoracal diseases (35% in 1996-1998 to 3% in 2020-2022) to lung disease (14% to 31%), OHS (23% to 33%), and amyotrophic lateral sclerosis (4% to 14%) by 2020 to 2022 (P < .001). The proportion of women increased from 47% to 54% (P < .013) and the age at initiation of HMV increased from 58 [SD, 15] to 66 [SD, 14] years (P < .001). Lung function measured as vital capacity at treatment start increased significantly in all diagnosis groups except for OHS, where both vital capacity and FEV1 decreased. In the registry's first and last 3-year periods, the proportion of patients ventilated invasively decreased from 10% to 2% (P < .001).

INTERPRETATION: In the 27 years until 2022, the incidence and prevalence of HMV in Sweden have increased markedly, patient demographics have changed, and use of invasive ventilation has decreased. The average age of patients initiated on HMV has increased, but treatment is started earlier in the disease trajectory.}, } @article {pmid42548788, year = {2026}, author = {Erazo, D and Hesters, A and Bruneteau, G and De La Cruz, E and Bernard, E and Grapperon, AM and Le Masson, G and Cintas, P and Soriani, MH and Guy, N and Cassereau, J and Camdessanché, JP and Genestet, S and Corcia, P and Pittion, S and Danel, V and Filliatre, M and Choumert, A and Jacquin-Piques, A and Salachas, F and Esselin, F and Bohic, A and Lautrette, G and Attarian, S and Catteau, J and Guissart, C and Vincent, MC and Mouzat, K and Temple, M and Vourc'h, P and Couratier, P}, title = {Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {10}, number = {5}, pages = {100739}, pmid = {42548788}, issn = {2542-4548}, abstract = {OBJECTIVE: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort.

PATIENTS AND METHODS: Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline.

RESULTS: In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03).

CONCLUSION: Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.}, } @article {pmid42552039, year = {2026}, author = {Venu, G and A, VP and Justin, A}, title = {Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {International review of neurobiology}, volume = {188}, number = {}, pages = {113-143}, doi = {10.1016/bs.irn.2026.05.014}, pmid = {42552039}, issn = {2162-5514}, mesh = {Humans ; *PPAR gamma/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Signal Transduction/physiology ; Animals ; *Huntington Disease/metabolism ; }, abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.}, } @article {pmid42553297, year = {2026}, author = {Li, Q and You, M}, title = {Targeting mitochondria for the treatment of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {20}, number = {}, pages = {1835506}, pmid = {42553297}, issn = {1662-4548}, support = {R01 CA205633/CA/NCI NIH HHS/United States ; R01 CA223804/CA/NCI NIH HHS/United States ; R01 CA232433/CA/NCI NIH HHS/United States ; R01 CA280746/CA/NCI NIH HHS/United States ; }, abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.}, } @article {pmid42554695, year = {2026}, author = {Krajewski, TJ and Koch, GG}, title = {Randomization-based covariance analysis for hypothesis testing of treatment comparisons based on restricted mean survival time with categorized time-to-event data.}, journal = {Journal of biopharmaceutical statistics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/10543406.2026.2699854}, pmid = {42554695}, issn = {1520-5711}, abstract = {This paper introduces randomization-based analysis of covariance (RB-ANCOVA) for hypothesis testing of restricted mean survival time (RMST) differences between two randomized treatments in trials with categorized time-to-event data. RMST treatment differences over a prespecified time period are clinically meaningful and avoid assumptions like proportional hazards. The proposed method tests the strong null hypothesis that each participant's time-to-event would remain unchanged regardless of treatment assignment. Covariate adjustment is achieved by constraining baseline covariate means to be equal across arms, which reduces variance. The follow-up period is partitioned into mutually exclusive intervals, and RMST is approximated as the area under the survival curve. Under the strong null hypothesis, the joint asymptotic covariance structure of RMST and covariate means is known and used to construct a chi-squared test statistic for the covariate-adjusted RMST difference. The method accommodates stratified trial designs and supports hypothesis testing over single or several time intervals, enabling testing within internal intervals. The difference in RMSTs over an interval can be divided by its length to yield an average survival rate difference. Additionally, the approach allows the computation of essentially exact p-values via re-randomization. We illustrate the method with data from a randomized, placebo-controlled trial evaluating a test treatment for amyotrophic lateral sclerosis. This method provides a hypothesis testing approach for RMST treatment differences that leverages RB-ANCOVA to adjust for their correlations with baseline covariate differences. Under the strong null hypothesis, it enables hypothesis testing with clear control of Type I error and reduced variance without relying on model-based assumptions.}, } @article {pmid42556956, year = {2026}, author = {Rahman, U and Yang, SC}, title = {Management of Anastomotic Leaks: Endoscopic, Interventional, and Surgical Strategies.}, journal = {Advances in surgery}, volume = {60}, number = {1}, pages = {259-270}, doi = {10.1016/j.yasu.2026.03.017}, pmid = {42556956}, issn = {1878-0555}, mesh = {Humans ; *Anastomotic Leak/therapy/surgery/etiology ; }, abstract = {Anastomotic leaks (ALs) are a significant source of morbidity and mortality. Every step should be implemented to prevent AL, including careful patient selection, optimizing patient's clinical and nutritional status, and ensuring proper technique. The appropriate management of an AL depends on several factors, such as patient's clinical status, the type of surgery, location of the AL, induction therapies, and the resources available. Surgeons should be familiar with the armamentarium of treatment modalities available to manage AL and use a patient-tailored approach when selecting the most appropriate treatment.}, } @article {pmid42558984, year = {2026}, author = {Pourasghari, M and Babaie, S and Markazi-Movaghar, R and Salehpour, S and Eftekharsadat, B and Farshbaf-Khalili, A}, title = {The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Stem cells international}, volume = {2026}, number = {}, pages = {4122493}, pmid = {42558984}, issn = {1687-966X}, abstract = {BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products.

METHODS: The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I [2] statistics, and subgroup analyses were conducted based on treatment duration and dosing.

RESULTS: A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 10[6] and <10 × 10[6] dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups.

CONCLUSION: Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.}, } @article {pmid42561511, year = {2026}, author = {Al Ojaimi, Y and Dupuis, A and Palla, M and Lanznaster, D and Hergesheimer, R and Galineau, L and Serriere, S and Chami, AA and Martineau, P and Alouane, T and Marouillat, S and Dupuy, C and Schneider, BL and Veyrat-Durebex, C and Masse, F and Trovero, F and Andres, CR and Corcia, P and Vourcʼh, P and Blasco, H}, title = {Intrabody B1 targeting TDP-43 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01032}, pmid = {42561511}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *DNA-Binding Proteins/metabolism/antagonists & inhibitors/immunology/genetics ; Mice, Transgenic ; Mice ; Humans ; Disease Models, Animal ; *Single-Chain Antibodies/administration & dosage ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Metabolic Networks and Pathways/drug effects/physiology ; Motor Neurons/metabolism/drug effects ; }, abstract = {TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS), yet no therapeutic strategy effectively targets its upstream molecular consequences. Here, we investigated whether the anti-TDP-43 intrabody scFv B1 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model, and whether these effects translate into functional benefit after symptom onset. Using phage display, we previously identified single-chain variable fragments (scFvs) binding TDP-43, including the candidate therapeutic scFv B1. In NSC-34 motor neuron-like cells overexpressing human wildtype TDP-43, B1 reduced NF-κB activation, consistent with disruption of TDP-43-driven inflammatory signaling. For in vivo assessment, B1 was delivered via AAV-CAP.B10 after symptom onset in the hTDP-43(WTxA315T) transgenic mouse model, enabling neuro-specific expression. Two cohorts were analyzed - longitudinal (nine months) and terminal (six months post-treatment) - through behavioral testing, PET imaging, metabolomics, transcriptomics, and plasma biomarker analyses. B1 achieved robust CNS expression and modulated several disease-relevant molecular pathways. RNA-sequencing revealed attenuation of NF-κB-related inflammatory signatures and partial normalization of metabolic and trophic gene expression. Metabolomic profiling identified shifts toward wild-type-like levels in oxidative stress, mitochondrial, and membrane phospholipid metabolites. Despite these molecular effects, symptomatic B1 administration did not improve motor behavior or reduce plasma neurofilament light chain (NfL) concentrations. Notably, plasma TDP-43 levels were stabilized, indicating systemic target engagement. Collectively, scFv B1 modulates upstream pathogenic processes associated with TDP-43 proteinopathy but is insufficient to reverse established neurodegeneration after symptom onset, underscoring the need for earlier and likely combinatorial intervention strategies in ALS.}, } @article {pmid42561943, year = {2026}, author = {Rostalski, H and Hietanen, T and Hoffmann, D and Heikkinen, S and Huber, N and Dhingra, A and Rodriguez-Nieto, S and Kuulasmaa, T and Ohtonen, S and Jäntti, H and Pekkala, V and Leskelä, S and Mäkinen, P and Katisko, K and Hartikainen, P and Lehtonen, Š and Solje, E and Koistinaho, J and Malm, T and Portaankorva, AM and Natunen, T and Martiskainen, H and Takalo, M and Hiltunen, M and Haapasalo, A}, title = {C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.}, journal = {Stem cell reports}, volume = {21}, number = {9}, pages = {103026}, pmid = {42561943}, issn = {2213-6711}, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Phagocytosis/genetics ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Microglia/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Female ; Male ; Amyotrophic Lateral Sclerosis/genetics ; Gene Expression Regulation ; }, abstract = {C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.}, } @article {pmid42561977, year = {2026}, author = {Helmold, B and Armon, C and Benatar, M and Bertorini, T and Bromberg, M and Brown, A and Cadavid, JM and Carbunar, O and Carter, GT and Crayle, J and Feldman, E and Foucher, J and Glass, J and Greenstein, E and Jhooty, S and Jiang, N and Kochen, NN and McDermott, C and Olby, N and Pattee, G and Porter, D and Premasari, A and Rao, A and Ratner, D and Staats, K and Tito, E and Vieira, F and Wicks, P and Bedlack, R}, title = {ALSUntangled #84 - ivermectin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2026.2714724}, pmid = {42561977}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.}, } @article {pmid42562776, year = {2026}, author = {Wan, Y and Gao, C and Li, J and Luan, M and Lu, Y and Wang, J and Yang, B and Zheng, J and Yuan, Y and Wei, J and Wang, Z and Deng, J}, title = {Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlag013}, pmid = {42562776}, issn = {1554-6578}, support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we found that repeated administration of neural stem cell-derived extracellular vesicles (NSC-derived EVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model of ALS. Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.}, } @article {pmid42575772, year = {2026}, author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT}, title = {Voice Disorders as Early Biomarkers of Cognitive Decline.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2026.07.037}, pmid = {42575772}, issn = {1873-4588}, abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.

RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).

CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.}, } @article {pmid42576069, year = {2026}, author = {Saleem, M and Khan, MS and Syed Khaja, AS and Alraey, Y and Ahmad, I and Almuzaini, Y and AlShammari, A and Alshamamri, YM and Alharbi, T}, title = {Prevalence, antifungal susceptibility, and virulence determinants of Candida species causing vulvovaginal candidiasis in pregnant women in Saudi Arabia.}, journal = {Antonie van Leeuwenhoek}, volume = {119}, number = {9}, pages = {}, pmid = {42576069}, issn = {1572-9699}, support = {RGP.01/146/46//the Deanship of Research and Graduate Studies at King Khalid University/ ; }, mesh = {Humans ; Female ; *Candidiasis, Vulvovaginal/epidemiology/microbiology/drug therapy ; Saudi Arabia/epidemiology ; *Antifungal Agents/pharmacology ; Pregnancy ; Prevalence ; *Virulence Factors/genetics ; Microbial Sensitivity Tests ; *Candida/drug effects/pathogenicity/genetics/classification/isolation & purification ; Adult ; Young Adult ; Adolescent ; *Pregnancy Complications, Infectious/microbiology/epidemiology ; Drug Resistance, Fungal ; Virulence ; }, abstract = {Vulvovaginal candidiasis (VVC) is a common opportunistic fungal infection of the female genital tract, primarily associated with Candida overgrowth influenced by host factors, hormonal changes, microbial imbalance, and environmental conditions. This study examined the prevalence, antifungal susceptibility, and virulence factors of Candida species in 440 pregnant women (ages 18-55) with vulvovaginitis and vaginal discharge at a Saudi Arabian hospital. The study was conducted from March 2022 to February 2023 at a tertiary hospital in Hail, Saudi Arabia, including 440 pregnant women with vaginitis. Vaginal swabs were cultured for Candida, with species identification and antifungal susceptibility testing performed using the Vitek-2 Compact system against five antifungals. Multiplex PCR was used to detect virulence genes (Hwp, Als, Sap, Hlp). Among them, 114 (25.9%) tested positive for Candida species, with Candida albicans being most prevalent (42.1%), followed by C. glabrata (19.3%) and C. tropicalis (12.3%). Most cases occurred during the second trimester (67%), with an average age of 27 years. Antifungal susceptibility testing showed that nystatin exhibited 49.1% susceptibility, 19.3% susceptible-dose dependence (SDD), and 31.6% resistance. Clotrimazole demonstrated 40.4% susceptibility, 26.3% SDD, and 33.3% resistance. Itraconazole showed 50.9% susceptibility, 28% SDD, and 21.1% resistance. Fluconazole exhibited 43.8% susceptibility, 8.8% SDD, and the highest resistance rate (47.4%). Voriconazole was the most effective antifungal agent, with 93% susceptibility, 3.5% SDD, and 3.5% resistance. Virulence analysis showed C. albicans had high Hwp (91.7%) and Sap (54.2%) gene detection, while C. glabrata and C. tropicalis exhibited elevated Hlp and Als levels, respectively. This study highlights the high prevalence of VVC in the second trimester and emphasizes the importance of virulence factors in pathogenicity. Voriconazole emerges as the most effective treatment, emphasizing the need for targeted diagnostics and therapies.}, } @article {pmid42576199, year = {2026}, author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F}, title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.}, journal = {Cellular & molecular biology letters}, volume = {31}, number = {1}, pages = {}, pmid = {42576199}, issn = {1689-1392}, mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.}, } @article {pmid42580389, year = {2026}, author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q}, title = {Neuron-derived neuroinflammation in neurodegenerative diseases: Mechanisms and intervention prospects.}, journal = {Pharmacological research}, volume = {231}, number = {}, pages = {108383}, doi = {10.1016/j.phrs.2026.108383}, pmid = {42580389}, issn = {1096-1186}, mesh = {Humans ; Animals ; *Neurodegenerative Diseases/immunology/drug therapy/pathology ; *Neurons/immunology/drug effects/pathology ; *Neuroinflammatory Diseases/immunology/drug therapy/pathology ; Brain/immunology/pathology/drug effects ; Neuroglia/immunology ; }, abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid42580829, year = {2026}, author = {Gaube, LM and Sparks, ED and Iten, M and Knapp, J and Fürholz, M and Schefold, JC and Hunziker Munsch, L and Hänggi, M and Krummrey, G and Müller, M and Hautz, WE}, title = {In-hospital cardiopulmonary resuscitation with balloon occlusion of the descending aorta: protocol of the randomised controlled CPReboa study.}, journal = {BMJ open}, volume = {16}, number = {8}, pages = {e119691}, pmid = {42580829}, issn = {2044-6055}, mesh = {Humans ; *Aorta, Thoracic ; *Balloon Occlusion/methods ; *Cardiopulmonary Resuscitation/methods ; *Heart Arrest/therapy/mortality ; Prospective Studies ; Randomized Controlled Trials as Topic ; Return of Spontaneous Circulation ; }, abstract = {INTRODUCTION: Cardiac arrest (CA) remains a major health burden with poor survival and poor neurological outcomes despite decades of advances in resuscitation science. Although high-quality cardiopulmonary resuscitation is essential, it provides only limited cerebral and coronary perfusion, and current strategies relying on high-dose epinephrine may adversely affect cerebral microcirculation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a potential adjunct to improve coronary and cerebral perfusion without compromising microvascular blood flow. Although animal studies and small human case series suggest physiological and clinical benefits of REBOA in CA, randomised clinical trials are lacking.

METHODS AND ANALYSIS: This prospective, randomised controlled, single-centre clinical trial investigates the effect of REBOA during the treatment of CA. The planned study duration is 36 months, with a total of 98 patients to be randomised to either standard advanced life support (ALS) or ALS plus REBOA. Adult patients with an in-hospital CA, successful placement of a femoral artery introducer sheath and any electrical cardiac activity in the initial rhythm analysis are eligible for inclusion. Exclusion criteria comprise traumatic CA, asystole as the initial rhythm, pregnancy and CA occurring on intensive care units, in the operating room or in cardiac catheter laboratory. The primary outcome is sustained return of spontaneous circulation lasting for at least 20 min. Secondary and exploratory outcomes include survival, neurological outcome, changes in aortic blood pressure, end-tidal CO₂ and near-infrared spectroscopy values as well as causes of death and vascular complications related to the intervention. Statistical analyses will be performed on a modified intention-to-treat basis.

ETHICS AND DISSEMINATION: The study protocol (Version 2.1, 11.02.2026) was approved by the Cantonal Ethics Committee of Cantone Bern (2025-D0108). Study results will be disseminated through peer-reviewed journals.

TRIAL REGISTRATION NUMBER: NCT07434726.}, } @article {pmid42581415, year = {2026}, author = {Goehring, K and Abler, E and Vavra, J and Mayer, K and Dorst, J and Elmas, Z and Wiesenfarth, M and Richter, L and Petri, S and Regensburger, M and Reilich, P and Bjelica, B and Lumi, R and Süß, P and Tumani, H and Otto, M and Weishaupt, JH and Ludolph, AC and Oeckl, P}, title = {Blood SOD1 Activity in ALS Patients Receiving Tofersen Treatment.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.78328}, pmid = {42581415}, issn = {1531-8249}, abstract = {OBJECTIVE: The antisense oligonucleotide tofersen is the first disease-modifying drug for SOD1-related amyotrophic lateral sclerosis (ALS) and was approved because of its ability to reduce SOD1 protein and neurofilament levels. The effect of tofersen on SOD1 activity is unclear but of clinical relevance because homozygous SOD1 mutations, linked to reduced SOD1 activity, cause severe motor neuron impairment and tofersen-induced reduction could be deleterious. Therefore, monitoring of SOD1 activity is urgently needed.

METHODS: SOD1 activity was analyzed in blood samples from a discovery (n = 120) and a validation cohort (n = 208), including controls, patients with sporadic ALS (sALS), C9orf72 mutation carriers (c9ALS), asymptomatic (SOD1-asym), and symptomatic SOD1 mutation carriers (SOD1-ALS). SOD1 activity was characterized in 18 patients receiving tofersen treatment.

RESULTS: SOD1 activity was significantly lower in both SOD1-asym (median = 7.5 U/mg, interquartile range [IQR] = 7.0-9.0 U/mg) and SOD1-ALS (median = 7.9 U/mg, IQR = 7.1-9.1 U/mg) relative to controls (median = 9.2 U/mg, IQR = 8.9-10.0 U/mg, p < 0.0001), c9ALS (median = 9.4 U/mg, IQR = 8.9-10.2 U/mg, p < 0.0001) and sALS (median 9.5 U/mg, IQR 8.8-9.9 U/mg, p < 0.0001). SOD1 activity was significantly lower in individuals with deleterious SOD1 variants than in individuals with neutral variants. During tofersen treatment, neurofilament and SOD1 protein levels decreased, whereas SOD1 activity remained stable.

INTERPRETATION: The data indicate that the positive tofersen treatment effect is independent of SOD1 activity. Lower SOD1 activity is specific to SOD1-ALS, already present in the asymptomatic phase and depends on the mutation type. Future studies should determine whether tofersen treatment affects cerebrospinal fluid (CSF) SOD1 activity. ANN NEUROL 2026.}, } @article {pmid42594043, year = {2026}, author = {Nair, T and Larson, T and Raymond, J and Horton, DK and Mehta, P}, title = {Motor Neuron Disease Mortality in the United States, 2010-2023: A demographic, geographic, and temporal analysis.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-24}, pmid = {42594043}, issn = {1423-0208}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, abstract = {INTRODUCTION: Our objective was to calculate age-adjusted motor-neuron disease (MND) mortality rates in the United States, 2010-2023, by year, age, sex, race, origin, period, and state. Amyotrophic lateral sclerosis makes up almost 80% of all MNDs.

METHODS: Multiple cause mortality data was obtained from the National Center for Health Statistics (NCHS) for years 2010-2023. Cases were included if code G12.2, the code for MND listed in the International Classification of Disease, 10th Revision (ICD-10), was listed as a cause of death. Using the direct method, cases were age-adjusted to the 2000 U.S. Standard population and mortality rates were calculated.

RESULTS: The overall national MND associated mortality rate was 2.07 per 100,000 population (95% CI 2.06, 2.09). Rates were highest in those aged 80+ years (13.69, 95% CI 13.49, 13.89) at death, non-Hispanic (2.17, 95% CI 2.15, 2.18), and male (2.50, 95% CI 2.48, 2.52). Northern states had higher rates (2.26, 95% CI 2.23, 2.29) with a rate ratio of (1.05, (95% CI 1.04, 1.07) when compared to the middle state tier (2.14, 95% CI 2.12, 2.17, p<0.01). State rates ranged from 3.07 (95% CI 2.75, 3.42) in Vermont to 1.41 (95% CI 1.27, 1.57) in Hawaii. The average annual percentage change was -1.62, corresponding to a statistically significant negative trend.

CONCLUSION: MND associated mortality rates were higher among northern states, decedents who were male, White, or non-Hispanic, which is consistent with previous studies of U.S. MND mortality. Decreasing mortality rates may indicate longer patient life spans due to increased treatment options and care access, but further research is needed.}, } @article {pmid42594365, year = {2026}, author = {Berry-Kilgour, N and Wiseman, R and Grundy, K}, title = {Prescribing and monitoring of riluzole in amyotrophic lateral sclerosis: a retrospective cohort study from Health New Zealand - Te Whatu Ora Waitaha Canterbury.}, journal = {The New Zealand medical journal}, volume = {139}, number = {1640}, pages = {23-30}, doi = {10.26635/6965.7367}, pmid = {42594365}, issn = {1175-8716}, mesh = {Humans ; Retrospective Studies ; *Riluzole/therapeutic use/adverse effects ; New Zealand ; *Amyotrophic Lateral Sclerosis/drug therapy ; Female ; Male ; Middle Aged ; Aged ; *Guideline Adherence/statistics & numerical data ; *Drug Monitoring ; *Neuroprotective Agents/therapeutic use/adverse effects ; Practice Guidelines as Topic ; *Practice Patterns, Physicians'/statistics & numerical data ; Spirometry ; Adult ; }, abstract = {AIM: This retrospective cohort study assessed adherence to the Motor Neurone Disease New Zealand best practice guidelines and Pharmac Special Authority criteria for riluzole in a Canterbury-based amyotrophic lateral sclerosis (ALS) cohort. Secondary objectives included reasons for not prescribing, side effects and treatment initiation relative to diagnosis.

METHOD: A retrospective cohort study was conducted using the Christchurch Hospital respiratory department's ALS database. Patients diagnosed between January 2020 and November 2024 were included. Electronic health records and Special Authority records were reviewed. Patients with incomplete data or non-motor neurone disease (MND) diagnoses were excluded.

RESULTS: Of 115 patients, 69 (60%) were prescribed riluzole. Less than 45% of patients had baseline blood tests, and pre-treatment spirometry was completed in 70% of patients. Delays in prescribing improved rates of baseline spirometry, but not blood test completion. Ongoing monitoring was poor, with less than 60% of patients completing recommended tests across all time points. Eight patients (11.6%) reported side effects, and three discontinued treatment following alanine aminotransferase derangement.

CONCLUSION: Adherence to recommended monitoring and Special Authority criteria for riluzole was inconsistent in this cohort. In the context of emerging evidence supporting broader survival benefit and reduced drug cost, further evaluation of current Special Authority prescribing criteria may be warranted.}, } @article {pmid42597576, year = {2026}, author = {Maeta, T and Kobayashi, K and Asano, K and Sato, T and Ito, S}, title = {Ruxolitinib-Associated Improvement in Post-transplant Air-Leak Syndrome Complicating Steroid-Dependent Organizing Pneumonia: A Case Report.}, journal = {Cureus}, volume = {18}, number = {7}, pages = {e112618}, pmid = {42597576}, issn = {2168-8184}, abstract = {Air-leak syndrome (ALS), including pneumothorax, pneumomediastinum, and subcutaneous emphysema, is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, no standard treatment has yet been established. Here, we report the case of a 60-year-old man with acute myeloid leukemia who underwent allogeneic HSCT. He developed chronic graft-versus-host disease (GVHD) and cryptogenic organizing pneumonia (COP) on day 126 after transplantation. Although initial corticosteroid therapy improved the COP, the relapse occurred during tapering, and repeated steroid treatment failed to achieve sustained disease control. The patient subsequently developed pneumomediastinum, consistent with ALS. Ruxolitinib treatment was initiated on day 265 for steroid-dependent chronic GVHD and organizing pneumonia. Following treatment, oxygenation improved, pneumomediastinum improved, and corticosteroids were successfully tapered and discontinued without COP recurrence. Serum Krebs von den Lungen-6 (KL-6) levels decreased in parallel with clinical and radiological improvement. The introduction of ruxolitinib is associated with improvements in ALS and enabled the discontinuation of steroids. Adverse events included cytopenia and mild liver dysfunction, consistent with known safety profiles. The patient died of acute respiratory failure after transfusion, which was not considered a direct complication of the ruxolitinib treatment. This case suggests that ruxolitinib may facilitate corticosteroid tapering and radiographic improvement of organizing pneumonia-associated ALS after allogeneic transplantation.}, } @article {pmid42606797, year = {2026}, author = {Raghunathan, T and Parthasarathy, B and Prabhu, P and Mahesh, P and Dhanushkodi, A}, title = {Regenerative strategies for ALS: stem cells and extracellular vesicles.}, journal = {Discover nano}, volume = {21}, number = {1}, pages = {}, pmid = {42606797}, issn = {2731-9229}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is caused by progressive degeneration of upper and lower motor neurons. The disease is late onset, and to date, no early diagnosis is possible. Patients with ALS have a 5-year survival rate since diagnosis. Though recent studies highlighted the possible mechanisms of motor neuron degeneration in ALS, the treatment options are extremely limited. This underscores the urgent need to develop effective therapeutic strategies that can prolong patient survival and ultimately slow/halt ALS progression. Extracellular vesicles released from the degenerative milieu contribute to ALS propagation and progression by shuttling misfolded proteins, proinflammatory cytokines, and neurotoxins; thus, they could serve as a biomarker for diagnosis and prognosis. The advancement of stem cell-based therapies for neurodegenerative diseases and the evolving understanding of extracellular vesicles as potential biotherapeutics provide a ray of hope for millions of patients suffering from neurological disorders/neurodegenerative diseases like ALS.}, } @article {pmid42613144, year = {2026}, author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J}, title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.}, journal = {International review of neurobiology}, volume = {189}, number = {}, pages = {205-236}, doi = {10.1016/bs.irn.2026.01.013}, pmid = {42613144}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; }, abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.}, } @article {pmid42613627, year = {2026}, author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA}, title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.}, journal = {Stem cell research & therapy}, volume = {17}, number = {1}, pages = {}, pmid = {42613627}, issn = {1757-6512}, mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; }, abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.}, } @article {pmid42613694, year = {2026}, author = {Shukla, S and Srivastava, V and Gaur, H and Rai, A}, title = {Myelin and Oligodendrocyte Dysfunction in Demyelinating and Neurodegenerative Disorders: Signaling Pathways and Therapeutic Targets.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273437393260729093129}, pmid = {42613694}, issn = {1996-3181}, abstract = {INTRODUCTION: Oligodendrocytes (OLs) synthesize myelin, a substance that plays a significant role in ensuring proper functioning of the Central Nervous System (CNS). Myelin abnormalities are involved in disease pathogenesis in AD, MS, and ALS. In contrast, MS involves autoimmune reactions directed against myelin. On the other hand, AD and ALS are characterized by neurodegeneration. This article seeks to give a critical discussion on myelin and OL dysfunction in these diseases, among others.

METHODS: A narrative literature search was carried out in various databases including Scopus, Google Scholar, Web of Science, and PubMed, focusing on papers relating to myelination, remyelination, and OLs, particularly those addressing signaling pathways and treatment strategies.

RESULTS: MS is an autoimmune disease characterized by inflammation that causes demyelination and OL dysfunction. Oxidative stress and mitochondrial dysfunction play roles in the pathogenesis of ALS, whereas AD is a result of disrupted neuronal supportive functions and myelin damage. Important signaling pathways involved in OL formation and myelin repair include the Wnt/β-catenin, AKT/mTOR, and ERK/MAPK pathways. Drugs like edaravone, ocrelizumab, and siponimod have been identified for promoting myelin repair.

DISCUSSION: The relationship between abnormal oligodendrocyte function, demyelination, and specific disease-related pathological processes demonstrates that although there is a similarity among MS, AD, and ALS, each condition possesses its own unique molecular foundation. One potential treatment approach would be targeting shared signaling pathways relevant to myelination and remyelination. Nonetheless, disease variability and specific pathogenic characteristics demand a targeted therapy approach.

CONCLUSION: Myelin integrity and oligodendrocyte function are central to the progression of demyelinating and neurodegenerative diseases. Targeting molecular pathways involved in myelination offers significant potential for improving disease outcomes and developing advanced therapeutic strategies.}, } @article {pmid42620667, year = {2026}, author = {Hawley, ZCE and Guise, AJ and Pardo, ID and Chowdhury, T and Hana, S and Zavodszky, MI and Engle, L and Wiltberger, K and Bartlett, D and Raitcheva, D and Bommegowda, S and Lee, WH and Chen, SK and Sheehy, A and Driscoll, R and Peterson, M and Sebalusky, J and Hamann, S and Marsh, G and Doherty, J and Chicoine, KE and Cundiff, P and Dwyer, S and Clarner, P and Zeng, W and Ferretti, D and Tuczkewycz, T and Isaza, I and Patrovanie, M and Mcgladrigan, C and Chu, J and Morrison, JP and Arnold, HM and Shen, S and Hurt, JA and Trapa, P and Graham, DL and Plowey, ED and Lo, SC}, title = {Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {3}, pages = {201818}, pmid = {42620667}, issn = {3117-387X}, abstract = {Adeno-associated virus (AAV) artificial microRNAs (amiRNAs) targeting superoxide dismutase 1 (SOD1) have been proposed as a therapeutic strategy for people living with amyotrophic lateral sclerosis (ALS) who harbor toxic gain-of-function variants in the SOD1 gene. Clinical efforts have primarily focused on AAV delivery via the cerebrospinal fluid (CSF), as blood-brain-barrier-crossing capsids are still being developed preclinically. However, intra-CSF delivery has been shown to be highly variable and increases the risk for AAV-related adverse events such as dorsal root ganglion (DRG) toxicity. Here, we show that immunosuppressants (IMS) following intra-CSF delivery of AAV9-amiR-SOD1 in non-human primates (NHPs) prevented AAV-related DRG toxicity, and this benefit was maintained for over 300 days even after immunotherapy stopped at 90 days post-AAV treatment. In line with prior literature, we found intra-CSF delivery of AAV9-amiR-SOD1 to be highly variable in adult mice and NHPs, requiring higher doses of virus to achieve efficacious endpoints. To address this concern, we developed a proof-of-principle study showing that AAV9-amiR-SOD1, in combination with a SOD1-targeting antisense oligonucleotide, provided an additive therapeutic benefit in SOD1-G93A mice compared with AAV9-amiR-SOD1 alone. This combinatorial approach lowered the viral load needed to reach efficacious endpoints, which could mitigate AAV-related adverse events alongside IMS.}, } @article {pmid42622454, year = {2026}, author = {Boccanegra, B and Tulimiero, L and Quarta, R and Conte, E and Licandro, SA and Decio, A and Lenti, R and Ladisa, A and Dinoi, G and Carbone, G and Claudione, L and Camerino, GM and Pierno, S and Mantuano, P and Cappellari, O and Fossati, G and Steinkühler, C and De Luca, A}, title = {LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors.}, journal = {Annals of the New York Academy of Sciences}, volume = {1562}, number = {1}, pages = {e70364}, pmid = {42622454}, issn = {1749-6632}, support = {22.004//Duchenne Parent Project/ ; GJC25P084//Fondazione Telethon/ ; PRIN MUR 2020ELYA32//Ministero dell'Università e della Ricerca/ ; 2023-UNBACLE-0245439//Università degli Studi di Bari "Aldo Moro"/ ; }, mesh = {Animals ; *Histone Deacetylase Inhibitors/pharmacology ; *Muscular Dystrophy, Duchenne/genetics/metabolism/drug therapy ; Mice ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Humans ; *Epigenesis, Genetic/drug effects ; Disease Models, Animal ; AMP-Activated Protein Kinase Kinases ; MicroRNAs/genetics/metabolism ; Mice, Inbred mdx ; Vorinostat ; AMP-Activated Protein Kinases/metabolism ; Muscle, Skeletal/metabolism/drug effects ; }, abstract = {Efficient skeletal muscle contraction requires tight mechano-metabolic coupling, a process regulated by AMP-activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1-STRADα-MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx) and patient-derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad-spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR-451, miR-195, and miR-17, which function as post-transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin-A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1-STRADα-MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.}, } @article {pmid42624937, year = {2026}, author = {Aboukhalil, FM and Khamis, EF and El-Sayed, MA and Youssef, RM and El-Yazbi, AF}, title = {Green analytical methods for quantification of a new combination therapy for amyotrophic lateral sclerosis: assessment by EPPI framework.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42624937}, issn = {2045-2322}, mesh = {*Celecoxib/therapeutic use/analysis ; *Ciprofloxacin/therapeutic use/analysis ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Chromatography, High Pressure Liquid/methods ; *Green Chemistry Technology/methods ; Spectrophotometry, Ultraviolet/methods ; Tablets ; Drug Therapy, Combination ; Reproducibility of Results ; }, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to progressive muscle weakness, paralysis, and respiratory failure. The recently proposed combination therapy consisting of celecoxib and ciprofloxacin hydrochloride has emerged as a potential treatment for amyotrophic lateral sclerosis and other neurodegenerative disorders. The present study aimed to develop and validate simple, sensitive, environmentally friendly, and cost-effective analytical methods for the simultaneous determination of celecoxib and ciprofloxacin hydrochloride in bulk powders, laboratory-prepared tablets and plasma. Two ultraviolet spectrophotometric methods were established. The first method relies on direct absorbance measurements of ciprofloxacin hydrochloride at 318 nm and celecoxib at the isosbestic point at 266 nm, while the second one employs first-derivative ratio spectrophotometry for the selective determination of ciprofloxacin hydrochloride and celecoxib at 280 nm and 254 nm, respectively. Moreover, a reversed-phase high-performance liquid chromatographic method was developed using a C18 stationary phase, an optimized mobile phase composition and both diode array and fluorescence detectors, achieving efficient separation and accurate quantification of both analytes. The developed procedures were successfully applied to laboratory-prepared tablets and plasma following optimization of the sample preparation protocol to minimize matrix interference and to improve analytes recovery. Validation results showed excellent linearity over the investigated concentration ranges together with satisfactory accuracy, precision, selectivity, and sensitivity, confirming the reliability of the proposed methods for routine quality control and bioanalytical applications. The overall analytical performance and environmental sustainability of the developed methods were further assessed using the environmental performance and practicality Index framework, demonstrating their suitability as reliable and sustainable analytical approaches for the determination of celecoxib and ciprofloxacin hydrochloride.}, } @article {pmid42626598, year = {2026}, author = {Pinky, PP and Wang, ZM and Khare, P and Jhaveri, JR and Sullivan, A and Basudkar, V and Rao, KS and Lawrence, A and Pingali, A and Dave, KM and Stolz, DB and Sun, M and Zheng, SY and Shiva, SS and Milligan, C and Delbono, O and Manickam, DS}, title = {Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.}, journal = {Extracellular vesicle}, volume = {7}, number = {}, pages = {}, pmid = {42626598}, issn = {2773-0417}, support = {R25 NS100118/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1[G93A] transgenic mouse model of ALS.}, } @article {pmid42632702, year = {2026}, author = {Wu, L and Zhu, X and Wang, X and Wu, Y and Bu, Q and Dai, T and Wen, X and Zhong, K and Guo, H and Gao, H}, title = {Fermentation with aspergillus costiformis enhances the anti-migratory activity of Aquilaria sinensis leaves with possible involvement of MAPK-related pathways.}, journal = {Food research international (Ottawa, Ont.)}, volume = {242}, number = {Pt 2}, pages = {119955}, doi = {10.1016/j.foodres.2026.119955}, pmid = {42632702}, issn = {1873-7145}, mesh = {Humans ; *Aspergillus/metabolism ; *Plant Leaves/chemistry ; *Fermentation ; *Thymelaeaceae/chemistry/metabolism ; HeLa Cells ; *Plant Extracts/pharmacology ; *Cell Movement/drug effects ; *MAP Kinase Signaling System/drug effects ; Flavonoids ; Cell Proliferation/drug effects ; }, abstract = {Aquilaria sinensis leaves (ALs) are an underutilized plant resource rich in polyphenols and flavonoids. Microbial fermentation has been proposed as an effective strategy to enhance the functional value of plant materials. However, its impact on the bioactivity and mechanisms of ALs remains unclear. This study aimed to evaluate the effects of fermentation with Aspergillus costiformis AHHC on the chemical composition and biological activities of ALs, and to elucidate the molecular mechanisms underlying the fermentation-induced functional changes. Non-targeted metabolomic analysis was performed to assess fermentation-induced metabolic alterations. The biological activities of fermented ALs (ALDT) and non-fermented ALs (ALT) extracts were evaluated using HeLa S3 cell-based assays. Network pharmacology and transcriptomic analyses were integrated to identify potential pathways and molecular targets, which were further validated by molecular analyses. The results revealed that fermentation significantly reshaped the metabolite profile of ALDT, particularly in flavonoid-related pathways. Compared with ALT, ALDT showed a stronger inhibitory effect on HeLa S3 cell migration while maintaining comparable anti-proliferative activities at higher concentrations. The integrated analyses indicated that fermentation-enriched metabolites were mainly associated with pathways related to cell migration and stress response, with prominent involvement of MAPK signaling. Molecular assays confirmed enhanced phosphorylation of MAPK components and increased expression of regulatory genes such as GADD45B and NR4A1 in response to ALDT treatment. Overall, fermentation with A. costiformis enhanced the anti-migratory activity of ALDT in HeLa S3 cells, with possible involvement of MAPK-related signaling pathways. These findings provide molecular-level evidence supporting microbial fermentation as a strategy to improve the functional value of this plant resource.}, } @article {pmid42637106, year = {2026}, author = {Heinsinger, N and Wang, Y and Grauer, S and Zhang, Z and Wong, J and Simov, V and Bukhtiyarova, M and Ai, X and Parish, C and Klein, RM and Uslaner, J and Smith, S and Tian, Y}, title = {Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107582}, doi = {10.1016/j.nbd.2026.107582}, pmid = {42637106}, issn = {1095-953X}, abstract = {ATXN2 is associated with an increased risk of Amyotrophic Lateral Sclerosis (ALS), while down-regulation of ATXN2 has been shown to mitigate TDP-43 proteinopathy in ALS models. In this study, we demonstrated that Ataxin-2 protein levels were upregulated in rNLS8 mice following doxycycline withdrawal, which coincided with TDP-43 overexpression, phosphorylation, and aggregation. To reduce Ataxin-2 protein levels, we explored the approach of splicing modulation at the RNA level. Through bioinformatical analysis, we identified an alternative 5' splicing site of ATXN2 in intron 8. This alternative splicing results in an additional 47 base pairs at the 3' end after Exon 8. The insertion of the extra nucleotides causes a frameshift that leads to reduced mRNA production and, consequently, protein levels. Following the discovery of this alternative splicing site, we conducted an antisense oligonucleotide (ASO) micro-walk to screen ASOs targeting this region. We identified ASOs that specifically modulate this splicing, including those that either enhance or inhibit alternative splicing. We validated that the ASOs that promote alternative splicing and reduce constitutive splicing can lower Ataxin-2 protein levels, which in turn decreases TDP-43 aggregation and stress granule formation in a cell-based model of TDP-43 toxicity. Furthermore, we confirmed that reducing Ataxin-2 levels via previously validated ASO delivery ameliorated TDP-43 pathology in rNLS8 mice. The discovery of ATXN2 alternative splicing, along with the confirmation of splicing modulation using ASOs in human cell-based assays, provides evidence for a proof-of-principle strategy to modulate Ataxin-2 protein levels for the treatment of ALS.}, } @article {pmid42637886, year = {2026}, author = {Rashed, AM and El-Sayed, IET and Lu, X and Abdel-Bary, HM and Fouad, MK and Tony, MA}, title = {Re-engineering alum sludge using choline-glycine ionic liquid for enhanced dewatering and dye adsorption in wastewater treatment.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {42637886}, issn = {2045-2322}, abstract = {Large quantities of by-product alum sludge (Al-S) generated from drinking water treatment plants pose significant environmental and disposal challenges due to their high water content and large volume. This study aims to develop a sustainable conditioning and valorization strategy for Al-S using a choline-glycine ionic liquid ([Ch]-[AA]). The ionic liquid was synthesized and applied as a sludge conditioner to enhance dewatering performance. Under optimized conditions, the dewatering efficiency reached 47%, accompanied by a notable zeta potential shift, indicating partial charge neutralization and improved floc structure. To enable sludge valorization, the conditioned sludge was reused as an adsorbent, either directly or after thermal treatment. The modified materials exhibited high adsorption capacities toward Synozol KHL dyes, reaching 43.6 and 90.1 mg g[-][1] for Red and Blue dyes, respectively. Adsorption behavior was well described by the Langmuir isotherm and pseudo-second-order kinetic model. Thermodynamic analysis indicated an exothermic adsorption process, with spontaneity dependent on operating conditions. Overall, the results demonstrate an effective waste-to-resource approach in which enhanced dewatering facilitates the conversion of alum sludge into a functional adsorbent for wastewater treatment, supporting sustainable sludge management.}, } @article {pmid42638122, year = {2026}, author = {Zhang, Y and Liu, Y and Shi, S and Li, Q and Huo, Y and You, P and Shu, M and Cheng, X and Zhang, J and Liang, D and Zhang, A and Lu, C and Shen, B and Zhou, J and Niu, Q}, title = {JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42638122}, issn = {1741-7015}, support = {82071434//the National Natural Science Foundation of China/ ; DL202410//the clinical Research Disease Project of Jiangsu Provincial People's Hospital/ ; LC202404//Jiangsu Provincial People's Hospital-Zero magnetic Medicine Special Project/ ; JSPH-MA-2023-5//Jiangsu Province Hospital Clinical Capacity Enhancement Project/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Autophagy/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Antioxidant Response Elements ; Signal Transduction/drug effects ; *Oligopeptides/pharmacology ; Male ; Humans ; Spinal Cord/metabolism ; }, abstract = {BACKGROUND: The simultaneous modulation of oxidative stress and autophagy represents a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS), yet agents capable of coordinately regulating both processes remain scarce. The Keap1‑Nrf2‑ARE pathway serves as a critical hub linking redox homeostasis and autophagic regulation, making it an attractive target for ALS intervention. JWA is a stress‑responsive protein involved in cellular protection against oxidative injury, and its neuroprotective effects have been shown to depend on activation of the MEK/ERK‑Nrf2 axis. JP1 is a functional oligopeptide derived from the JWA protein that has been engineered to cross the blood-brain barrier and specifically target integrin αVβ3. Based on the link between JWA and Nrf2 signaling, we hypothesized that JP1 activates the Keap1‑Nrf2‑ARE pathway to coordinate antioxidant defense and autophagic clearance. Here, we evaluated this hypothesis in the SOD1‑G93A mouse model, a well‑established transgenic model of familial ALS, and elucidated the underlying mechanisms.

METHODS: We evaluated the efficacy of JP1 in the SOD1-G93A mice model using behavioral phenotyping and survival analysis. The coordinated mechanism was investigated in spinal cord tissues by profiling the Keap1-Nrf2-ARE pathway and oxidative stress, quantifying autophagic flux (by Western blotting and transmission electron microscopy) and neuronal apoptosis, and evaluating histology (by Nissl staining and immunofluorescence). Integrated transcriptomic and proteomic analyses further elucidated the global molecular landscape underlying the therapeutic effects of JP1.

RESULTS: JP1 treatment ameliorated motor deficits and extended survival in SOD1-G93A mice without adversely affecting liver or kidney function. JP1 crossed the blood-brain barrier, targeted motor neurons expressing integrin αVβ3, and activated the ERK pathway. This promoted Keap1/Cul3 degradation and Nrf2 nuclear translocation, thereby activating the Keap1-Nrf2-ARE pathway to alleviate oxidative stress. Concurrently, JP1 restored autophagic flux, increased autophagic activity, attenuated motor neuron injury, suppressed neuronal apoptosis, and preserved neuronal structural integrity. The Nrf2 inhibitor ML385 reversed the protective effects of JP1 on survival, motor function, autophagy, oxidative stress, and neuronal apoptosis, which confirms that JP1 acts via the Nrf2 pathway.

CONCLUSIONS: JP1 acts as a promising coordinator of antioxidant and autophagic processes by targeting the Keap1-Nrf2-ARE pathway, thus highlighting its therapeutic potential for ALS.}, } @article {pmid42642938, year = {2026}, author = {Zou, L and Song, L and Yin, P and Cui, H and Lian, L and Peng, X and Jin, T and Wang, H and Liu, W}, title = {Glutathione S-transferase genes PfGSTU6 and PfGSTL1 involved in mesosulfuron-methyl resistance in Polypogon fugax.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.71227}, pmid = {42642938}, issn = {1526-4998}, support = {//National Natural Science Foundation of China (32372570, 32572857)/ ; //Shandong Provincial Natural Science Foundation (ZR2025MS289)/ ; }, abstract = {BACKGROUND: Polypogon fugax is a major weed in wheat and winter canola fields in China. Two populations, SD-4 and JS-13, showing resistance to the ALS inhibitor mesosulfuron-methyl, were collected from winter wheat fields. This study aimed to characterize their resistance level and cross-resistance profile, investigate the resistance mechanism and identify its functional genes.

RESULTS: Dose-response assays showed that SD-4 and JS-13 have high-level resistance to mesosulfuron-methyl (15.9-and 16.4-fold, respectively) and cross-resistance to the ACCase inhibitors clodinafop-propargyl, fenoxaprop-P-ethyl, quizalofop-p-ethyl, and the PDS inhibitor diflufenican. Sequencing of the ALS gene revealed no known target-site mutations within the eight conserved resistance-associated regions. Pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor NBD-Cl increased herbicide sensitivity in resistant plants. The resistant plants showed higher inducible GST activity. Herbicide residues analysis observed that resistant plants exhibiting increased mesosulfuron-methyl metabolism, and the enhanced metabolism could be reduced by both inhibitors. Integrated transcriptomic and qRT-PCR analysis identified 17 stably upregulated genes, including PfGSTU6 and PfGSTL1. Escherichia coli and rice callus overexpressing PfGSTU6 and PfGSTL1 exhibit significantly enhanced herbicide tolerance to mesosulfuron-methyl, and molecular docking analysis confirmed the strong binding affinity of GST proteins to the target herbicide.

CONCLUSIONS: The P450s and GSTs mediated herbicide metabolism confer mesosulfuron-methyl resistance in P. fugax. This study elucidates the resistance mechanism and provides genetic resources for resistance monitoring and crop breeding. In addition, we characterized the cross-resistance profile of the resistant P. fugax population, which provides guidance for developing targeted field weed resistance management strategies. © 2026 Society of Chemical Industry.}, } @article {pmid42646579, year = {2026}, author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A}, title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {42646579}, issn = {2076-3271}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; }, abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.}, } @article {pmid42651639, year = {2026}, author = {Ciuro, M and Rovetto, C and Sirna, AA and Giunta, S and Leanza, G and Gulino, R}, title = {Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Biology}, volume = {15}, number = {16}, pages = {}, pmid = {42651639}, issn = {2079-7737}, support = {PG_6/2022//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1[G93A] mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS.}, } @article {pmid42652767, year = {2026}, author = {Friebel, J and Manni, M and Gozdowsky, SC and Brettschneider, P and Grün, D and Baumann, AM and Spielmann, E}, title = {Reorganisation of the Basic Life Support Segment in a Physician-Led Emergency Medical Service: A Retrospective Evaluation of Operational and Clinical Characteristics.}, journal = {Journal of clinical medicine}, volume = {15}, number = {16}, pages = {}, pmid = {42652767}, issn = {2077-0383}, abstract = {Background: Increasing demand for emergency medical services (EMS) challenges prehospital resource availability, particularly for time-critical emergencies requiring advanced life support (ALS). Although tiered BLS and ALS response models are established in many non-physician-led EMS systems, evidence regarding qualification-based dispatch stratification within physician-led EMS systems remains limited. This study evaluated the clinical and operational characteristics of an expanded BLS dispatch segment in Berlin EMS. Methods: A retrospective observational study analysed 2,132,246 EMS missions in Berlin, Germany, between 2020 and 2024. Missions were retrospectively classified according to dispatch codes included in the expanded BLS segment, designed to allocate incidents with lower expected requirements for ALS-level interventions to appropriately qualified EMS personnel. Analyses included dispatch characteristics, clinical findings from electronic patient care records, observed safety-related indicators, and ALS response intervals. Results: Overall, 28.7% of EMS missions were classified within the expanded BLS segment. Traumatic and psychiatric presentations represented the most frequent diagnostic groups. Based on predefined clinical indicators, no immediately life-threatening condition was documented in more than 95% of missions. Cardiopulmonary resuscitation occurred in 0.03% of cases, and emergency physician involvement was documented in approximately 3% of cases. Conclusions: A substantial proportion of EMS missions represented a population with predominantly lower expected prehospital treatment complexity within a qualification-based dispatch framework. Structured emergency call interrogation combined with dispatch classification and linked clinical data enabled retrospective evaluation of this approach. Further validation against independent clinical reference standards and linkage with downstream outcomes are required to determine broader applicability.}, } @article {pmid42662266, year = {2026}, author = {Dresel, FC and Michaelis, M and Gourlay, CW}, title = {The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.}, journal = {International journal of cell biology}, volume = {2026}, number = {}, pages = {3022967}, pmid = {42662266}, issn = {1687-8876}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota-derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS-related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1[G85R]. Mechanistically, NaB recapitulated the effects of the pan-HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1[A4V], Sod1[G85R] or Sod1[G37R] in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.}, } @article {pmid42664377, year = {2026}, author = {Escobar-Villegas, PA and Realpe-Camelo, AI and Arana-Salas, DA and Velásquez, JG and Paulo, M and Martínez-Cajas, CH and Amaya-Sanchez, S and Gómez-Mesa, JE}, title = {Endodontic status of patients with coronary atherosclerosis: A cross-sectional study.}, journal = {Dental and medical problems}, volume = {63}, number = {4}, pages = {885-891}, doi = {10.17219/dmp/205472}, pmid = {42664377}, issn = {2300-9020}, mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Coronary Artery Disease/epidemiology/complications/diagnostic imaging ; Middle Aged ; Colombia/epidemiology ; Aged ; *Root Canal Therapy ; Adult ; Prevalence ; Coronary Angiography ; }, abstract = {BACKGROUND: There are no studies in the Colombian population assessing the prevalence and severity of apical lesions (ALs), or the relationship between the frequency and quality of endodontic treatment (ET) obturation and the presence of ALs in patients with coronary atherosclerosis (CA).

OBJECTIVES: The present study aimed to estimate the frequency of ALs and ET in Colombian patients with CA, and to identify a possible association between the frequency and severity of ALs and CA.

MATERIAL AND METHODS: The study had a cross-sectional design. We included patients with the evidence of CA diagnosed by coronary angiography. The main outcome variables were the number of compromised coronary arteries and their degree of obstruction, as well as ET, including ALs and previously treated teeth (PTT). The periapical index (PAI) was assessed using periapical radiographs.

RESULTS: A total of 1,394 teeth from 69 patients were evaluated (δ = 20.2 teeth/patient). The frequency of ALs and ET was 5.7% and 10.1%, respectively, considering all teeth evaluated, with a greater presence in the maxilla (50.6% and 51.4%, respectively). Apical lesions were most frequently observed in premolars and molars (35.4%), whereas ET was more frequent in molars (38.6%). Among teeth with ALs, PAI 3 was the most frequent score. Apical lesions were present in 40.0% of endodontically treated teeth; 79.2% of these teeth had inadequate obturation, of which 40 (39.2%) had ALs (p = 0.021).

CONCLUSIONS: In patients with CA, a high incidence of ALs and ET was observed, with no evidence of an association between the frequency of ALs, the severity of coronary vessel occlusion, and the number of coronary arteries affected. More ALs were observed in teeth with inadequate ET. However, as we did not have a control group for comparison, these findings should be interpreted with caution.}, } @article {pmid42666355, year = {2026}, author = {Wei, Y and Wang, J and Ji, Y and Shang, T and Shen, Y and Sun, H and Cai, Y}, title = {Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {626069}, pmid = {42666355}, issn = {1177-8881}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Precision Medicine ; Animals ; *Clinical Trials as Topic ; *Neuroprotective Agents/therapeutic use ; *Research Design ; Genetic Therapy ; Drug Development ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all" approach toward "precisely stratified" medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.}, } @article {pmid42670527, year = {2026}, author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L}, title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.}, journal = {International journal of nanomedicine}, volume = {21}, number = {}, pages = {628071}, pmid = {42670527}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; }, abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.}, } @article {pmid42674126, year = {2026}, author = {Raffaele, S and Bonifacino, T and Mannella, FC and Nguyen, N and Torazza, C and Marangon, D and Chinosi, EM and Schrøder, HD and Hejbøl, EK and Madsen, K and Marchetti, L and Trincavelli, ML and Milanese, M and Lecca, D and Lambertsen, KL and Bonanno, G and Abbracchio, MP and Fumagalli, M}, title = {Selective targeting of the oligodendroglial GPR17 receptor improves myelin integrity and motor function in female SOD1[G93A] mice.}, journal = {Pharmacological research}, volume = {232}, number = {}, pages = {108424}, doi = {10.1016/j.phrs.2026.108424}, pmid = {42674126}, issn = {1096-1186}, mesh = {Animals ; *Receptors, G-Protein-Coupled/metabolism/agonists/genetics ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology/genetics ; Humans ; *Oligodendroglia/drug effects/metabolism/pathology ; *Myelin Sheath/drug effects/metabolism/pathology ; Mice, Transgenic ; Male ; Superoxide Dismutase-1/genetics ; Spinal Cord/metabolism/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; *Motor Activity/drug effects ; Disease Models, Animal ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no definitive disease-modifying therapies available, underscoring the urgent need to identify novel druggable targets. The G protein-coupled receptor GPR17 is a critical regulator of oligodendrocyte maturation and has emerged as a candidate target in ALS, yet its relevance to human disease and its therapeutic potential remain unclear. Here, we demonstrate that pathological GPR17 upregulation defines a conserved, pathologically immature oligodendroglial state in human ALS that can be pharmacologically leveraged to restore myelin integrity and improve functional outcome in vivo. Publicly available transcriptomics datasets and histological analyses revealed an increased abundance of GPR17-expressing immature oligodendrocytes in post-mortem human spinal cord tissue from ALS cases. Moreover, sustained activation of GPR17 with a selective agonist induced GPR17 internalization in heterologous expression systems and promoted the differentiation of primary oligodendrocyte precursors derived from SOD1[G93A] mice. Translating these findings in vivo, chronic treatment with a brain-penetrant GPR17 agonist derived from the same pharmacological class significantly extended survival, delayed body weight loss, and improved motor performance in female SOD1[G93A] mice, whereas male mice showed no therapeutic benefit. These effects were associated with restored oligodendrocyte maturation, preserved myelin integrity, motor neuron survival, and attenuated reactive gliosis in the spinal cord of female SOD1[G93A] mice, while milder effects were observed in males. Together, these findings establish oligodendroglial GPR17 as a conserved and pharmacologically actionable target in ALS and show that sustained in vivo GPR17 agonism can reprogram altered oligodendroglial states and slow disease progression in a sex-dependent manner.}, } @article {pmid42685382, year = {2026}, author = {Ni, CC and Yu, CS and Wei, SY and Dai, JZ and Chang, CL and Ting, HC and Chang, CY and Chen, YC}, title = {UV-programmed gelatin methacryloyl hydrogel microenvironments reveal a bell-shaped vascularization window and enable compartmentalized neuromuscular disease modeling.}, journal = {Biomaterials}, volume = {338}, number = {Pt A}, pages = {124588}, doi = {10.1016/j.biomaterials.2026.124588}, pmid = {42685382}, issn = {1878-5905}, abstract = {Matrix mechanics and microarchitecture jointly regulate tissue morphogenesis and functional maturation; however, defining their combined effects remains challenging when microenvironmental tuning requires changes in material composition. Here, we establish a UV-programmable gelatin methacryloyl (GelMA) hydrogel system in which ultraviolet exposure coordinates changes in construct architecture, pore morphology, and apparent mechanical properties within a constant material formulation. This framework enables systematic mapping of biological responses to UV-programmed architectural-mechanical microenvironments without compositional confounders. In vivo subcutaneous implantation reveals a nonlinear, bell-shaped vascularization response to UV-programmed GelMA hydrogel properties, identifying a narrow microenvironmental window that supports blood-containing vessel formation, human-derived vascular structures, and host-perfused vascular integration. For neuromuscular modeling, a structurally stable UV-defined regime was selected to support long-term compartmentalized co-culture of human induced pluripotent stem cell-derived myoblasts and motor neuron spheroids. Within this same UV-defined compartmentalized neuromuscular microenvironment, amyotrophic lateral sclerosis (ALS)-derived constructs exhibit impaired myogenic maturation, reduced neuromuscular junction (NMJ)-like structural organization, and altered contractile responsiveness compared with gene-corrected Healthy controls. Pharmacological treatment with the FDA-approved drug Riluzole partially restores these disease-associated phenotypes. Together, these findings establish UV-programmed GelMA hydrogels as an adaptable architectural-mechanical platform for identifying vascularization-permissive microenvironments and supporting compartmentalized neuromuscular disease modeling.}, } @article {pmid42686219, year = {2026}, author = {Liu, J and Lin, J and Liu, H and Soh, K and Ju, Q and Soh, K and Dong, X}, title = {Efficacy of Antimicrobial Lock Solutions on Central Line-Associated Bloodstream Infection and Catheter Survival in Hemodialysis Patients: A Systematic Review and Meta-Analysis.}, journal = {Seminars in dialysis}, volume = {}, number = {}, pages = {}, doi = {10.1111/sdi.70046}, pmid = {42686219}, issn = {1525-139X}, support = {202301A014//Chengde Science and Technology Program/ ; GJXH2021-126//Hebei Higher Education Association "14th Five-Year Plan" Research Project/ ; H2026406068//Hebei Natural Science Foundation/ ; 202307//Chengde Medical university Project/ ; 202404//Chengde Medical university Project/ ; }, abstract = {Hemodialysis (HD) catheters carry a high risk of life-threatening bloodstream infections and failure. Antimicrobial lock solutions (ALS) are used to reduce this risk, but their overall efficacy on key outcomes like infection rates and catheter survival requires comprehensive evaluation. This systematic review and meta-analysis assess the impact of ALS on preventing catheter-related bloodstream infections (including incidence and density) and on improving catheter survival. A systematic search was conducted across the databases of PubMed, Embase, Scopus, Cochrane Library, and Google Scholar. A meta-analysis was conducted using STATA software. A total of 1183 studies were screened based on title and abstract, and further 282 studies were evaluated in full text. Eventually, 14 studies with 15 treatment arms were included. Key outcomes including central line-associated bloodstream infection (CLABSI), exit infection, and catheter-free survival were conducted separately. ALS demonstrated statistically significant benefits on CLABSI infection and catheter-free survival compared to nonantimicrobial solutions, showing a reduction in CLABSI density with a pooled log odd ratio (logOR) of -1.29 (95% CI: -1.59 to -0.99), lower CLABSI rates (pooled logOR = -1.50, 95% CI: -1.85 to -1.15), and improved catheter-free survival with log hazard ratio (logHR) of -1.11 (95% CI: -1.41 to -0.8). Consistent treatment effects were observed across all lock types with no significant heterogeneity detected. ALS demonstrate statistically significant and clinically important efficacy in reducing CLABSI incidence and density while improving catheter survival in HD patients, establishing them as an essential preventive strategy in clinical practice.}, } @article {pmid42693185, year = {2026}, author = {Dalakas, MC and Lünemann, JD}, title = {Role of complement and complement-targeted therapeutics in neurological diseases.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {42693185}, issn = {1759-4766}, abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.}, } @article {pmid42697152, year = {2026}, author = {Fernández-Beltrán, LC and García-Toledo, I and Javaloyes García, K and Jiménez-Coca, I and Jiménez-Rodríguez, J and Fernández-Bernal, A and Godoy-Corchuelo, JM and Portero-Otín, M and Corrochano, S}, title = {Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1[G93A] mouse model of ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {23}, number = {5}, pages = {e01062}, pmid = {42697152}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics/metabolism ; *Hydrocarbons, Fluorinated/pharmacology/therapeutic use ; *Liver X Receptors/agonists/metabolism ; *Sulfonamides/pharmacology/therapeutic use ; Fluorocarbons ; Benzenesulfonamides ; Mice ; Female ; *Superoxide Dismutase-1/genetics ; Disease Models, Animal ; Male ; Mice, Transgenic ; Spinal Cord/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Humans ; *Motor Neurons/drug effects/pathology/metabolism ; }, abstract = {Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1[G93A] mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.}, } @article {pmid42697379, year = {2026}, author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS}, title = {Extracellular vesicles in neurodegenerative diseases: A new frontier in diagnosis and therapy.}, journal = {Behavioural brain research}, volume = {516}, number = {}, pages = {116455}, doi = {10.1016/j.bbr.2026.116455}, pmid = {42697379}, issn = {1872-7549}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.}, } @article {pmid42701411, year = {2026}, author = {Gonzo, P and Dunkl, S and Gatterbauer, M and Heider, S and Girsa, M and Krammel, M and Schnaubelt, S}, title = {Structured Evaluation and Treatment of cardiac arrest via the ABCDE approach (SETA) - Rethinking high-performance CPR and cause-finding during Advanced Life Support.}, journal = {Resuscitation plus}, volume = {31}, number = {}, pages = {101458}, pmid = {42701411}, issn = {2666-5204}, abstract = {The European Resuscitation Council (ERC) Guidelines 2025 continue to summarize the causes of cardiac arrest that should be sought during advanced life support (ALS) as "4Hs and 4Ts". While well established, this list-based mnemonic does not map onto the airway-breathing-circulation-disability-exposure (ABCDE) sequence that emergency teams use for every other patient assessment, and it excludes causes that are clinically treatable but not classically "reversible" in the prehospital phase. We present SETA (Structured Evaluation and Treatment of cardiac arrest via the ABCDE approach), a concept developed within the Emergency Medical Service Vienna that restructures both cause-finding during cardiopulmonary resuscitation (CPR) and evaluation of high-performance CPR around the ABCDE sequence, embeds protocol-linked actions at each step, and is designed to run within ongoing chest compressions without interrupting them. We outline its rationale, its relationship to existing pit-crew and ABCDE-based resuscitation models, and the prospective evaluation now needed before considered for wider use.}, } @article {pmid42701881, year = {2026}, author = {Zhu, Y and Zhang, Y and Yan, T and Li, Y and Du, H and Zhang, S and Zhang, T and Zhou, W}, title = {The role of overdose folic acid in promoting neuroinflammation, oxidative stress, and apoptosis in SOD1-G93A mice.}, journal = {Free radical research}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/10715762.2026.2729677}, pmid = {42701881}, issn = {1029-2470}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that involves the targeted degeneration of motor neurons. The precise pathogenetic mechanisms are still largely unclear. In this study, we utilized the SOD1-G93A mouse model of ALS to investigate the effects of folic acid (FA), an important factor involved in homocysteine metabolism. Our results indicated that a little FA prolonged the lifespan of the SOD1-G93A mice and medium and high-dose FA significantly shortened the lifespan of the SOD1-G93A mice. Furthermore, we observed that an overdose of FA significantly elevated inflammation levels in the cerebellum, as evidenced by increased concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cluster of differentiation 68 (CD68), cluster of differentiation 86 (CD86), and monocyte chemoattractant protein-1 (MCP-1), facilitating microglial activation. The low-dose FA effects were the opposite of the overdose FA. Additionally, high-dose FA increased the levels of phosphorylated p65 (p-p65)/p65, thereby promoting the NF-κB signaling pathway. Conversely, high-dose FA inhibited the expression of total superoxide dismutase (T-SOD) while increasing the level of malondialdehyde (MDA) in the cerebellum; these effects were not observed in muscle tissue. Moreover, high-dose FA elevated the levels of Bax2/Bcl-2. Concurrently, high-dose FA induced increased apoptosis in SOD1-G93A mice, as demonstrated by TUNEL staining. Notably, the brain iron content of SOD1-G93A mice remained unchanged following FA treatment. These findings provide evidence that an overdose of FA supplementation may exert pro-inflammatory effects by promoting the NF-κB pathway, oxidative stress, and apoptosis in the context of ALS.}, } @article {pmid42706741, year = {2026}, author = {Grouls, A and Ubel, PA and Nguyen, M and Pathapati, N and Doerstling, S and Sloan, CE}, title = {Online Crowdfunding Campaigns for People Living With ALS Demonstrate Financial Burden and Unmet Needs.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.70395}, pmid = {42706741}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: People living with amyotrophic lateral sclerosis (ALS; pALS) have extensive care needs, from wheelchairs to feeding tubes to caregiving support. The financial impact of these needs on pALS and their caregivers (cALS) has not been fully explored. We aimed to explore the types of expenses for which pALS and cALS crowdfund, and the financial circumstances that lead them to resort to crowdfunding.

METHODS: We randomly selected 320 ALS-related crowdfunding campaigns posted on the GoFundMe platform from 2010-2020. We conducted a summative content analysis to categorize the expenses for which campaigns requested money and descriptions of financial burden.

RESULTS: We included 266 campaigns. Most campaigns were written by people who were not the pALS or cALS, such as children or coworkers (85.3%). Most campaigns fundraised for medication and treatment costs (21.4%), equipment (25.2%), accessibility needs for home (24.0%), and transportation (19.5%), and in-home caregiving services (18%). Multiple campaigns (22.9%) requested assistance with nonmedical expenses ranging from rent and utilities to personal travel and hobby goals. Many campaign writers (47.7%) described financial burden related to the pALS' diagnosis, including medical debt (4.5%) and job loss of the pALS (30.5%) and/or cALS (6.8%).

DISCUSSION: Our analysis of ALS-related crowdfunding campaigns highlights the breadth of medical and nonmedical care needs and quality of life goals for which people request additional financial support throughout the disease course. These findings provide important insights for ALS care teams into the expenses of pALS.}, } @article {pmid42709165, year = {2026}, author = {Hamzeh, LH and Seyed, E and Elgendy, MA and Heib, D and Sadek, BI and Mohammed, COS and El Refaei, K and Soliman, YF and Eldmrdash, N and Abdelgalil, MS and Elsayed, MM}, title = {Efficacy and safety of memantine in adults with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {42709165}, issn = {1435-1463}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.}, } @article {pmid42709336, year = {2026}, author = {Colosimo, C}, title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {42709336}, issn = {1179-1918}, abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.}, } @article {pmid42710553, year = {2026}, author = {Babu, D and Le, TH and Liu, H and Raji, D and Tran, NH and Lockhart, S and Tran, P and Eldalal, O and Tonoyan, L and Siraki, AG}, title = {Edaravone as an antioxidant adjuvant to attenuate clozapine toxicity in vitro.}, journal = {Toxicology letters}, volume = {425}, number = {}, pages = {113188}, doi = {10.1016/j.toxlet.2026.113188}, pmid = {42710553}, issn = {1879-3169}, abstract = {Despite being the gold-standard therapy for treatment-resistant schizophrenia, clozapine use remains constrained by the risk of rare but serious adverse drug reactions, including severe neutropenia and agranulocytosis. Neutrophil myeloperoxidase (MPO)-mediated bioactivation of clozapine to reactive metabolites has long been implicated in agranulocytosis. Although clozapine is metabolized by MPO, there are numerous other compounds that can also be metabolized by this enzyme. Edaravone is a drug used to treat amyotrophic lateral sclerosis and has potent antioxidant activity; we have previously shown that edaravone is metabolized by MPO. Therefore, we hypothesized that edaravone can attenuate early toxicological events associated with clozapine through MPO modulation. Using purified human MPO, MPO-rich human promyelocytic leukemia (HL-60) cells, and isolated human neutrophils, we evaluated clozapine oxidation, competitive intracellular uptake, protein adduct formation, and cytotoxicity. UV-visible spectroscopy demonstrated concentration-dependent inhibition of MPO-catalyzed clozapine oxidation by edaravone, with 100 µM edaravone producing suppression comparable to 100 µM 4-aminobenzoic acid hydrazide. LC-MS analysis showed that MPO/H2O2 reduced clozapine levels to 26.7 ± 2.9% of control, whereas co-incubation with edaravone preserved clozapine to 67.9 ± 16.2%. Under the same conditions, edaravone was almost completely consumed (0.03 ± 0.02% remaining), consistent with its sacrificial antioxidant activity. In HL-60 cells, edaravone attenuated MPO activity and did not significantly alter clozapine uptake after 30 min (97.2 ± 7.6% of clozapine alone). Immunoblotting revealed that edaravone reduced clozapine-protein adduct formation in purified MPO, HL-60 cells, and neutrophils. Clozapine (75 µM) induced marked HL-60 cytotoxicity after 24 h, whereas edaravone concentration-dependently restored viability, with 200 µM fully preventing toxicity. These findings provide proof-of-concept that edaravone mitigates multiple mechanistic events linked to clozapine-induced hematological toxicity and may represent a potential strategy to improve clozapine safety.}, } @article {pmid42716044, year = {2026}, author = {Cudkowicz, ME and Shefner, J and van den Berg, LH and Chio, A and Fan, D and Großkreutz, J and Lunetta, C and Tsai, RM and Li, Y and Wallstroem, E and Xiong, L and Chen, Y and Atassi, N and , }, title = {Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {900-910}, doi = {10.1016/S1474-4422(26)00277-2}, pmid = {42716044}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Middle Aged ; Male ; Female ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Treatment Outcome ; Adolescent ; }, abstract = {BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS.

METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early.

FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820.

INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted.

FUNDING: Sanofi.}, } @article {pmid42716045, year = {2026}, author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR}, title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.}, journal = {The Lancet. Neurology}, volume = {25}, number = {10}, pages = {926-938}, doi = {10.1016/S1474-4422(26)00246-2}, pmid = {42716045}, issn = {1474-4465}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; }, abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.}, } @article {pmid42719214, year = {2026}, author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP}, title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.}, journal = {3 Biotech}, volume = {16}, number = {10}, pages = {420}, pmid = {42719214}, issn = {2190-572X}, abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.}, } @article {pmid42720979, year = {2026}, author = {Huang, CS and Sanchez-Santos, C and Martinez-Gonzalez, L and Gil, C and Martinez, A}, title = {Innovative therapies under clinical development for ALS treatment. Part 2: biologics and natural products.}, journal = {Expert opinion on investigational drugs}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/13543784.2026.2729512}, pmid = {42720979}, issn = {1744-7658}, abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is rapidly expanding despite ongoing translational challenges. Following our 2022 analysis and as a continuation of Part 1, which focused on small molecules, this review provides a structured overview of biologics and natural products in the ALS clinical pipeline. Particular emphasis is placed on candidates that entered, advanced through, or completed clinical evaluation between 2022 and the end of 2025.

AREAS COVERED: Clinical trials for ALS registered in the United States (ClinicalTrials.gov) and the European Union (EU Clinical Trials Register/CTIS) were systematically reviewed and are summarized in this report.

EXPERT OPINION: Modern biotechnology, ethnopharmacology, and classical pharmacology are increasingly converging in ALS therapeutic development, making this one of the most active areas of neurodegenerative disease research. Nevertheless, major challenges remain, including central nervous system (CNS) penetration, long-term safety, interpatient variability, limited clinical evidence, and the need for reliable biomarkers. Emerging technologies, such as big data analytics and artificial intelligence, may help accelerate and optimize therapeutic development, as well as improve patient recruitment and stratification.}, } @article {pmid42721706, year = {2026}, author = {Viljoen, S and Chaves, JCS and Peall, I and White, AR and Oikari, LE}, title = {Dysfunction of the blood-brain barrier and neurovascular unit in amyotrophic lateral sclerosis - From advanced human models to treatments.}, journal = {Journal of the neurological sciences}, volume = {490}, number = {}, pages = {126168}, doi = {10.1016/j.jns.2026.126168}, pmid = {42721706}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/metabolism/therapy/pathology ; *Blood-Brain Barrier/physiopathology/metabolism/pathology ; Animals ; *Neurovascular Coupling/physiology ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by the degeneration of motor neurons, resulting in progressive and eventually complete loss of motor function. The phenotypical heterogeneity of ALS poses a challenge to early diagnosis and treatment, with currently available therapeutics only capable of relieving symptoms and slowing progression. While ALS is classified as a motor neuron disease (MND), research has identified significant impairment to the blood-brain barrier (BBB) and neurovascular unit (NVU) of ALS patients. The BBB along with supporting cells of the NVU selectively control the entry of substances into the central nervous system (CNS) and maintain brain homeostasis, with its many cellular components demonstrating impaired function, specifically relating to inflammation, oxidative stress and TDP-43 proteinopathy. The advent of more advanced in vitro techniques as well as use of patient-derived BBB cells has presented a promising alternative to recreate the in vivo structure of the BBB/NVU in a highly controlled platform. Such approaches have ranged from simple 2-dimensional (2D) cell culture to intricate 3-dimensional (3D) co-culture systems, as well as microfluidic systems and organoids, with a potential to investigate ALS associated BBB/NVU dysfunction and drug discovery. This review provides a comprehensive assessment of known BBB/NVU dysfunction in ALS and methods of investigating this using in vitro and in vivo platforms with a focus on inflammation, oxidative stress and pathological TDP-43 expression. This review also presents a future perspective to overcoming barriers to treatment of ALS using new patient-derived BBB/NVU model systems.}, } @article {pmid42722039, year = {2026}, author = {Morisaki, Y and Nomura, N and Matsuda, M and Ohshima, M and Fukuda, R and Komine, O and Okuda, T and Yamanaka, K and Misawa, H}, title = {Anti-LAG-3 antibody treatment initiated after symptom onset extends survival in ALS model mice.}, journal = {Neuroscience research}, volume = {231}, number = {}, pages = {105119}, doi = {10.1016/j.neures.2026.105119}, pmid = {42722039}, issn = {1872-8111}, abstract = {Immune checkpoint molecules have emerged as regulators of microglial function in neurodegenerative diseases. We previously demonstrated that LAG-3 shapes disease-associated microglial phenotypes in ALS and that germline LAG-3 deletion in SOD1[G93A] mice accelerated disease onset but extended duration, leaving survival unchanged. Here, we investigated the therapeutic efficacy of anti-LAG-3 antibody treatment starting after symptom onset. Anti-LAG-3 treatment extended survival, slowed neurological and motor decline, preserved body weight and motor neurons, and reduced microgliosis. Within microglia, the Axl[+] phagocytic-module fraction increased while the Dectin-1[+] inflammatory-module fraction decreased. These findings indicate that post-onset LAG-3 inhibition is a promising therapeutic strategy for ALS.}, } @article {pmid42722112, year = {2026}, author = {Butt, TH and Strait, M and Marcinczyk, L and Katz, G and Kalia, V and Jaafar, C and Saxena, R and Divjan, A and Saglimbeni, B and Munoz Umanes, ME and Tipps, E and Han, M and Mehta, P and Lee, I and Mitsumoto, H and Factor-Litvak, P and Shneider, NA and Kioumourtzoglou, MA and Re, DB}, title = {Astrocyte-derived extracellular vesicle phosphorylated TDP-43 as a blood-based biomarker for amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107601}, doi = {10.1016/j.nbd.2026.107601}, pmid = {42722112}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by central nervous system (CNS) neuroglial TAR DNA-binding protein 43 (TDP-43) pathology in ∼90-95% of cases. Non-invasive biomarkers are critically needed to reduce diagnostic delay, enable patient stratification, and assess treatment efficacy in clinical trials. Astrocyte-derived extracellular vesicles (ADEVs) represent promising CNS liquid biopsy biomarkers, given astrocyte involvement in ALS pathogenesis and the ability of ADEVs to cross the blood-brain barrier and carry TDP-43. Here, we assessed the diagnostic performance of TDP-43 and its hyperphosphorylated pathological form, phospho-Ser409 (pTDP-43), quantified in ADEVs, for distinguishing ALS cases from matched healthy controls. ADEVs were immunoisolated from whole blood (n = 76) and plasma (n = 86) across three ALS biorepositories/cohorts. ADEV quality and enrichment were validated in accordance with minimal information for studies of extracellular vesicles guidelines, and protein levels were normalized by ratio to tetraspanin cluster of differentiation 81 (CD81). Diagnostic accuracy was evaluated by logistic regression and random forest models with cross-validation, adjusting for age and sex across 100 random seeds. Plasma ADEV pTDP-43/CD81 ratio best predicted ALS case status, with a mean AUC of 0.89 (95% CI: 0.75-0.99) from logistic models, corresponding to a mean sensitivity and specificity of 87% and 89%, respectively, and a mean AUC of 0.86 (95% CI: 0.82-0.90) from random forest models. Although the specificity of ADEV pTDP-43 relative to disease mimics and associations with disease progression require further investigation, these findings support its potential as a biomarker candidate for ALS and for patient stratification in TDP-43-targeted clinical trials.}, } @article {pmid42725432, year = {2026}, author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, EL and Asher, MJ and Isaacs, AM and Garner, AL and Todd, PK}, title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.}, journal = {Nucleic acids research}, volume = {54}, number = {17}, pages = {}, pmid = {42725432}, issn = {1362-4962}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; R01NS099280/NH/NIH HHS/United States ; I01BX004842-04/BX/BLRD VA/United States ; F31 NS113513/NS/NINDS NIH HHS/United States ; R35 GM153185/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R35 GM153185/NH/NIH HHS/United States ; //NGP/ ; T32 GM141840/NH/NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; P50HD104463/NH/NIH HHS/United States ; F31NS113513/NH/NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; //UM MSTP/ ; R01NS086810/NH/NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; }, mesh = {*Neurons/metabolism ; *Codon, Initiator ; Animals ; Humans ; RNA Caps/metabolism/genetics ; C9orf72 Protein/genetics ; *Peptide Chain Initiation, Translational ; *Protein Biosynthesis ; DNA Repeat Expansion ; Eukaryotic Initiation Factor-4E/antagonists & inhibitors ; RNA, Messenger/metabolism/genetics ; Guanosine/analogs & derivatives/metabolism ; }, abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.}, } @article {pmid42725564, year = {2026}, author = {Peng, L and Ma, S and Liu, Y and Liu, S and Tang, L}, title = {Artificial liver support therapy alters TNFα and CD4+ T cell counts in liver failure: A pilot self-controlled study.}, journal = {The International journal of artificial organs}, volume = {}, number = {}, pages = {3913988261479971}, doi = {10.1177/03913988261479971}, pmid = {42725564}, issn = {1724-6040}, abstract = {BACKGROUND: Artificial liver support therapy (ALS) is increasingly used in liver failure, but its immunomodulatory effects remain incompletely understood. This pilot study aimed to investigate changes in plasma cytokines and T lymphocyte subsets following ALS.

METHODS: Twenty-seven patients with liver failure who received ALS were enrolled. Plasma levels of TNFα, IL-4, IL-6, IL-10, IL-17, IL-2, and IFN-γ, as well as T lymphocyte subsets (CD4+ T cell absolute count, CD4+/CD8+ ratio), were measured before and after treatment. Paired t‑tests were used for comparisons. Patients were dichotomized by median pre-treatment TNFα level to compare clinical outcomes.

RESULTS: After ALS, TNFα levels decreased significantly (2.537 ± 1.519 vs 1.522 ± 0.749 pg/mL, p = 0.004). IL-4 also showed a significant reduction (1.463 ± 1.165 vs 0.893 ± 0.648 pg/mL, p = 0.031). CD4+ T cell absolute count increased significantly (430.85 ± 220.15 vs 636.63 ± 429.27 cells/μL, p = 0.034). Total T cell count showed an increasing trend (788.70 vs 1093.63 cells/μL, p = 0.064). Patients with low pre-treatment TNFα levels (below median) had a significantly higher improvement rate compared to those with high TNFα levels (100% vs 71.4%, p = 0.036).

CONCLUSION: ALS therapy is associated with a significant reduction in TNFα and a significant increase in CD4+ T cell absolute count, suggesting potential anti‑inflammatory and immune‑restorative effects. Lower baseline TNFα levels may predict favorable short‑term outcomes.}, } @article {pmid42728797, year = {2026}, author = {Sanghai, N and Pierce, K and Sharma, N and Leggett, S and Yadav, TC and Masrori, P and Atukorallaya, D and Palaniyandi, S and Marcogliese, PC and Tranmer, GK}, title = {Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).}, journal = {CNS neuroscience & therapeutics}, volume = {32}, number = {9}, pages = {e71078}, pmid = {42728797}, issn = {1755-5949}, support = {RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant/ ; 202210PJT-495295/CAPMC/CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Blood-Brain Barrier/drug effects/metabolism ; Animals ; *Drug Delivery Systems/methods/trends ; Blood-Spinal Cord Barrier/drug effects/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology.

OBJECTIVE: To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes.

METHODS: Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed.

RESULTS: Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes.

CONCLUSIONS: Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.}, } @article {pmid42735682, year = {2026}, author = {Cousin, MA and Dagli, AI and Mignon, L and Shah, JS and Prudencio, M and Gendron, TF and Jain, A and Udine, E and van Blitterswijk, M and Middlebrooks, EH and Donahue, MH and Dagher, JE and Watzlawik, JO and Springer, W and Parekh, T and McEachin, ZT and Petrucelli, L and Oskarsson, B}, title = {N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.}, journal = {Med (New York, N.Y.)}, volume = {}, number = {}, pages = {101295}, pmid = {42735682}, issn = {2666-6340}, support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; U01 NS134684/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Pathogenic CHCHD10 variants cause a rare, dominantly inherited form of amyotrophic lateral sclerosis (ALS). Non-allele-selective CHCHD10 knockdown may mitigate a toxic gain-of-function mechanism. We evaluated nL-CHCHD-001 in one participant with the p.Arg15Leu variant.

METHODS: In this open-label N-of-1 study, 320-gapmer antisense oligonucleotides (ASOs) were screened, and a lead candidate was selected according to specificity and non-clinical safety criteria. Six intrathecal doses were administered over 12 months (three 50-mg doses followed by three 75-mg doses). Prespecified primary outcomes were 12-month changes in functional, cognitive, quality-of-life, respiratory, neurofilament light (NfL), and survival measures; secondary outcomes assessed were safety and tolerability. Analyses were descriptive.

FINDINGS: No serious adverse events occurred. Post-dose headache and fatigue were mild to moderate, and cerebrospinal fluid safety results were unremarkable. Plasma NfL decreased by approximately 50% from a mildly elevated pretreatment baseline and entered the laboratory reference range. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score increased from 33 to 36, vital capacity increased from 48% to 55% (as predicted), cognitive and quality-of-life scores remained stable, and the participant was alive at 12 months.

CONCLUSIONS: Individualized CHCHD10-directed treatment was feasible and well tolerated and was temporally associated with biomarker and clinical stability or improvement. This N-of-1 study demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit. These findings support further evaluation of nL-CHCHD-001 and highlight NfL as a practical treatment-response biomarker for personalized therapeutics in ALS.

CLINICALTRIALS: gov: NCT06392126.

FUNDING: This study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.}, } @article {pmid42738680, year = {2026}, author = {Strekalova, T and Gorlova, A and Munter, JPM and Chervinskaya, M and Deykin, A and Aladysheva, Z and Grigorieva, E and Lyundup, A and Askarova, S and Kostin, A and Pomytkin, I}, title = {Beneficial Effects of Putative Hydrogen Sulfide (H2S) Donor POM16 in a Genetic Model of Amyotrophic Lateral Sclerosis, FUS [1-359]-Transgenic Mice.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {17}, pages = {}, pmid = {42738680}, issn = {1420-3049}, support = {AP23485236//Ministry of Science and Higher Education of the R public of Kazakhstan/ ; FZWG-2024-0003//Ministry of Science and Higher Education of RF/ ; 101086453//European Union/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Hydrogen Sulfide/metabolism/chemistry ; Mice, Transgenic ; Disease Models, Animal ; Mice ; Spinal Cord/metabolism/drug effects/pathology ; Oxidative Stress/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by rapid motoneuron degeneration. Hydrogen sulfide (H2S), a signaling molecule that regulates post-translational modification, has recently been implicated in the pathophysiology of ALS. Our study aimed to design, synthesize, and investigate the potential effects of (2S)-2-aminopentanethioic S-acid (POM16), an isomer of the slow-releasing H2S donor thiovaline, in a genetic ALS model. FUS [1-359]-tg mice, which recapitulate ALS syndrome, and their wild-type (WT) littermates received POM16 (at a dose of 50/mg/kg) or standard ALS therapy riluzole (at a dose of 8 mg/kg/day) dissolved in drinking water, or vehicle, for six weeks starting at nine weeks of age. The onset of paralysis, physiological and motor functions, muscle atrophy, density of spinal cord motoneurons, gene expression of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF), and concentration of oxidative stress marker malondialdehyde (MDA) in the spinal cord were studied. POM16-treated mutants displayed significant improvements in body weight, water and diet intake, as well as behavior in the rotarod, wire, and pole tests. The percentage of mice with paralysis on the 6th week of dosing was reduced from 48% in vehicle-treated mutants to 16% in POM16-treated FUS [1-359]-tg mice, while in the riluzole-treated group, it was 38%, not reaching significance. Notably, muscle weight was not significantly improved by the latter treatment, unlike the dosing with POM16. In comparison with vehicle-treated FUS [1-359]-tg mice, POM16-treated mutants had significantly higher motor neuron density in the spinal cord, lower MDA levels, and reduced muscle atrophy ranking. Thus, new compound POM16 has a therapeutic potential to counteract ALS pathology that is likely mediated via anti-oxidative stress mechanisms. Given that any effective treatment of this devastating disease is currently lacking, it is hoped that POM16 can be a promising therapy for ALS.}, } @article {pmid42738864, year = {2026}, author = {Ma, X and Liu, J and Guan, Y and Xu, C and Li, M and Zhang, X and Li, Z and Zhang, L and Wang, X and Zhang, H and Chen, Y}, title = {Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {15}, number = {17}, pages = {}, pmid = {42738864}, issn = {2073-4409}, support = {No.82571627//National Natural Science Foundation of China/ ; No.82271483//National Natural Science Foundation of China/ ; No. ZR2024MH112//Shandong Province Natural Science Foundation of China/ ; 202402010641//Shandong Provincial Medical and Health Science and Technology Development Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Lactic Acid/metabolism ; *Signal Transduction ; Animals ; Motor Neurons/metabolism/pathology ; Energy Metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons (MNs). Although the specific pathogenesis of ALS is not yet fully understood, there is increasing evidence that abnormal energy metabolism plays a key role in the onset and progression of the disease. Lactate has traditionally been considered a metabolic by-product of glycolysis and has received increasing attention in recent years. Research has shown that lactate is not only an important energy substrate but also a signaling molecule that regulates a variety of physiological processes, including neuron-glia metabolic coupling, neuroprotection and inflammatory responses. In ALS, abnormalities in lactate metabolism, dysfunction of the lactate shuttle, and dysregulation of lactate-related signaling pathways may jointly lead to neuronal energy deficits and increased neuroinflammation, thereby promoting MN degeneration. This review summarizes the latest advances in lactate metabolism and lactate-mediated signaling in ALS, with particular emphasis on their roles in neuronal energy regulation, neuroprotection and inflammatory regulation. In addition, we also discuss potential therapeutic strategies for lactate metabolism and its related pathways, aiming to provide new insights into the pathogenesis of ALS and the development of treatment methods for lactate-related metabolism.}, } @article {pmid42739287, year = {2026}, author = {Chen, M and Li, H and Jin, Q}, title = {Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {17}, pages = {}, pmid = {42739287}, issn = {2075-4418}, support = {81671117//National Natural Science Foundation of China/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic abnormalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable prodromal phenotypes and predicting phenoconversion timing. Operational MMI criteria, longitudinal imaging in chromosome 9 open reading frame 72 (C9orf72) expansion carriers, TAR DNA-binding protein 43 (TDP-43)-related fluid biomarkers, and plasma proteomic models spanning prediction horizons have broadened early identification. The ATLAS study, a trial of tofersen initiated in clinically presymptomatic carriers of superoxide dismutase 1 (SOD1) variants, incorporated specific SOD1 variants and within-person NfL increases into risk monitoring and used these criteria to select participants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconversion. Identification requires genotype-specific natural history, serial clinical examinations and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.}, } @article {pmid42740795, year = {2026}, author = {Imamura, K and Yoshioka, S and Kamizato, K and Oki, R and Hioki, H and Tsukita, K and Inoue, I and Shimizu, R and Takiguchi, M and Sakasai, T and Okusa, A and Shibukawa, R and Niki, T and Sakurai, S and Okunomiya, T and Kondo, T and Kato, T and Miyanohara, A and Kakinohana, M and Yamamoto, T and Marsala, M and Nishida, K and Izumi, Y and Inoue, H}, title = {Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {4}, pages = {201835}, pmid = {42740795}, issn = {3117-387X}, abstract = {In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.}, } @article {pmid42740868, year = {2026}, author = {Barker, TH and Bulto, LN and Holland, G and Schubert, C and Merlin, T and Karam, SG and Wiercioch, W and Pollock, D and Stern, C and Beasley-Hall, J and Shrestha, N and Vucic, S and Giles, L and Munn, Z}, title = {The Values and Preferences of People Living With Motor Neurone Disease (MND): A Systematic Review and Meta-Analysis.}, journal = {Clinical and public health guidelines}, volume = {3}, number = {3}, pages = {e70080}, pmid = {42740868}, issn = {2836-3973}, abstract = {AIM: To synthesise quantitative evidence on the values and preferences of people living with Motor Neurone Disease (MND), caregivers, and genetic carriers regarding health-related outcomes to inform the Australian MND Guideline.

METHODS: A systematic review was conducted following Cochrane and GRADE guidance, informed by an a priori protocol. Major electronic databases (including MEDLINE, Embase, CENTRAL) and trial registries were searched to identify studies that met the eligibility criteria. Risk of bias of the studies that met the eligibility criteria was assessed using the Risk of Bias in Studies of Values and Utilities (ROBVALU) tool. Data on health state utility values were synthesised using meta-analysis where appropriate, while other quantitative data deemed inappropriate for meta-analysis were synthesised narratively. The certainty of the evidence for each outcome was assessed using the GRADE approach.

RESULTS: Twenty-four studies (n = 10,397) were included. Overall health-related quality of life (hrQoL) utility values for adults with MND varied significantly based on the regional preference set utilised (mean EQ-5D utility ranging from 0.57 in UK cohort (high certainty in the evidence) to 0.72 in Chinese cohorts (low certainty in the evidence). Utility values declined consistently with increasing disease severity across multiple staging systems, such as King's and MiToS. Narrative synthesis identified clear preferences across physical, psychosocial, and healthcare domains regarding both current and hypothetical treatment strategies.

CONCLUSION: This review provides a comprehensive synthesis of the values and preferences of the broad MND community. This review has been conducted following rigorous best-practice methodology, to directly inform the selection and prioritisation of outcomes for the development of the Australian MND Guideline, ensuring the guideline adheres to a patient-centred approach. Standardisation of preference elicitation methods from the MND community, and the development of a core outcome set for future MND research are key future priorities.}, } @article {pmid42740981, year = {2026}, author = {Xie, G and Guo, Y and Wang, Z}, title = {Prevalence of and associated factors for sleep disorders in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {17}, number = {}, pages = {1889217}, pmid = {42740981}, issn = {1664-2295}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; *Sleep Wake Disorders/epidemiology/etiology ; Prevalence ; }, abstract = {BACKGROUND: Sleep disorders stand as prevalent non-motor symptoms in individuals with amyotrophic lateral sclerosis (ALS) and may be linked to respiratory muscle weakness, neurodegenerative changes, and disruption of sleep architecture. Existing studies have reported considerable variability in the prevalence of sleep disorders in ALS patients, and findings regarding associated factors remain inconsistent. Therefore, this study intended to integrate the existing evidence through a meta-analysis to further clarify the prevalence of sleep disorders and their clinical relevant factors.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from database inception to January 10, 2026. Cross-sectional, cohort, and case-control studies involving clinically diagnosed adult patients with ALS were included. A random-effects model was used to estimate the pooled prevalence of sleep disorders. Subgroup analyses were performed according to sex, site of onset, age, disease duration, body mass index (BMI), sleep disorder category based on the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), sleep-related treatment status, and assessment method (polysomnography [PSG] versus questionnaire-based assessment).

RESULTS: A total of 31 studies involving 2,762 patients with ALS were included. The pooled prevalence of sleep disorders was 50% (95% confidence interval [CI], 45-56%). Patients with sleep disorders were significantly older than those without sleep disorders (mean difference [MD] = 3.72 years, 95% CI, 2.39-5.05), whereas no significant associations were observed for sex, body mass index (BMI), disease duration, or site of onset. The prevalence did not differ significantly across the ICSD-3-TR categories (p = 0.7367), whereas questionnaire-based studies yielded a significantly higher pooled prevalence than PSG-based studies (p = 0.0367). Sensitivity analyses confirmed the robustness of the findings.

CONCLUSION: Approximately half of ALS patients have sleep disorders. Age may be related to the occurrence of sleep disorders, whereas no substantial relations were identified for sex, BMI, disease duration, or site of onset. Routine screening and early intervention for sleep issues should be strengthened in clinical management. Large-scale, multicenter prospective studies are still needed to further clarify the underlying mechanisms and clinical implications.

The publicly accessible registration URL is: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287352. The systematic review was registered with PROSPERO (registration number: CRD420261287352).}, } @article {pmid42741938, year = {2026}, author = {Zhang, B and He, Y and Su, T and Li, X and Zhang, X and Liu, R and Han, X and Zhang, R and Yang, C and Liu, X and Hou, Q and Zhang, Z and Xie, Y and Liu, G and Yang, X}, title = {UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {18}, pages = {}, pmid = {42741938}, issn = {1558-8238}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Mitophagy/drug effects ; Mice ; Forkhead Box Protein O3/metabolism/genetics ; Mice, Transgenic ; Humans ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.}, } @article {pmid42742464, year = {2026}, author = {Zheng, Y and Ellison, TJ and Garrard, R and Gao, J and Lai, X and Lan, L and Xie, J and Jiang, J and Yao, Y}, title = {Neural Stem Cell-Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis.}, journal = {Journal of extracellular vesicles}, volume = {15}, number = {9}, pages = {e70370}, pmid = {42742464}, issn = {2001-3078}, support = {R01 AG068247/AG/NIA NIH HHS/United States ; R01AG068247/AG/NIA NIH HHS/United States ; W81XWH2210261//Department of Defense/ ; /NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; *Extracellular Vesicles/metabolism ; *Oligonucleotides, Antisense/administration & dosage/pharmacology/therapeutic use ; *Neural Stem Cells/metabolism ; Mice ; Humans ; Disease Models, Animal ; *Central Nervous System/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/metabolism ; Male ; Administration, Intranasal ; }, abstract = {Antisense oligonucleotides (ASOs) hold clinical promise for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Yet, their efficacy is constrained by the need for invasive delivery, poor central nervous system (CNS) penetration, inefficient cellular uptake and rapid clearance. Here, we developed neural stem cell-derived extracellular vesicles (NSC-EVs) as natural carriers to enhance CNS targeting and therapeutic efficacy of ASO-based treatments for ALS. Using a passive loading method, therapeutic ASOs were efficiently associated with NSC-EVs (NSC-EV-ASO). Compared with free ASOs, NSC-EVs- ASOs exhibited markedly enhanced neuronal uptake in vitro and increased CNS accumulation and neuronal localization in vivo following intracerebroventricular, intranasal, or intravenous administration. Functionally, NSC-EV-ASOs reduced the mutant SOD1 protein expression and the pathogenic hexanucleotide repeats in the C9orf72 loci in ALS cellular models. In the ALS mouse model, intranasal administration of NSC-EV-ASOs more efficiently delayed disease onset, improved motor performance, preserved motor neurons and attenuated astrocyte activation during the study period compared with free ASOs. These findings provide proof-of-concept evidence supporting the potential of NSC-EV as a promising platform that not only enhances CNS delivery of ASOs but also contributes to overall therapeutic activity, offering a synergistic strategy to advance nucleic acid therapeutics for ALS and potentially other neurological diseases.}, } @article {pmid42746532, year = {2026}, author = {Zhang, E and Oh, P and Shamas, T and Patwa, HS and Johung, KL}, title = {Radiation Therapy for Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Case Series and Critical Review.}, journal = {Advances in radiation oncology}, volume = {11}, number = {9}, pages = {102135}, pmid = {42746532}, issn = {2452-1094}, abstract = {PURPOSE: Radiation therapy (RT) for sialorrhea has historically used 3-dimensional techniques that broadly irradiate both major and minor salivary glands. However, some reports indicate that treatment of minor salivary glands may contribute to excessive xerostomia. In this retrospective case series, we assessed the efficacy and tolerability of oral-cavity-sparing volumetric modulated arc therapy (VMAT) and bilateral electron field radiation for sialorrhea in patients with amyotrophic lateral sclerosis (ALS) and reviewed the relevant literature.

METHODS AND MATERIALS: From 2014 to 2025, 6 patients with bulbar-onset ALS and medically refractory sialorrhea were treated with RT to the parotid and submandibular glands (20 Gy in 5 fractions) at a single institution. Five patients received VMAT with 6 MV photons, and one received bilateral 16 MeV electrons. Clinical response, medication use, toxicity, and dosimetry were assessed. A PubMed search using "sialorrhea," "RT," and "amyotrophic lateral sclerosis" was performed for the literature review.

RESULTS: At a median follow-up of 15.05 months (range, 3.0-61.7 months), 5 of 6 patients (83.3%) achieved symptomatic improvement, with an average 60% patient-reported reduction in salivation and ≥2 point improvement in ALS Functional Rating Scale saliva subscore. Two discontinued anticholinergics, and 1 achieved complete resolution for 3 years. Acute toxicities with VMAT were mild and self-limiting, most commonly parotitis and thickened secretions. The patient treated with electrons developed grade 2 mucositis, not observed with VMAT. Late toxicities, including xerostomia, were minimal and transient. Dosimetry showed higher larynx and oral cavity doses with electrons, whereas VMAT delivered slightly higher spinal cord doses. Critical literature review supported RT as an effective and well-tolerated intervention.

CONCLUSIONS: RT provides durable relief of refractory sialorrhea in ALS with manageable toxicity. VMAT response is comparable with historical outcomes and may offer dosimetric advantages that correlate with reduced acute toxicities, although its clinical benefit and cost-effectiveness warrant further validation.}, } @article {pmid42751965, year = {2026}, author = {van Eijk, RPA and Lu, Y}, title = {Comparing Missing Data Strategies for Generalized Pairwise Comparisons in Randomized Clinical Trials: A Simulation Study.}, journal = {Statistics in medicine}, volume = {45}, number = {20-22}, pages = {e70737}, pmid = {42751965}, issn = {1097-0258}, support = {VENI 09150162210036//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; AL230152//U.S. Department of Defense/ ; }, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Bias ; Amyotrophic Lateral Sclerosis/therapy ; Data Interpretation, Statistical ; Models, Statistical ; Longitudinal Studies ; Survival Analysis ; Endpoint Determination ; }, abstract = {Generalized pairwise comparisons are increasingly being used in randomized clinical trials. This study evaluates how missing data strategies impact the operating characteristics of endpoints combining overall survival and a longitudinal outcome. A simulation study was conducted to evaluate the impact of censoring and missing longitudinal data on the Type I error, power, and bias of a hierarchical composite endpoint. Seven missing data strategies were identified from the literature, including assigning ties to missing patient pairs, comparing patients at their last common visit, and applying multiple imputation. Conditional longitudinal and survival data were generated based on the natural history of amyotrophic lateral sclerosis. Simulation scenarios varied in censoring rates, extent of missing longitudinal data, differential attrition between treatment arms, and the dependency of missingness on disease severity. All methods were unbiased and maintained nominal Type I error when censoring and missingness were balanced across treatment arms. Under imbalance, however, Type I error increased-reaching up to 0.378 for some strategies. The last common visit strategy was the only approach that consistently preserved nominal error rates (0.025 ± 0.002). Regarding statistical power, all methods exhibited a loss of precision and increased bias under the alternative hypothesis as missingness increased. Multiple imputation partially recovered power and reduced bias but inflated the Type I error rate in scenarios with differential attrition. As generalized pairwise comparisons are increasingly used in pivotal clinical trials-and therefore in regulatory contexts-our findings provide practical guidance for selecting a robust primary analysis strategy and minimizing bias arising from incomplete data.}, } @article {pmid42756552, year = {2026}, author = {Thompson, D and Williams, C and Price, G and Tosolini, AP and Falker-Gieske, C and Gilthorpe, JD and Schiavo, G and Fisher, EMC and Cunningham, TJ}, title = {Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1[A5V] mice.}, journal = {Brain communications}, volume = {8}, number = {5}, pages = {fcag302}, pmid = {42756552}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1) accounts for 15-30% of familial cases and is typically autosomal dominant. How single amino acid changes in this small protein cause neurodegeneration is unknown. In North America, SOD1[A5V] is the most common familial SOD1 mutation and results in an aggressive form of amyotrophic lateral sclerosis. Here, we present a novel genomically humanized mouse model of SOD1[A5V] , in which the mouse Sod1 locus has been replaced by the human SOD1 gene, with intact genomic architecture of exons and introns, but bearing an A5 V mutation. In agreement with previously reported human genomic knock-in mice, the phenotype is mild; however, transcriptomic and metabolomic profiling reveal significant dysregulation of glycolysis, the tricarboxylic acid cycle, and lipid metabolism. These changes suggest an early bioenergetic imbalance that precedes neuromuscular impairment. Our findings support metabolic dysfunction as an early event in amyotrophic lateral sclerosis pathogenesis. This freely available SOD1[A5V] model provides a valuable tool for studying amyotrophic lateral sclerosis progression and identifying therapeutic targets for pre-symptomatic treatment.}, } @article {pmid42758107, year = {2026}, author = {Abdanipour, A and Nikfar, A and Feizi, H}, title = {Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {72}, number = {5}, pages = {47-53}, doi = {10.14715/cmb/2026.72.5.7}, pmid = {42758107}, issn = {1165-158X}, mesh = {*Selegiline/pharmacology ; *Hydrogen Peroxide/pharmacology/toxicity ; Animals ; *NF-E2-Related Factor 2/genetics/metabolism ; *Hippocampus/cytology ; *Neural Stem Cells/drug effects/metabolism/cytology ; *Up-Regulation/drug effects ; Apoptosis/drug effects ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; Rats ; Cells, Cultured ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Neuroprotection/drug effects ; }, abstract = {Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H2O2)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10[-3] to 10[-9] M) prior to exposure to 125 μM H2O2. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10[-7] M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.}, } @article {pmid42758317, year = {2026}, author = {Calvo, A and Moglia, C and Callegaro, S and Canosa, A and Manera, U and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Maccabeo, A and Pellegrino, G and Minerva, E and Pascariu, D and D'Ovidio, F and Vasta, R and Mazzini, L and De Marchi, F and Chiò, A}, title = {What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions.}, journal = {Journal of neurology}, volume = {273}, number = {10}, pages = {}, pmid = {42758317}, issn = {1432-1459}, support = {PNRR-MAD-2022-12375731//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; 101017598//Horizon 2020 Framework Programme/ ; 259867//FP7 Ideas: European Research Council/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Female ; Prognosis ; Phenotype ; Male ; Middle Aged ; Aged ; Registries ; *Motor Neurons/pathology ; Prospective Studies ; }, abstract = {BACKGROUND: The ALS-OPM 3.3 classification stratifies incident ALS through three axes: onset region (O), propagation time (P) and motor-neuron pattern (M). We assessed whether OPM 3.3 improves prognostic discrimination over established classifications and characterised how it decomposes their prognostic signal in a population-based cohort.

METHODS: In the prospective Piedmont and Aosta Valley ALS Register (2000-2022), patients were classified on the three axes; M was operationalised as M_3class (M0 balanced, M1d UMN-predominant, M2d LMN-predominant), with the PLS-spectrum M1p analysed separately. Outcome was survival (death or tracheostomy) from onset. Multivariable Cox models (O, P1(n), M_3class, age, sex) underwent bootstrap optimism-correction and fivefold cross-validation, and were compared against alternative taxonomies and clinical staging systems.

RESULTS: Amongst 2,738 non-PLS patients (2,561 events, 93.5%), median survival differed across M classes (M0 27.0, M2d 36.0, M1d 41.9 months). OPM 3.3 outperformed the bulbar/spinal dichotomy but matched the classical phenotype (optimism-corrected C-index 0.703, 95% CI 0.685-0.719 vs 0.701). In the arm-proximal cell (95.7% M2d), the O2p protective effect vanished after M adjustment (HR 0.99, 95% CI 0.79-1.24), whilst M2d retained HR 0.83 (95% CI 0.72-0.95), showing prognosis reflects motor-neuron pattern, not anatomy. Adding King's, Milano-Torino (MiToS), or Fine'til 9 (FT9) clinical staging further improved discrimination.

CONCLUSIONS: OPM 3.3 did not improve discrimination over established phenotypes but decomposed their prognostic signal into independently interpretable dimensions. Favourable prognosis of arm-proximal/flail-arm onset reflects the underlying LMN-predominant phenotype, not onset site. The motor-neuron axis is robust to the treatment of the propagation axis and independent of clinical staging.}, } @article {pmid42759848, year = {2026}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HJ and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Nishimune, H and Arnold, WD}, title = {Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43[Q331K] mice.}, journal = {Neurobiology of disease}, volume = {229}, number = {}, pages = {107610}, doi = {10.1016/j.nbd.2026.107610}, pmid = {42759848}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence - a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype - has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43[Q331K] ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43[Q331K] mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.}, } @article {pmid42760861, year = {2026}, author = {De Nardi, A and Paris, A and Lauria, M and Martinelli, I and Zucchi, E and Simonini, C and Mandrioli, J and Marchetti, L}, title = {Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.}, journal = {European journal of neurology}, volume = {33}, number = {9}, pages = {e70756}, pmid = {42760861}, issn = {1468-1331}, support = {FGCR02/2015//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; GPG/2022/1343//Emilia Romagna Regional Health Authority/ ; 53232941//Pfizer/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/mortality/diagnosis ; *C9orf72 Protein/genetics ; Female ; Male ; Prognosis ; *Sirolimus/therapeutic use ; Middle Aged ; Survival Analysis ; Retrospective Studies ; Multivariate Analysis ; Aged ; Mutation ; Heterozygote ; Adult ; *Immunosuppressive Agents/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP-ALS, a clinical trial investigating the effects of rapamycin in ALS patients (n = 63).

METHODS: Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best-performing multivariate models in cross-validation. Longitudinal measures were incorporated by modeling covariates as time-dependent. Survival times of treated C9orf72 mutation carriers (n = 6) were further investigated through log-rank tests and restricted mean survival time analysis.

RESULTS: Univariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time-varying covariates allowed us to investigate late-stage risk factors, such as the neutrophil-to-lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log-rank test, p = 0.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort (n = 40; RMST test, p = 0.04).

CONCLUSIONS: The survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high-performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.}, } @article {pmid42770300, year = {2026}, author = {Oikawa, Y and Luo, Y and Suzuki, N and Kasahara, T and Tongu, Y and Yoshida, Y and Tominari, T and Tanabe, S and Suto, Y and Kashiwagi, H and Saito, S and Ikeda, K and Suzuki, C and Kuranaga, A and Akiyama, T and Morimoto, S and Aoki, Y and Muramatsu, R and Soga, T and Aoki, M and Okano, H and Tanaka, T and Abe, T and Kuranaga, E and Toyohara, T}, title = {Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation.}, journal = {JCI insight}, volume = {11}, number = {18}, pages = {}, pmid = {42770300}, issn = {2379-3708}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Animals ; Humans ; *Mitochondria/drug effects/metabolism ; Disease Models, Animal ; Phenotype ; Superoxide Dismutase-1/genetics/metabolism ; Fibroblasts/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Drosophila ; Induced Pluripotent Stem Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.}, } @article {pmid42771346, year = {2026}, author = {Paganoni, S and Chibnik, LB and Quintana, M and Macklin, EA and Detry, MA and Vestrucci, M and Paulon, G and McGlothlin, A and Wang, J and Walk, D and Elman, L and Chase, M and Heyd, L and Harkey, B and Sherman, AV and Shefner, J and Berry, JD and Scirocco, E and Giacomelli, E and Yu, H and Kittle, G and Hall, M and Ho, D and Jawdat, O and Ladha, S and Locatelli, E and Rivner, M and Felice, K and Katz, J and Ajroud-Driss, S and Fee, D and Miller, T and Rosow, L and Quick, A and Heitzman, D and Foster, LA and Maragakis, NJ and Goutman, SA and Rosenfeld, J and Benatar, M and Swenson, A and Connors, RD and Shroff, S and Bedlack, R and McIlduff, CE and Chen, IA and Fernandes, JAM and Walsh, A and Peltier, A and Ilieva, H and Diaz, F and Kushlaf, H and Beydoun, SR and Myers, B and Arcila-Londono, X and Heiman-Patterson, T and Elliott, M and Whitesell, J and Al-Lahham, T and Elliott, M and Olney, N and Baer, M and Jackson, C and Young, E and Caress, J and Weiss, MD and Kuenzler, R and Nayar, S and Kasarskis, EJ and Simmons, Z and Gibson, S and Owegi, MA and Goyal, NA and Wymer, JP and Gwathmey, KG and Erickson, A and Gursoy, N and Alameda, G and Bodkin, C and Wu, A and Martinez-Thompson, J and Twydell, PT and Andrews, J and Bayat, E and Rezania, K and Usman, U and McCluskey, L and Kovvuru, S and Jennings, D and Garza-Meilandt, A and Maciuca, R and Cohen, IV and Tamuly, D and Eren, E and Cudkowicz, ME and Babu, S and , }, title = {DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {9}, number = {9}, pages = {e2634809}, pmid = {42771346}, issn = {2574-3805}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Double-Blind Method ; Treatment Outcome ; }, abstract = {IMPORTANCE: DNL343 is a brain-penetrant small molecule that acts as an activator of eukaryotic translation initiation factor 2B (eIF2b), designed to inhibit the integrated stress response. A prior phase 1B trial of DNL343 in amyotrophic lateral sclerosis (ALS) provided evidence of a favorable safety profile, central nervous system penetrance, and target engagement based on integrated stress response biomarkers in blood and cerebrospinal fluid.

OBJECTIVES: To evaluate the safety and efficacy of a 200-mg formulation of DNL343 given once daily in individuals living with ALS.

DNL343 was evaluated as a regimen of the HEALEY ALS Platform Trial, a double-blind, multiregimen, placebo-controlled randomized clinical trial conducted at 74 centers in the US between May 24, 2023, and May 22, 2025. Eligible participants were randomized in a 3:1 ratio to receive DNL343 or matching placebo, with both groups enrolling concurrently. The analysis included shared randomized participants receiving placebo from an additional regimen.

INTERVENTION: The study drug was administered for a placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary analysis was a bayesian shared parameter model of function and survival that provided an integrated estimate of the relative rate of disease progression among participants receiving DNL343 relative to placebo. The model had components for function and survival linked through an integrated estimate of disease slowing in treatment relative to controls across the 2 outcomes (denoted as the disease rate ratio [DRR]). Several safety, secondary, and exploratory end points were also evaluated.

RESULTS: A total of 259 screenings were completed in this regimen; 249 participants met eligibility and were randomized to DNL343 (n = 186) and regimen-specific placebo (n = 63), with an additional 76 participants from a concurrent regimen receiving placebo included for a total of 139 shared placebo participants (325 participants, with 196 (60.3%) male and mean [SD] age of 59.3 [11.5] years). The estimated median DRR common to the ALS Functional Rating Scale-Revised and survival was 1.04 (95% credible interval, 0.83-1.32; probability of DRR <1, 0.37). Secondary outcome measures were not statistically different between the DNL343 and placebo groups. Overall, the incidence rates of adverse events were similar in participants receiving DNL343 and placebo.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, despite the relevance of the eIF2b activation pathway in ALS disease biology and supporting evidence of proof of mechanism and optimal dose selection in a prior phase 1B ALS clinical trial, 200-mg/d DNL343 did not show evidence of slowing disease progression in ALS, highlighting the need for alternative therapeutic approaches.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05842941.}, } @article {pmid42772919, year = {2026}, author = {Kernaghan, A and Harvey, A and Currie, H and McAlister, O and Walker, R and Chapman, F and McEneaney, D and Adgey, J}, title = {Incidence of refibrillation and shock-resistant ventricular fibrillation during OHCA when treated with a public access defibrillator: implications for CPR timing in lay rescuer-treated OHCA.}, journal = {Open heart}, volume = {13}, number = {2}, pages = {}, pmid = {42772919}, issn = {2053-3624}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/physiopathology/diagnosis ; *Ventricular Fibrillation/therapy/physiopathology/diagnosis/epidemiology/etiology ; *Electric Countershock/instrumentation/adverse effects ; *Defibrillators ; *Cardiopulmonary Resuscitation/methods/adverse effects ; Time Factors ; Retrospective Studies ; Incidence ; Female ; Male ; Aged ; Middle Aged ; Electrocardiography ; Emergency Medical Services ; Treatment Outcome ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) treatment often requires multiple defibrillatory shocks due to failed defibrillation or refibrillation. The complete nature of refractory ventricular fibrillation (VF) is unknown, as many studies do not consider shocks delivered by lay rescuers prior to the arrival of basic life support (BLS)/advanced life support (ALS) when quantifying refractory VF. ERC guidelines define refractory VF as continuous VF after three consecutive shocks, not differentiating between patients who refibrillate and those with shock-resistant VF (three consecutive failed shocks) which may contribute to this variation in reported incidence. There are some differences in treatment recommendations for patients who refibrillate and those with shock-resistant VF. Therefore, understanding the number of shocks delivered by lay-rescuers with public access defibrillators (PADs) and the patient's response to them prior to BLS/ALS arrival may inform treatment strategies.

METHODS: ECG data collected retrospectively from OHCAs treated by lay-rescuers using PADs were analysed. Cardiac rhythm, shock success, refibrillation, time to refibrillation and presence of shock-resistant VF (three consecutive failed shocks) were determined by two investigators.

RESULTS: Data were available for 1459 patients receiving at least one shock. Refibrillation occurred in 498 (34.1%) patients. The median number of refibrillations per patient was 1 (IQR 1, 2). Median time to refibrillation was 29.8 s. Three consecutive shocks were observed in 231 of the 1459 (15.8%) patients, 11 patients (4.8% of 231 patients) had shock-resistant VF.

CONCLUSION: When treated by lay-rescuers with PADs, refibrillation occurrence is lower than that reported for patients treated by BLS/ALS. However, aligned with BLS/ALS studies, in lay-rescuer treated OHCA, refibrillation typically occurs within the first 30 s following a successful shock. Therefore, patients who refibrillate are typically in VF for an additional 1.5 min before receiving a subsequent shock for PADs with a 2 min cardiopulmonary resuscitation (CPR) cycle. This finding emphasises the need for investigation into optimal CPR duration for patients requiring multiple shocks.}, } @article {pmid42780196, year = {2026}, author = {Okuda, M and Okinaka, Y and Saino, O and Taguchi, A}, title = {Case Report: Autologous bone marrow mononuclear cell transplantation improved motor function in a patient with amyotrophic lateral sclerosis.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1940826}, pmid = {42780196}, issn = {2296-858X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, and no established treatment restores impaired motor function. In mouse models of ALS, bone marrow mononuclear cell (BM-MNC) injection improved motor function. In patients with ALS, direct spinal cord injection of BM-MNCs has also been reported to improve motor function. Here, we report the case of a 52-year-old male patient with ALS who underwent intravenous autologous BM-MNC transplantation and demonstrated improved motor function. His revised ALS Functional Rating Scale score increased from 17 before treatment to 18 at 24 weeks after transplantation. The score of Manual Muscle Testing of fifth finger metacarpophalangeal joint flexion improved from 0 before treatment to 2(-) at 24 weeks after transplantation. No serious adverse events were observed. As this is a single case report, additional case series and subsequent randomized clinical trials are essential to clarify the effect of BM-MNC transplantation on ALS outcomes. This case suggests, however, that motor dysfunction in patients with ALS might be reversible. These findings encourage future studies investigating motor function improvement, rather than disease progression slowing, by elucidating the mechanisms underlying BM-MNC transplantation and optimizing treatment.}, } @article {pmid42783767, year = {2026}, author = {Kang, Z and Meng, R and Nie, M and Wang, T}, title = {Gut Microbial Metabolism as a Dynamic Interface in Neurodegenerative Diseases.}, journal = {Metabolites}, volume = {16}, number = {9}, pages = {}, pmid = {42783767}, issn = {2218-1989}, support = {No.82405557//China National Natural Science Foundation of youth project/ ; KM202410025018//R&D Program of Beijing Municipal Education Commission 2024: Study on the improvement of clinical symptoms and mechanism of acupuncture in amyotrophic lateral sclerosis/ ; 20250639//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; 2024-QNRC2-B08//2024-2026 Chinese Association of Chinese Medicine young Talent lifting project/ ; }, abstract = {Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer's disease (AD) as the principal model and compares selected features with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host-microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets.}, } @article {pmid42789802, year = {2026}, author = {Eng, NY and Rizvi, S and LaBarbera, V}, title = {Recognition and Treatment of Concurrent Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Rhode Island medical journal (2013)}, volume = {109}, number = {10}, pages = {11-14}, pmid = {42789802}, issn = {2327-2228}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/drug therapy/therapy ; *Multiple Sclerosis/diagnosis/complications/drug therapy/therapy ; Diagnosis, Differential ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are neurological disorders with different underlying pathophysiology but can share similar clinical features. Co-occurrence of both diseases is extremely rare with only 46 documented cases in literature to our knowledge. This case report relays the diagnosis of ALS in a patient with a decades'-long history of MS, and illustrates the importance of expanding the differential diagnosis and pursuing additional workup in a patient with overlapping progressive symptoms that can be caused by an alternate neurological etiology.}, } @article {pmid42790169, year = {2026}, author = {Zhang, B and Nan, J and Zhang, Y and Zhang, B and Ke, C and Wang, W and Wu, T and Xia, J and Yang, F and He, M and Tian, L and Yang, Z and Liang, C}, title = {Phytocannabinoid cannabidiol (CBD) in neurodegenerative diseases: From polypharmacology to drug development.}, journal = {European journal of medicinal chemistry}, volume = {320}, number = {}, pages = {119360}, doi = {10.1016/j.ejmech.2026.119360}, pmid = {42790169}, issn = {1768-3254}, abstract = {Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has attracted interest as a multi-target neurotherapeutic candidate for neurodegenerative diseases. CBD is a lipophilic terpenophenolic chemotype whose phenolic redox chemistry, membrane partitioning, cytochrome P450-mediated metabolism, and formulation-dependent exposure are central to its biological activity and translational limitations. In addition, CBD engages a broad target network relevant to neurodegeneration. Major components include cannabinoid receptors, transient receptor potential channels, peroxisome proliferator-activated receptor-γ, adenosine and serotonin signaling systems, voltage-gated calcium channels, and redox-regulatory pathways. These mechanisms converge on neuroinflammation, excitotoxicity, mitochondrial dysfunction, impaired proteostasis, and synaptic injury. Preclinical studies across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis consistently support CBD's anti-inflammatory, antioxidant, mitochondria-protective, and neuroprotective pharmacology. The magnitude of these effects depends on dose, treatment timing, model system, and route of administration. Clinical evidence remains preliminary and is mainly symptomatic, with signals in agitation, sleep disturbance, spasticity, quality of life, and neuropsychiatric symptoms rather than proven disease modification. Key barriers to development include low and variable oral bioavailability, incomplete brain exposure data, uncertain active metabolite contributions, limited target-engagement biomarkers, and insufficient exposure-response definition. Future development of CBD and optimized cannabinoid-derived analogues will require medicinal chemistry strategies to improve potency, selectivity, metabolic stability, CNS exposure, and formulation performance. Parallel biomarker-driven clinical trials are needed to define pharmacokinetic-pharmacodynamic relationships and evaluate disease-modifying potential.}, } @article {pmid42792156, year = {2026}, author = {Valerio, HP and Oliveira, V and Ferreira, SY and Pereira, IR and Palmisano, G and Massafera, MP and Bispo, VS and Prado, FM and Di Mascio, P and Medeiros, MHG}, title = {Carnosine Potentiates a Compensatory Mitochondrial-Synaptic Proteomic Response in the ALS Cerebellum.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {42792156}, issn = {2076-3921}, support = {2013/07937-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 408213/2024-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 2022/11334-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 304350/2023-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 304945/2021-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and chronic neuroinflammation in the brain and spinal cord, involving complex interactions between neurons and immune cells. Carnosine (β-alanyl-L-histidine) has pathophysiological relevance due to its ability to detoxify reactive carbonyl species, including α,β-unsaturated aldehydes, scavenge free radicals, and chelate zinc, and has also been proposed to function in the central nervous system as a histidine reservoir for histamine synthesis. Here, we investigated the effects of carnosine supplementation on the cerebellar proteome of SOD1[G93A] ALS rats using quantitative proteomics. Carnosine treatment extensively remodeled mitochondrial, antioxidant, and synaptic vesicle-trafficking protein networks and increased the abundance of glutamatergic and GABAergic receptor subunits relative to untreated ALS animals, with several of these changes exceeding wild-type levels. Pathway enrichment analyses identified significant up-regulation of Rab-mediated vesicle trafficking, synaptic vesicle cycling, and neurotransmitter transport/secretion pathways, alongside a partial reduction in RNA splicing and proteasomal subunits that were elevated in untreated ALS animals. Cross-comparison with the ALS-associated proteomic signature revealed that most carnosine-responsive proteins followed, rather than reversed, the direction of disease-associated change, indicating that carnosine predominantly potentiates an endogenous compensatory program rather than restoring a wild-type-like proteome. Collectively, these findings show that carnosine drives systems-level remodeling of mitochondrial and synaptic networks in the ALS cerebellum, identifying candidate compensatory pathways and supporting further functional validation of carnosine as a component of multimodal therapeutic strategies in ALS.}, } @article {pmid42792233, year = {2026}, author = {Sharbafshaaer, M and Pepe, R and Cortini, E and Biscardi, T and Notariale, R and Mesini, N and Zucchi, E and Mandrioli, J and Tessitore, A and Bergamo, P and Trojsi, F}, title = {Effects of Dietary Supplementation with Conjugated Linoleic Acid on Redox Marker Profiles and Neuroaxonal Degeneration in Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {15}, number = {9}, pages = {}, pmid = {42792233}, issn = {2076-3921}, support = {P202224WKC//European Union Next Generation EU/ ; }, abstract = {The revised ALS Functional Rating Scale (ALSFRS-R) and the blood plasma accumulation of neurofilament light chain (NfL) are key markers for tracking amyotrophic lateral sclerosis (ALS) progression. Based on recent studies indicating that dietary supplementation with conjugated linoleic acid (CLA) may boost antioxidant enzyme activity in ALS patients, in this study, ALSFRS-R scores (and subscores), NfL and thiol-bound protein (P-SH) levels, and intracellular activity of antioxidant enzymes (G6PD and GSR) were measured in ALS patients after 6 months (T6) of treatment with riluzole (R) or riluzole + CLA (R + CLA); we also investigated the correlations between these markers. At baseline (T0), G6PD activity in the R group was positively correlated with ALSFRS-R score (p < 0.001), whereas plasma P-SH levels in the R + CLA group were inversely correlated with ALSFRS-R score (p = 0.033). No significant baseline association was found between NfL levels and total ALSFRS-R score in the R group. At six months (T6), GSR and G6PD activities in the R + CLA group were significantly higher than in the R group (p < 0.05). Furthermore, a significant inverse correlation between plasma NfL levels and ALSFRS-R total score emerged at T6 exclusively in the R group (p = 0.002). Subscore analysis at T6 showed that plasma NfL levels negatively correlated with bulbar function in both groups (R: p = 0.010; R + CLA: p = 0.020) and with fine motor function in the R group (p = 0.031); whereas no significant correlation was observed for the respiratory subscore in either treatment group. These findings are consistent with an enhanced antioxidant activity associated with CLA supplementation. Overall, these preliminary exploratory results suggest that systemic redox biomarkers and plasma NfL may provide complementary, non-redundant information on distinct aspects of ALS pathobiology, though their precise temporal and mechanistic interactions require confirmation by dedicated longitudinal studies. The need for the combined use of neurodegeneration and oxidative-stress biomarkers for monitoring the progression of ALS is highlighted.}, } @article {pmid42793425, year = {2026}, author = {Mangiardi, M}, title = {Beyond Biomarkers: Reclaiming the Central Role of Clinical Neurophysiology in Neuromuscular Disorders.}, journal = {Brain sciences}, volume = {16}, number = {9}, pages = {}, pmid = {42793425}, issn = {2076-3425}, abstract = {Over the past two decades, advances in molecular genetics, immunology, neuroimaging, fluid biomarkers, and artificial intelligence have substantially transformed the diagnosis, classification, and treatment of neuromuscular disorders. However, increasing biological precision has also highlighted an important distinction between identifying disease mechanisms and characterizing their functional expression. Clinical neurophysiology occupies a specific position within this evolving diagnostic landscape by directly assessing nervous system function and providing objective information on impulse conduction, neuromuscular transmission, motor unit integrity, physiological reserve, and disease activity. Consequently, neurophysiological assessment contributes not only to diagnosis but also to differential diagnosis, longitudinal monitoring, prognostic assessment, and therapeutic evaluation. In this critical review, I examine the factors that have progressively shifted clinical neurophysiology from an interpretative clinical discipline toward a more procedural role. Using representative examples from myasthenia gravis, immune-mediated neuropathies, myopathies, and amyotrophic lateral sclerosis, I discuss how physiological information complements molecular, serological, imaging, and other biological biomarkers. I further examine the emerging role of artificial intelligence, including its potential for automated signal analysis and quantitative assessment, as well as current limitations related to generalizability, validation, and overreliance on pattern recognition. I propose a complementary conceptual framework in which biological and molecular approaches characterize disease mechanisms, while clinical neurophysiology defines their functional expression and clinical relevance in the individual patient. Within this framework, clinical neurophysiology should not be considered an alternative to precision medicine, but an integrated physiological dimension of it, connecting biological characterization with clinically actionable functional information.}, } @article {pmid42794615, year = {2026}, author = {Hedström, AK}, title = {Interpreting Viral Associations in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {27}, number = {18}, pages = {}, pmid = {42794615}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/virology ; Animals ; *Virus Diseases/complications/virology ; Parkinson Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Herpesvirus 4, Human ; }, abstract = {Viral infections have been associated with multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), but the associations may reflect different relationships to the disease process. This review evaluates evidence for viral involvement in disease initiation, modification of established disease, impaired viral control secondary to disease or treatment, and incidental detection. The strongest temporal evidence concerns Epstein-Barr virus (EBV) and MS. Prospective data place EBV seroconversion before clinical onset and the first observed increase in serum neurofilament light chain, while mechanistic studies link EBV infection, B-cell biology, and CNS-directed immunity. However, evidence that ongoing EBV activity modifies established MS remains limited. In AD, experimental studies support interactions between herpesviruses and AD-associated proteins, while the reduced incidence of all-cause dementia after herpes zoster vaccination suggests that viral or immunological pathways may be modifiable, without establishing that a specific herpesvirus initiates AD. Viral associations in PD rely mainly on epidemiological, experimental, and postmortem findings. Human pegivirus detection in a subset of PD brains remains a candidate association requiring independent confirmation and evidence of biological activity. Evidence in ALS is similarly limited. Enterovirus detection has been inconsistent, and altered human endogenous retrovirus K (HERV-K) expression in postmortem tissue does not establish an acquired viral infection. Stronger inference across these diseases will require longitudinal studies relating viral activity and antiviral immunity to subsequent disease-related changes, together with intervention studies that document the intended effect on the implicated viral process and separately assess subsequent disease risk or progression.}, } @article {pmid42801200, year = {2026}, author = {Liu, R and Yue, H and Li, X and Sun, W and Yang, J}, title = {The Versatile Roles of Exosomes in Neurodegenerative Disorders: From Pathological Mechanism and Diagnostic Biomarkers to Therapeutic Application.}, journal = {Drug design, development and therapy}, volume = {20}, number = {}, pages = {631482}, pmid = {42801200}, issn = {1177-8881}, mesh = {Humans ; *Exosomes/metabolism/pathology ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/pathology/therapy ; Biomarkers/metabolism/analysis ; Animals ; }, abstract = {Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.}, } @article {pmid37279301, year = {2023}, author = {Fehlings, MG and Moghaddamjou, A and Harrop, JS and Stanford, R and Ball, J and Aarabi, B and Freeman, BJC and Arnold, PM and Guest, JD and Kurpad, SN and Schuster, JM and Nassr, A and Schmitt, KM and Wilson, JR and Brodke, DS and Ahmad, FU and Yee, A and Ray, WZ and Brooks, NP and Wilson, J and Chow, DS and Toups, EG and Kopjar, B}, title = {Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.}, journal = {Journal of neurotrauma}, volume = {40}, number = {17-18}, pages = {1878-1888}, pmid = {37279301}, issn = {1557-9042}, mesh = {Humans ; Riluzole/adverse effects ; *Neuroprotective Agents/adverse effects ; Pandemics ; Prospective Studies ; Treatment Outcome ; Double-Blind Method ; *COVID-19 ; *Spinal Cord Injuries/drug therapy/chemically induced ; }, abstract = {Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.}, } @article {pmid37280513, year = {2023}, author = {Vidovic, M and Freigang, M and Aust, E and Linse, K and Petzold, D and Günther, R}, title = {Cognitive performance of adult patients with SMA before and after treatment initiation with nusinersen.}, journal = {BMC neurology}, volume = {23}, number = {1}, pages = {216}, pmid = {37280513}, issn = {1471-2377}, mesh = {Humans ; Adult ; Longitudinal Studies ; *Muscular Atrophy, Spinal/drug therapy ; *Spinal Muscular Atrophies of Childhood ; Cognition ; Oligonucleotides ; }, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by mutations of the SMN1 gene. Deficient SMN protein causes irreversible degeneration of alpha motor neurons characterized by progressive muscle weakness and atrophy. Considering that SMA is a multi-systemic disorder and SMN protein was found to be expressed in cortical structures, the cognitive profile of adult patients with SMA has recently been of particular interest. With nusinersen, a novel, disease-modifying drug has been established, but its effects on neuropsychological functions have not been validated yet. Aim of this study was to investigate the cognitive profile of adult patients with SMA during treatment initiation with nusinersen and to reveal improvement or deterioration in cognitive performance.

METHODS: This monocentric longitudinal study included 23 patients with SMA type 2 and 3. All patients were assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) before and after 14 months of treatment initiation with nusinersen. Additionally, motor function was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R).

RESULTS: Of the treatment-naive patients, only three were below the age- and education-matched cut-off for cognitive impairment in the ECAS total score. Significant differences between SMA type 2 and 3 were only detected in the domain of Language. After 14 months of treatment, patients showed significant improvement of absolute scores in all three ALS-specific domains, in the non-ALS-specific domain of Memory, in both subscores and in the ECAS total score. No associations were detected between cognitive and functional outcome measures.

CONCLUSIONS: In some adult patients with SMA abnormal cognitive performance in ALS-specific functions of the ECAS was evident. However, the presented results suggest no clinically significant cognitive changes during the observed treatment period with nusinersen.}, } @article {pmid37288776, year = {2023}, author = {Hatch, J and Barkhaus, P and Barnes, B and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Mascias Cadavid, J and Carter, GT and Cole, N and Crayle, J and Dimachkie, M and Ennist, D and Feldman, E and Fullam, T and Heiman-Patterson, T and Jhooty, S and Levine, T and Li, X and Lund, I and Mallon, E and Maragakis, N and McDermott, C and Pattee, G and Pierce, K and Ratner, D and Staats, K and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #70: caffeine.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {7-8}, pages = {766-770}, doi = {10.1080/21678421.2023.2220742}, pmid = {37288776}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.}, } @article {pmid37290723, year = {2023}, author = {Lu, Y and Wang, JT and Li, N and Zhu, X and Li, Y and Bansal, S and Wang, Y and Al-Jamal, KT}, title = {Intranasal administration of edaravone nanoparticles improves its stability and brain bioavailability.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {359}, number = {}, pages = {257-267}, doi = {10.1016/j.jconrel.2023.06.001}, pmid = {37290723}, issn = {1873-4995}, mesh = {Animals ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/drug therapy ; Biological Availability ; Brain/metabolism ; Chromatography, Liquid ; Drug Carriers/chemistry ; Drug Delivery Systems ; *Edaravone/administration & dosage/pharmacokinetics ; Hydrogen Peroxide/metabolism ; *Nanoparticles/administration & dosage ; Particle Size ; Polylactic Acid-Polyglycolic Acid Copolymer/metabolism ; Tandem Mass Spectrometry ; Tissue Distribution ; Cell Line ; }, abstract = {The clinical application of EDV, a potent antioxidant drug approved for amyotrophic lateral sclerosis (ALS), is limited by its short biological half-life and poor water solubility necessitating hospitalization during intravenous infusion. Nanotechnology-based drug delivery constitutes a powerful tool through inferring drug stability and targeted drug delivery improving drug bioavailability at the diseased site. Nose-to-brain drug delivery offers direct access to the brain bypassing the blood brain barrier and reducing systemic biodistribution. In this study, we designed EDV-loaded poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles (NP-EDV) for intranasal administration. NPs were formulated by the nanoprecipitation method. Morphology, EDV loading, physicochemical properties, shelf-life stability, in vitro release and pharmacokinetic assessment in mice were conducted. EDV was efficiently loaded into ∼90 nm NPs, stable up to 30 days of storage, at ∼3% drug loading. NP-EDV reduced H2O2-induced oxidative stress toxicity in mouse microglial cell line BV-2. Optical imaging and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed that intranasal delivery of NP-EDV offered higher and more sustained brain uptake of EDV compared to intravenous administration. This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited to two clinically approved drugs only.}, } @article {pmid37296644, year = {2023}, author = {Tzeplaeff, L and Wilfling, S and Requardt, MV and Herdick, M}, title = {Current State and Future Directions in the Therapy of ALS.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296644}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Riluzole/therapeutic use ; Motor Neurons/pathology ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.}, } @article {pmid37302030, year = {2023}, author = {Rudge, JD}, title = {The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {94}, number = {2}, pages = {457-470}, pmid = {37302030}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Blood-Brain Barrier/metabolism ; Cholesterol ; }, abstract = {The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer's disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.}, } @article {pmid37304072, year = {2023}, author = {Santiago, JA and Potashkin, JA}, title = {Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1185671}, pmid = {37304072}, issn = {1663-4365}, support = {R01 AG062176/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases have reached alarming numbers in the past decade. Unfortunately, clinical trials testing potential therapeutics have proven futile. In the absence of disease-modifying therapies, physical activity has emerged as the single most accessible lifestyle modification with the potential to fight off cognitive decline and neurodegeneration. In this review, we discuss findings from epidemiological, clinical, and molecular studies investigating the potential of lifestyle modifications in promoting brain health. We propose an evidence-based multidomain approach that includes physical activity, diet, cognitive training, and sleep hygiene to treat and prevent neurodegenerative diseases.}, } @article {pmid37307822, year = {2024}, author = {Chen, S and Cai, X and Lao, L and Wang, Y and Su, H and Sun, H}, title = {Brain-Gut-Microbiota Axis in Amyotrophic Lateral Sclerosis: A Historical Overview and Future Directions.}, journal = {Aging and disease}, volume = {15}, number = {1}, pages = {74-95}, pmid = {37307822}, issn = {2152-5250}, mesh = {Humans ; Aged ; Child, Preschool ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Neurodegenerative Diseases/complications ; *Gastrointestinal Microbiome/physiology ; Brain-Gut Axis ; Brain ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease which is strongly associated with age. The incidence of ALS increases from the age of 40 and peaks between the ages of 65 and 70. Most patients die of respiratory muscle paralysis or lung infections within three to five years of the appearance of symptoms, dealing a huge blow to patients and their families. With aging populations, improved diagnostic methods and changes in reporting criteria, the incidence of ALS is likely to show an upward trend in the coming decades. Despite extensive researches have been done, the cause and pathogenesis of ALS remains unclear. In recent decades, large quantities of studies focusing on gut microbiota have shown that gut microbiota and its metabolites seem to change the evolvement of ALS through the brain-gut-microbiota axis, and in turn, the progression of ALS will exacerbate the imbalance of gut microbiota, thereby forming a vicious cycle. This suggests that further exploration and identification of the function of gut microbiota in ALS may be crucial to break the bottleneck in the diagnosis and treatment of this disease. Hence, the current review summarizes and discusses the latest research advancement and future directions of ALS and brain-gut-microbiota axis, so as to help relevant researchers gain correlative information instantly.}, } @article {pmid37310359, year = {2023}, author = {Fang, J and Huang, Y and Wu, J and Shen, B and Yang, Y and Ju, M}, title = {Fluorogenic methodology for visualization of phase separation in chemical biology.}, journal = {Organic & biomolecular chemistry}, volume = {21}, number = {25}, pages = {5140-5149}, doi = {10.1039/d3ob00660c}, pmid = {37310359}, issn = {1477-0539}, mesh = {Humans ; *Alzheimer Disease ; Biology ; }, abstract = {Phase separation is a common biological phenomenon in the liquid environment of organisms. Phase separation has been shown to be a key cause of many existing incurable diseases, such as the protein aggregates formed by phase separation of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, etc. Tracking the occurrence of phase separation in vivo is critical to many disease detection methods and solving many treatment problems. Its physicochemical properties and visual detection methods have flourished in the last few years in chemical biology, among which the fluorogenic toolbox has great application potential compared to the traditional detection methods that cannot visualize the phase separation process intuitively, but just show some parameters indirectly. This paper reviews the mechanism and disease correlation proven in recent years for phase separation and analyzes the detection methods for phase separation, including functional microscope imaging techniques, turbidity monitoring, macromolecule congestion sensing, in silico analysis, etc. It is worth mentioning that the qualitative and quantitative analysis of aggregates formed by phase separation using in vitro parameters has successfully provided basic physical and chemical properties for phase separation aggregates, and is an important cornerstone for researchers to carry forward the past and break through the existing technical shackles to create new in vivo monitoring methods such as fluorescence methodology. Crucially, fluorescence methods for cell microenvironment imaging based on different mechanisms are discussed, such as AIE-based probes, TICT-based probes and FRET-based probes, etc.}, } @article {pmid37314311, year = {2023}, author = {Sharma, S and Tomar, VR and Deep, S}, title = {Myricetin: A Potent Anti-Amyloidogenic Polyphenol against Superoxide Dismutase 1 Aggregation.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {13}, pages = {2461-2475}, doi = {10.1021/acschemneuro.3c00276}, pmid = {37314311}, issn = {1948-7193}, mesh = {Humans ; Superoxide Dismutase-1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Polyphenols/pharmacology ; Flavonoids/pharmacology ; Superoxide Dismutase/metabolism ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is believed to be caused by the aggregation of misfolded or mutated superoxide dismutase 1 (SOD1). As there is currently no treatment, research into aggregation inhibitors continues. Based on docking, molecular dynamics (MD) simulations, and experimental observations, we propose that myricetin, a plant flavonoid, can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Our MD simulation results showed that myricetin stabilizes the protein interface, destabilizes the preformed fibril, and decreases the rate of fibril elongation. Myricetin inhibits the aggregation of SOD1 in a dose-dependent manner as shown by the ThT aggregation kinetics curves. Our transmission electron microscopy, dynamic light scattering, and circular dichroism experiments indicate that fewer shorter fibrils have formed. Fluorescence spectroscopy results predict the involvement of a static quenching mechanism characterized by a strong binding between protein and myricetin. Importantly, size exclusion chromatography revealed the potential of myricetin for fibril destabilization and depolymerization. These experimental observations complement the MD results. Thus, myricetin is a potent SOD1 aggregation inhibitor that can reduce the fibril load. Using the structure of myricetin as a reference, it is possible to design more effective therapeutic inhibitors against ALS that prevent the disease and reverse its effects.}, } @article {pmid37316165, year = {2023}, author = {Ziegler, A and Öner, A and Quadflieg, G and Betschart, RO and Thiéry, A and Babel, H and Mwambi, HG and Neumeyer, H and Mackschin, S and Hintz, S and Mann, M and Dittrich, H and Schmidt, C}, title = {Cost-effectiveness of a telemonitoring programme in patients with cardiovascular diseases compared with standard of care.}, journal = {Heart (British Cardiac Society)}, volume = {109}, number = {21}, pages = {1617-1623}, pmid = {37316165}, issn = {1468-201X}, mesh = {Humans ; *Cardiovascular Diseases/therapy ; Cost-Benefit Analysis ; Quality of Life ; Standard of Care ; *Hypertension/diagnosis/therapy ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: The main aim of this work was to analyse the cost-effectiveness of an integrated care concept (NICC) that combines telemonitoring with the support of a care centre in addition to guideline therapy for patients. Secondary aims were to compare health utility and health-related quality of life (QoL) between NICC and standard of care (SoC).

METHODS: The randomised controlled CardioCare MV Trial compared NICC and SoC in patients from Mecklenburg-West Pomerania (Germany) with atrial fibrillation, heart failure or treatment-resistant hypertension. QoL was measured using the EQ-5D-5L at baseline, 6 months and 1 year follow-up. Quality-adjusted life years (QALYs), EQ5D utility scores, Visual Analogue Scale (VAS) Scores and VAS adjusted life years (VAS-AL) were calculated. Cost data were obtained from health insurance companies, and the payer perspective was taken in health economic analyses. Quantile regression was used with adjustments for stratification variables.

RESULTS: The net benefit of NICC (QALY) was 0.031 (95% CI 0.012 to 0.050; p=0.001) in this trial involving 957 patients. EQ5D Index values, VAS-ALs and VAS were larger for NICC compared with SoC at 1 year follow-up (all p≤0.004). Direct cost per patient and year were €323 (CI €157 to €489) lower in the NICC group. When 2000 patients are served by the care centre, NICC is cost-effective if one is willing to pay €10 652 per QALY per year.

CONCLUSION: NICC was associated with higher QoL and health utility. The programme is cost-effective if one is willing to pay approximately €11 000 per QALY per year.}, } @article {pmid37316681, year = {2023}, author = {Blair, HA}, title = {Tofersen: First Approval.}, journal = {Drugs}, volume = {83}, number = {11}, pages = {1039-1043}, pmid = {37316681}, issn = {1179-1950}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase/genetics ; Oligonucleotides/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Tofersen (Qalsody[™]) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.}, } @article {pmid37316950, year = {2023}, author = {Petri, S and Grehl, T and Grosskreutz, J and Hecht, M and Hermann, A and Jesse, S and Lingor, P and Löscher, W and Maier, A and Schoser, B and Weber, M and Ludolph, AC}, title = {Guideline "Motor neuron diseases" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie).}, journal = {Neurological research and practice}, volume = {5}, number = {1}, pages = {25}, pmid = {37316950}, issn = {2524-3489}, abstract = {INTRODUCTION: In 2021, the Deutsche Gesellschaft für Neurology published a new guideline on diagnosis and therapy of motor neuron disorders. Motor neuron disorders affect upper motor neurons in the primary motor cortex and/or lower motor neurons in the brain stem and spinal cord. The most frequent motor neuron disease amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with an average life expectancy of 2-4 years with a yearly incidence of 3.1/100,000 in Central Europe (Rosenbohm et al. in J Neurol 264(4):749-757, 2017. https://doi.org/10.1007/s00415-017-8413-3). It is considered a rare disease mainly due to its low prevalence as a consequence of short disease duration.

RECOMMENDATIONS: These guidelines comprise recommendations regarding differential diagnosis, neuroprotective therapies and multidisciplinary palliative care including management of respiration and nutrition as well as provision of assistive devices and end-of-life situations.

CONCLUSION: Diagnostic and therapeutic guidelines are necessary due the comparatively high number of cases and the aggressive disease course. Given the low prevalence and the severe impairment of patients, it is often impossible to generate evidence-based data so that ALS guidelines are partially dependent on expert opinion.}, } @article {pmid37317638, year = {2023}, author = {Yang, Y and Rowe, D and McCann, H and Shepherd, CE and Kril, JJ and Kiernan, MC and Halliday, GM and Tan, RH}, title = {Treatment with the copper compound CuATSM has no significant effect on motor neuronal pathology in patients with ALS.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {4}, pages = {e12919}, pmid = {37317638}, issn = {1365-2990}, support = {R28 AA012725/AA/NIAAA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Copper ; Superoxide Dismutase-1 ; Riluzole ; Superoxide Dismutase ; Motor Neurons/pathology ; Spinal Cord/pathology ; DNA-Binding Proteins ; Mice, Transgenic ; Organocopper Compounds ; }, abstract = {AIMS: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown.

METHODS: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS-TDP (n = 5) and ALS-SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS-TDP (n = 4) and ALS-SOD1 (n = 2)].

RESULTS: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62-immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment.

DISCUSSION: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.}, } @article {pmid37319115, year = {2023}, author = {Yang, F and Mahaman, YAR and Zhang, B and Wang, JZ and Liu, R and Liu, F and Wang, X}, title = {C9orf72 poly-PR helps p53 escape from the ubiquitin-proteasome system and promotes its stability.}, journal = {Journal of neurochemistry}, volume = {166}, number = {2}, pages = {389-402}, doi = {10.1111/jnc.15872}, pmid = {37319115}, issn = {1471-4159}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Proteasome Endopeptidase Complex/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Ubiquitin/metabolism ; C9orf72 Protein/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Cytoplasm/metabolism ; Dipeptides/genetics ; DNA Repeat Expansion ; }, abstract = {C9orf72-derived dipeptide repeats (DPRs) proteins have been regarded as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). As the most toxic DPRs in C9-ALS/FTD, poly-proline-arginine (poly-PR) is associated with the stability and accumulation of p53, which consequently induces neurodegeneration. However, the exact molecular mechanism via which C9orf72 poly-PR stabilizes p53 remains unclear. In this study, we showed that C9orf72 poly-PR induces not only neuronal damage but also p53 accumulation and p53 downstream gene activation in primary neurons. C9orf72 (PR)50 also slows down p53 protein turnover without affecting the p53 transcription level and thus promotes its stability in N2a cells. Interestingly, the ubiquitin-proteasome system but not the autophagy function was impaired in (PR)50 transfected N2a cells, resulting in defective p53 degradation. Moreover, we found that (PR)50 induces mdm2 mistranslocation from the nucleus to the cytoplasm and competitively binds to p53, reducing mdm2-p53 interactions in the nucleus in two different (PR)50 transfected cells. Our data strongly indicate that (PR)50 reduces mdm2-p53 interactions and causes p53 to escape from the ubiquitin-proteasome system, promoting its stability and accumulation. Inhibiting or at least downregulating (PR)50 binding with p53 may be therapeutically exploited for the treatment of C9-ALS/FTD.}, } @article {pmid37323141, year = {2023}, author = {Khatoon, S and Kalam, N and Rashid, S and Bano, G}, title = {Effects of gut microbiota on neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1145241}, pmid = {37323141}, issn = {1663-4365}, abstract = {A progressive degradation of the brain's structure and function, which results in a reduction in cognitive and motor skills, characterizes neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The morbidity linked to NDs is growing, which poses a severe threat to human being's mental and physical ability to live well. The gut-brain axis (GBA) is now known to have a crucial role in the emergence of NDs. The gut microbiota is a conduit for the GBA, a two-way communication system between the gut and the brain. The myriad microorganisms that make up the gut microbiota can affect brain physiology by transmitting numerous microbial chemicals from the gut to the brain via the GBA or neurological system. The synthesis of neurotransmitters, the immunological response, and the metabolism of lipids and glucose have all been demonstrated to be impacted by alterations in the gut microbiota, such as an imbalance of helpful and harmful bacteria. In order to develop innovative interventions and clinical therapies for NDs, it is crucial to comprehend the participation of the gut microbiota in these conditions. In addition to using antibiotics and other drugs to target particular bacterial species that may be a factor in NDs, this also includes using probiotics and other fecal microbiota transplantation to maintain a healthy gut microbiota. In conclusion, the examination of the GBA can aid in understanding the etiology and development of NDs, which may benefit the improvement of clinical treatments for these disorders and ND interventions. This review indicates existing knowledge about the involvement of microbiota present in the gut in NDs and potential treatment options.}, } @article {pmid37323688, year = {2021}, author = {Zhang, Y and Yang, H and Wei, D and Zhang, X and Wang, J and Wu, X and Chang, J}, title = {Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.}, journal = {Exploration (Beijing, China)}, volume = {1}, number = {3}, pages = {20210115}, pmid = {37323688}, issn = {2766-2098}, abstract = {Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.}, } @article {pmid37326908, year = {2023}, author = {Zheng, C and Li, W and Ali, T and Peng, Z and Liu, J and Pan, Z and Feng, J and Li, S}, title = {Ibrutinib Delays ALS Installation and Increases Survival of SOD1[G93A] Mice by Modulating PI3K/mTOR/Akt Signaling.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {18}, number = {3}, pages = {383-396}, pmid = {37326908}, issn = {1557-1904}, support = {NCT03721302//International Cooperation Project（NCT03721302）of Shenzhen Children's Hospital/ ; 2019SHIBS0004//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; JCYJ20220530155611026//Basic research of Shenzhen Science and Technology Plan Project（General Program/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics/prevention & control ; *Adenine/analogs & derivatives/pharmacology/therapeutic use ; Mice ; Signal Transduction/drug effects/physiology ; *TOR Serine-Threonine Kinases/metabolism ; *Piperidines/pharmacology/therapeutic use ; Mice, Transgenic ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Superoxide Dismutase-1/genetics ; Male ; Survival Rate/trends ; Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 [G93A] mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 [G93A] mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.}, } @article {pmid37326935, year = {2023}, author = {Cantisani, TA}, title = {Is there a treatment effective and safe for sialorrhea in people with amyotrophic lateral sclerosis (ALS)? Summary of a Cochrane Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {9}, pages = {3083-3085}, pmid = {37326935}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Botulinum Toxins/therapeutic use ; *Sialorrhea/therapy/drug therapy ; Treatment Outcome ; Systematic Reviews as Topic ; }, } @article {pmid37327376, year = {2023}, author = {Shefner, JM and Musaro, A and Ngo, ST and Lunetta, C and Steyn, FJ and Robitaille, R and De Carvalho, M and Rutkove, S and Ludolph, AC and Dupuis, L}, title = {Skeletal muscle in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4425-4436}, pmid = {37327376}, issn = {1460-2156}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Neuromuscular Junction/pathology ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.}, } @article {pmid37331636, year = {2023}, author = {Zhang, H and Qi, G and Wang, K and Yang, J and Shen, Y and Yang, X and Chen, X and Yao, X and Gu, X and Qi, L and Zhou, C and Sun, H}, title = {Oxidative stress: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {214}, number = {}, pages = {115664}, doi = {10.1016/j.bcp.2023.115664}, pmid = {37331636}, issn = {1873-2968}, mesh = {Humans ; *Muscular Atrophy/metabolism ; Oxidative Stress ; Muscle, Skeletal/metabolism ; *Sarcopenia/drug therapy/metabolism/pathology ; Antioxidants/metabolism ; Chronic Disease ; }, abstract = {Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.}, } @article {pmid37333039, year = {2023}, author = {Mann, RH}, title = {Impaired Thiamine Metabolism in Amyotrophic Lateral Sclerosis and Its Potential Treatment With Benfotiamine: A Case Report and a Review of the Literature.}, journal = {Cureus}, volume = {15}, number = {6}, pages = {e40511}, pmid = {37333039}, issn = {2168-8184}, abstract = {Homogenates of brain tissue from the frontal cortex at autopsy in patients with amyotrophic lateral sclerosis (ALS) showed dramatically reduced levels of the enzyme thiamine pyrophosphatase (TPPase), the enzyme responsible for the conversion of thiamine pyrophosphate (TPP) to thiamine monophosphate (TMP). Additionally, free thiamine (vitamin B1) and TMP levels have been shown to be significantly reduced in the plasma and cerebral spinal fluid (CSF) of patients with ALS. These findings suggest that there is impaired thiamine metabolism in patients with ALS. Impaired thiamine metabolism decreases adenosine triphosphate (ATP) production and is a well-established cause of neurodegeneration. Decreased levels of TPPase, resulting in decreased levels of TMP in the cells of the frontal cortex, might account for the focal neurodegenerative changes observed in motor neurons in ALS. Benfotiamine, a safe, lipid-soluble, highly absorbable thiamine analogue, significantly raises free thiamine, TMP, and TPP levels in the blood. A case in which benfotiamine may have positively impacted the symptoms of a patient with ALS is presented. The use of benfotiamine in patients with ALS appears to be a promising therapeutic option. Considering the severity and the lack of satisfactory treatment options associated with this disease, more research on the effects of benfotiamine on the course of ALS is urgently needed.}, } @article {pmid37334341, year = {2023}, author = {Galeazzi, L and Holzman, J and Mondoloni, M and Rochefort, J}, title = {Lingual fasciculation: A point of call for the diagnosis of amyotrophic lateral sclerosis.}, journal = {Clinical case reports}, volume = {11}, number = {6}, pages = {e7560}, pmid = {37334341}, issn = {2050-0904}, abstract = {A 60-year-old female patient, with no notable medical history, was referred by the internal medicine department for a dry mouth workup. The clinical examination revealed an absence of dryness, and the presence of lingual fasciculations, associated with difficulties in mastication and phonation. These symptoms appeared spontaneously 9 months before the consultation, after leaving confinement. Given the presence of lingual fasciculations, the diagnostic hypothesis of a neurological pathology, in particular amyotrophic lateral sclerosis (ALS), was suspected. After performing an electromyogram (EMG), the diagnosis of ALS was retained. Riluzole treatment was then started, and physical therapy sessions were scheduled. Riluzole allows an average gain of 4 to 6 months of life expectancy. Speech therapy and physical therapy allow to maintain the functions as long as possible and to improve the end-of-life conditions. The interest of early detection of ALS allows delaying the progression of the disease.}, } @article {pmid37338820, year = {2023}, author = {Willemse, SW and van Es, MA}, title = {Susceptibility and disease modifier genes in amyotrophic lateral sclerosis: from genetic associations to therapeutic implications.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {365-370}, pmid = {37338820}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Genes, Modifier ; Superoxide Dismutase-1/genetics/therapeutic use ; Motor Neurons ; Mutation ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies.

RECENT FINDINGS: The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations.

SUMMARY: Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow.}, } @article {pmid37342380, year = {2023}, author = {Shamsaei, G and Houshmand, F and Ahmadzadeh Deylami, A and Valizadeh, A and Rafie, S and Moradi, M}, title = {The Efficacy and Safety of Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis: A Pilot Study.}, journal = {Advanced pharmaceutical bulletin}, volume = {13}, number = {2}, pages = {361-367}, pmid = {37342380}, issn = {2228-5881}, abstract = {Purpose: Amyotrophic lateral sclerosis (ALS) is an uncommon and aggressive neurodegenerative disorder that influences the lower and upper motor neurons. There are low eligible drugs for ALS treatment; in this regard, supplemental and replacement treatments are essential. There are relative studies in the field of mesenchymal stromal cells (MSCs) therapy in ALS, but the different methods, differently used medium, and difference in follow-up periods affect the outcome treatment. Methods: The current survey is a single-center, phase I clinical trial to evaluating the efficacy and safety of autologous bone marrow (BM)-derived MSCs through intrathecal administration in ALS patients. MNCs were isolated from BM specimens and cultured. The clinical outcome was evaluated based Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) Scale. Results: Each patient received 15±3×10[6] cells through subarachnoid space. No adverse events (AEs) were detected. Just one patient experienced a mild headache after injection. Following injection, no new intradural cerebrospinal pathology transplant-related was observed. None of the patients' pathologic disruptions following transplantation were detected by magnetic resonance imaging (MRI). The additional analyses have shown the average rate of ALSFRS-R score and forced vital capacity (FVC) reduction have decreased during 10 months following MSCs transplantation versus the pretreatment period, from -5.4±2.3 to -2±3.08 ALSFRS-R points/period (P=0.014) and -12.6±5.22% to -4.8±14.72%/period (P<0.001), respectively. Conclusion: These results have shown that autologous MSCs transplantation reduces the disease's progression and has favorable safety. Trial Registration: This study performed as a phase I clinical trial (code IRCT20200828048551N1).}, } @article {pmid37344230, year = {2023}, author = {Bjornevik, K and Cortese, M and Furtado, JD and Paganoni, S and Schwarzschild, MA and Cudkowicz, ME and Ascherio, A}, title = {Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.}, journal = {Neurology}, volume = {101}, number = {7}, pages = {e690-e698}, pmid = {37344230}, issn = {1526-632X}, mesh = {Male ; Humans ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Fatty Acids, Unsaturated ; *Fatty Acids, Omega-3 ; Fatty Acids, Omega-6 ; Disease Progression ; Fatty Acids ; }, abstract = {BACKGROUND AND OBJECTIVES: Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS.

METHODS: We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival.

RESULTS: Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up.

DISCUSSION: Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.}, } @article {pmid37345246, year = {2023}, author = {Li, X and Tian, Y and Wu, H and Wang, T}, title = {Network Pharmacology and Molecular Docking to Unveil the Mechanism of Shudihuang against Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {29}, number = {19}, pages = {1535-1545}, doi = {10.2174/1381612829666230621105552}, pmid = {37345246}, issn = {1873-4286}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Network Pharmacology ; Sitosterols ; Cyclooxygenase 2 ; PPAR gamma ; Stigmasterol ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Medicine, Chinese Traditional ; }, abstract = {BACKGROUND: Shudihuang has been clinically proven to be an effective Chinese medicine compatible with the treatment of amyotrophic lateral sclerosis. However, the underlying mechanism of Shudihuang against amyotrophic lateral sclerosis remains unclear.

OBJECTIVES: The present study aims to elucidate the possible mechanism of Shudihuang in treating ALS using network pharmacology and molecular docking.

METHODS: The primary active components of Shudihuang and their relevant targets were identified by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Swiss Target Prediction database, respectively. The ALS-related targets were obtained from the Disgenet and OMIM databases. The shared targets were derived by the intersection of disease-associated and component-associated targets and then introduced into the Cytoscape software to construct a network of drug-component-target. In addition, protein interaction relationships among the shared targets were analyzed by the STRING and Cytoscape software. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis were conducted by the Metascape platform. The binding activities between the hub targets and the active components were assessed with molecular docking.

RESULTS: Stigmasterol and sitosterol were identified as the core components of Shudihuang, and the hub targets of ALS are PTGS2, PPARG, ESR1, IGF-1R, and MAPK3, with the highest degrees in the PPI network. The finding that stigmasterol and sitosterol had a good affinity with PTGS2, PPARG, ESR1, IGF-1R, and MAPK3 also supported this. Finally, it was revealed that Shudihuang treatment of ALS predominantly involves estrogen- related pathways such as nuclear receptor activity and steroid binding.

CONCLUSION: In summary, this study suggested that the main active components of Shudihuang (stigmasterol and sitosterol) may exert a critical effect in ALS treatment by binding to hub targets (PTGS2, PPARG, ESR1, IGF-1R, and MAPK3) and then modulating estrogen receptor-related pathways to attenuate glutamate excitotoxicity, inhibit oxidative stress and antagonize inflammation.}, } @article {pmid37353279, year = {2023}, author = {van Eenennaam, RM and Kruithof, W and Beelen, A and Bakker, LA and van Eijk, RPA and Maessen, M and Baardman, JF and Visser-Meily, JMA and Veldink, JH and van den Berg, LH}, title = {Frequency of euthanasia, factors associated with end-of-life practices, and quality of end-of-life care in patients with amyotrophic lateral sclerosis in the Netherlands: a population-based cohort study.}, journal = {The Lancet. Neurology}, volume = {22}, number = {7}, pages = {591-601}, doi = {10.1016/S1474-4422(23)00155-2}, pmid = {37353279}, issn = {1474-4465}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Netherlands/epidemiology ; Cohort Studies ; Quality of Life ; *Neurodegenerative Diseases/complications ; *Terminal Care ; *Suicide, Assisted ; Death ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive and lethal neurodegenerative disease that is at the forefront of debates on regulation of assisted dying. Since 2002, when euthanasia was legally regulated in the Netherlands, the frequency of this end-of-life practice has increased substantially from 1·7% of all deaths in 1990 and 2005 to 4·5% in 2015. We aimed to investigate whether the frequency of euthanasia in patients with amyotrophic lateral sclerosis had similarly increased since 2002, and to assess the factors associated with end-of-life practices and the quality of end-of-life care in patients with this disease.

METHODS: Using data from the Netherlands ALS registry, we did a population-based cohort study of clinicians and informal caregivers of patients with amyotrophic lateral sclerosis to assess factors associated with end-of-life decision making and the quality of end-of-life care. We included individuals who were diagnosed with amyotrophic lateral sclerosis according to the revised El-Escorial criteria, and who died between Jan 1, 2014, and Dec 31, 2016. We calculated the frequency of euthanasia in patients with amyotrophic lateral sclerosis from reports made to euthanasia review committees (ERCs) between 2012 and 2020. Results were compared with clinic-based survey studies conducted in 1994-2005. End-of-life practices were end-of-life decisions by a clinician when hastening of death was considered as the potential, probable, or definite effect comprising euthanasia, physician-assisted suicide, ending of life without explicit request, forgoing life-prolonging treatment, and intensified alleviation of symptoms.

FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 4130 reports of death from amyotrophic lateral sclerosis were made to ERCs, of which 1014 were from euthanasia or physician-assisted suicide (mean frequency 25% [SD 3] per year). Sex and gender data were unavailable from the ERC registry. Of 884 patients with amyotrophic lateral sclerosis who died between Jan 1, 2014, and Dec 31, 2016, their treating clinician was identified for 731 and a caregiver was identified for 741, of whom 356 (49%) and 450 (61%), respectively, agreed to participate in the population-based survey study. According to clinicians, end-of-life practices were chosen by 280 (79%) of 356 patients with amyotrophic lateral sclerosis who died. The frequency of euthanasia in patients with amyotrophic lateral sclerosis in 2014-16 (141 [40%] of 356 deaths in patients with amyotrophic lateral sclerosis) was higher than in 1994-98 (35 [17%] of 203) and 2000-05 (33 [16%] of 209). Median survival of patients with amyotrophic lateral sclerosis from diagnosis was 15·9 months (95% CI 12·6-17·6) for those who chose euthanasia and 16·1 months (13·4-19·1) for those who did not choose euthanasia (hazard ratio 1·07, 95% CI 0·85-1·34; p=0·58). According to caregivers, compared with other end-of-life practices, patients with amyotrophic lateral sclerosis choosing euthanasia commonly reported reasons to hasten death as no chance of improvement (53 [56%] of 94 patients who chose euthanasia vs 28 [39%] of 72 patients who chose other end-of-life practices), loss of dignity (47 [50%] vs 15 [21%]), dependency (34 [36%] vs five [7%]), and fatigue or extreme weakness (41 [44%] vs 14 [20%]). According to caregivers, people with amyotrophic lateral sclerosis-whether they chose euthanasia or did not-were satisfied with the general quality (83 [93%] of 89 patients who chose euthanasia vs 73 [86%] of 85 patients who did not) and availability (85 [97%] of 88 vs 81 [91%] of 90) of end-of-life care.

INTERPRETATION: The proportion of patients with amyotrophic lateral sclerosis who chose euthanasia in the Netherlands has increased since 2002. The choice of euthanasia was not associated with disease or patient characteristics, depression or hopelessness, or the availability or quality of end-of-life care. The choice of euthanasia had no effect on overall survival. Future studies could focus on the effect of discussing end-of-life options on quality of life as part of multidisciplinary care throughout the course of the disease, to reduce feelings of loss of autonomy and dignity in patients living with amyotrophic lateral sclerosis.

FUNDING: Netherlands ALS Foundation.}, } @article {pmid37356043, year = {2023}, author = {Nguyen, QT and Thanh, LN and Hoang, VT and Phan, TTK and Heke, M and Hoang, DM}, title = {Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {7}, pages = {3211-3250}, pmid = {37356043}, issn = {1573-6830}, mesh = {Humans ; *Autism Spectrum Disorder ; Bone Marrow ; *Stroke/therapy ; Bone Marrow Cells ; }, abstract = {Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.}, } @article {pmid37360345, year = {2023}, author = {Iijima, K and Watanabe, H and Nakashiro, Y and Iida, Y and Nonaka, M and Moriwaka, F and Hamada, S}, title = {Long-term effects of the gait treatment using a wearable cyborg hybrid assistive limb in a patient with spinal and bulbar muscular atrophy: a case report with 5 years of follow-up.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1143820}, pmid = {37360345}, issn = {1664-2295}, abstract = {BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular degenerative disease characterized by the degeneration of lower motor neurons in the spinal cord and brainstem and neurogenic atrophy of the skeletal muscle. Although the short-term effectiveness of gait treatment using a wearable cyborg hybrid assistive limb (HAL) has been demonstrated for the rehabilitation of patients with SBMA, the long-term effects of this treatment are unclear. Thus, this study aimed to investigate the long-term effects of the continued gait treatment with HAL in a patient with SBMA.

RESULTS: A 68-year-old man with SBMA had lower limb muscle weakness and atrophy, gait asymmetry, and decreased walking endurance. The patient performed nine courses of HAL gait treatment (as one course three times per week for 3 weeks, totaling nine times) for ~5 years. The patient performed HAL gait treatment to improve gait symmetry and endurance. A physical therapist adjusted HAL based on the gait analysis and physical function of the patient. Outcome measurements, such as 2-min walking distance (2MWD), 10-meter walking test (maximal walking speed, step length, cadence, and gait symmetry), muscle strength, Revised Amyotrophic Lateral Sclerosis Functional Assessment Scale (ALSFRS-R), and patient-reported outcomes, were evaluated immediately before and after gait treatment with HAL for each course. 2MWD improved from 94 m to 101.8 m, and the ALSFRS-R gait items remained unchanged (score 3) for approximately 5 years. The patient could maintain walking ability in terms of gait symmetry, walking endurance, and independence walking despite disease progression during HAL treatment.

CONCLUSION: The long-term gait treatment with HAL in a patient with SBMA may contribute to the maintenance and improvement of the gait endurance and ability to perform activities of daily living. The cybernics treatment using HAL may enable patients to relearn correct gait movements. The gait analysis and physical function assessment by a physical therapist might be important to maximize the benefits of HAL treatment.}, } @article {pmid37363428, year = {2022}, author = {Sienes Bailo, P and Llorente Martín, E and Calmarza, P and Montolio Breva, S and Bravo Gómez, A and Pozo Giráldez, A and Sánchez-Pascuala Callau, JJ and Vaquer Santamaría, JM and Dayaldasani Khialani, A and Cerdá Micó, C and Camps Andreu, J and Sáez Tormo, G and Fort Gallifa, I}, title = {The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies.}, journal = {Advances in laboratory medicine}, volume = {3}, number = {4}, pages = {342-360}, pmid = {37363428}, issn = {2628-491X}, abstract = {OBJECTIVES: The central nervous system (CNS) is essential for homeostasis and controls the physiological functions of the body. However, the biochemical characteristics of the CNS make it especially vulnerable to oxidative damage (OS). This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death.

CONTENTS: OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. These mechanisms include mitochondrial dysfunction; excessive production of reactive oxygen and nitrogen species; deficiency of antioxidant defenses; protein oligomerization; cytokine production and inflammatory response; blood-brain barrier abnormalities; and proteasome dysfunction. All these dysfunctions are involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis.

SUMMARY AND OUTLOOK: A curative treatment is currently not available. Research is focused on the search for therapies that reduce oxidative damage and delay disease progression. In the recent years, researchers have focused their attention on the effects of antioxidant therapies.}, } @article {pmid37369861, year = {2023}, author = {Zhu, Q and Xu, D and Huang, H and Li, D and Yang, D and Zhou, J and Zhao, Y}, title = {The safety and effectiveness of high-calorie therapy for treating amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4729-4743}, pmid = {37369861}, issn = {1432-1459}, support = {2022BCA055//Department of Science and Technology, Hubei Provincial People's Government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Lipids/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons, which can lead to death from respiratory failure within 3-5 years after the onset of this disease. Nowadays, no drug can effectively slow down the progression of this disease. High-calorie therapy, an emerging complementary alternative treatment, has been reported in studies to prolong the survival time of patients, prevent muscle atrophy and provide a better prognosis. However, no systematic review and meta-analysis were performed to summarize the evidence of this therapy. This meta-analysis comprehensively evaluates the effectiveness and safety of high-calorie therapy for treating ALS.

METHODS: We searched the electronic databases from inception to 1 April 2023: PubMed, Embase, Web of Science, Cochrane Library, Scopus, Ovid/Medline, and ProQuest. Randomized controlled trials (RCTs) that met the inclusion criteria were performed by meta-analysis. All statistical analyses were performed in STATA software.

RESULTS: A total of six eligible RCTs were included in this meta-analysis, involving 370 ALS patients. The meta-analyses showed that high-calorie therapy had superiority in improving body weight (SMD = 1, 95% CI 0.36, 1.65) and BMI (SMD = 0.83, 95% CI 0.02, 1.63). With respect to safety, there was no difference between the high-calorie therapy and the control group regarding the number of adverse events (RR = 3.61, 95% CI 0.08, 162.49). However, ALSFRS-R scores (SMD = 0.34, 95% CI - 0.4, 1.08), survival rate (RR = 1.23, 95% CI 0.98, 1.55), and lipid profile (LDL: SMD = 0.21, 95% CI - 0.33, 0.75; HDL: SMD = 0.17, 95% CI - 0.37, 0.71; TC: SMD = 0.21, 95% CI - 0.33, 0.75), CRP (SMD = 0.85, 95% CI - 1.37, 3.06) showed no significant difference compared to the control groups.

CONCLUSIONS: High-calorie therapy is effective in gaining weight and BMI with few side effects. However, no significant superiority was detected in ALSFRS-R scores, survival time, lipid profile, and CRP indicator. The overall quality of the included studies is high, and the results have some credibility, but future corroboration by high-quality RCTs is also expected.}, } @article {pmid37375216, year = {2023}, author = {De Luca, M and Ioele, G and Grande, F and Occhiuzzi, MA and Chieffallo, M and Garofalo, A and Ragno, G}, title = {Multivariate Curve Resolution Methodology Applied to the ATR-FTIR Data for Adulteration Assessment of Virgin Coconut Oil.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {12}, pages = {}, pmid = {37375216}, issn = {1420-3049}, support = {PON R&I 2014-2020 - ARS01_00568//PON R&I 2014-2020 - ARS01_00568 - SI.F.I.PA.CRO.DE. - Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE/ ; }, mesh = {Coconut Oil ; Spectroscopy, Fourier Transform Infrared/methods ; Fourier Analysis ; *Food Contamination/analysis ; *Plant Oils/analysis ; Least-Squares Analysis ; Olive Oil/analysis ; }, abstract = {Virgin coconut oil (VCO) is a functional food with important health benefits. Its economic interest encourages fraudsters to deliberately adulterate VCO with cheap and low-quality vegetable oils for financial gain, causing health and safety problems for consumers. In this context, there is an urgent need for rapid, accurate, and precise analytical techniques to detect VCO adulteration. In this study, the use of Fourier transform infrared (FTIR) spectroscopy combined with multivariate curve resolution-alternating least squares (MCR-ALS) methodology was evaluated to verify the purity or adulteration of VCO with reference to low-cost commercial oils such as sunflower (SO), maize (MO) and peanut (PO) oils. A two-step analytical procedure was developed, where an initial control chart approach was designed to assess the purity of oil samples using the MCR-ALS score values calculated on a data set of pure and adulterated oils. The pre-treatment of the spectral data by derivatization with the Savitzky-Golay algorithm allowed to obtain the classification limits able to distinguish the pure samples with 100% of correct classifications in the external validation. In the next step, three calibration models were developed using MCR-ALS with correlation constraints for analysis of adulterated coconut oil samples in order to assess the blend composition. Different data pre-treatment strategies were tested to best extract the information contained in the sample fingerprints. The best results were achieved by derivative and standard normal variate procedures obtaining RMSEP and RE% values in the ranges of 1.79-2.66 and 6.48-8.35%, respectively. The models were optimized using a genetic algorithm (GA) to select the most important variables and the final models in the external validations gave satisfactory results in quantifying adulterants, with absolute errors and RMSEP of less than 4.6% and 1.470, respectively.}, } @article {pmid37375224, year = {2023}, author = {Zhang, Y and Huang, J and Yu, K and Cui, X}, title = {G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {12}, pages = {}, pmid = {37375224}, issn = {1420-3049}, support = {KLEEMA202201//Key Laboratory of Ecology and Environment in 458 Minority Areas (Minzu University of China), National Ethnic Affairs Commission/ ; }, mesh = {Humans ; *Frontotemporal Dementia ; *G-Quadruplexes ; C9orf72 Protein/genetics ; Nucleotides ; *Amyotrophic Lateral Sclerosis/genetics ; RNA/chemistry ; DNA/genetics ; Benzylisoquinolines ; }, abstract = {The G-quadruplex (GQ)-forming hexanucleotide repeat expansion (HRE) in the C9orf72 (C9) gene has been found to be the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (collectively, C9ALS/FTD), implying the great significance of modulating C9-HRE GQ structures in C9ALS/FTD therapeutic treatment strategies. In this study, we investigated the GQ structures formed by varied lengths of C9-HRE DNA sequences d(GGGGCC)4 (C9-24mer) and d(GGGGCC)8 (C9-48mer), and found that the C9-24mer forms anti-parallel GQ (AP-GQ) in the presence of potassium ions, while the long C9-48mer bearing eight guanine tracts forms unstacked tandem GQ consisting of two C9-24mer unimolecular AP-GQs. Moreover, the natural small molecule Fangchinoline was screened out in order to be able to stabilize and alter the C9-HRE DNA to parallel GQ topology. Further study of the interaction of Fangchinoline with the C9-HRE RNA GQ unit r(GGGGCC)4 (C9-RNA) revealed that it can also recognize and improve the thermal stability of C9-HRE RNA GQ. Finally, use of AutoDock simulation results indicated that Fangchinoline binds to the groove regions of the parallel C9-HRE GQs. These findings pave the way for further studies of GQ structures formed by pathologically related long C9-HRE sequences, and also provide a natural small-molecule ligand that modulates the structure and stability of C9-HRE GQ, both in DNA and RNA levels. Altogether, this work may contribute to therapeutic approaches of C9ALS/FTD which take the upstream C9-HRE DNA region, as well as the toxic C9-HRE RNA, as targets.}, } @article {pmid37378756, year = {2023}, author = {Sassi, S and Bianchi, E and Diamanti, L and Tornabene, D and Sette, E and Medici, D and Matà, S and Leccese, D and Sperti, M and Martinelli, I and Ghezzi, A and Mandrioli, J and Iuzzolino, VV and Dubbioso, R and Trojsi, F and Passaniti, C and D'Alvano, G and Filosto, M and Padovani, A and Mazzini, L and De Marchi, F and Zinno, L and Nuredini, A and Bongioanni, P and Dolciotti, C and Canali, E and Toschi, G and Petrucci, A and Perna, A and Riso, V and Inghilleri, M and Libonati, L and Cambieri, C and Pupillo, E}, title = {Retrospective observational study on the use of acetyl-L-carnitine in ALS.}, journal = {Journal of neurology}, volume = {270}, number = {11}, pages = {5344-5357}, pmid = {37378756}, issn = {1432-1459}, mesh = {Humans ; *Acetylcarnitine/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis ; Retrospective Studies ; Case-Control Studies ; Double-Blind Method ; }, abstract = {ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.}, } @article {pmid37379726, year = {2023}, author = {Floudiotis, N and Modi, G and Mochan, A}, title = {Motor neuron disease in black African patients at a tertiary care hospital in Soweto, South Africa.}, journal = {Journal of the neurological sciences}, volume = {451}, number = {}, pages = {120710}, doi = {10.1016/j.jns.2023.120710}, pmid = {37379726}, issn = {1878-5883}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis ; Cross-Sectional Studies ; Delayed Diagnosis ; *Motor Neuron Disease ; South Africa/epidemiology ; Tertiary Care Centers ; Adult ; Middle Aged ; }, abstract = {INTRODUCTION: In this brief report, we describe the nature of ALS in a South African cohort of patients of Black African ancestry - a population which has been historically understudied.

METHODS: We performed a chart review of all patients attending the ALS/MND clinic at the Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, South Africa, during the period 1 January 2015 to 30 June 2020. Cross-sectional demographic and clinical data captured at the time of diagnosis was collected.

RESULTS: Seventy-one patients were included in the study. Males constituted 66% (n = 47), with a male to female sex ratio of 2:1. The median age at onset of symptoms was 46 years (IQR 40-57) with a median disease duration at diagnosis (diagnostic delay) of 2 years (IQR 1-3). The onset was spinal in 76% and bulbar in 23%. The median ALSFRS-R score at time of presentation was 29 (IQR 23-38.5). The median ALSFRS-R slope (unit/month) was 0.80 (IQR 0.43-1.39). Sixty five patients (92%) were diagnosed with the classic ALS phenotype. Fourteen patients were known to be HIV positive, and of those, 12 were on antiretroviral treatment (ART). None of the patients had familial ALS.

CONCLUSION: Our findings of an earlier age at symptom onset and seemingly advanced disease at presentation in patients with Black African ancestry support the existing literature on the African population.}, } @article {pmid37380145, year = {2023}, author = {Mercadante, S and Al-Husinat, L}, title = {Palliative Care in Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {66}, number = {4}, pages = {e485-e499}, doi = {10.1016/j.jpainsymman.2023.06.029}, pmid = {37380145}, issn = {1873-6513}, mesh = {Humans ; Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Quality of Life ; *Neurodegenerative Diseases ; *Hospice and Palliative Care Nursing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of the motor neurons. Given the evolutive characteristics of this disease, palliative care principles should be a foundation of ALS care. A multidisciplinary medical intervention is of paramount importance in the different phases of disease. The involvement of the palliative care team improves quality of life and symptoms, and prognosis. Early initiation is of paramount importance to ensuring patient-centered care, when the patient has still the capability to communicate effectively and participate in his medical care. Advance care planning supports patients and family members in understanding and sharing their preferences according to their personal values and life goals regarding future medical treatment. The principal problems which require intensive supportive care include cognitive disturbances, psychological distress, pain, sialorrhrea, nutrition, and ventilatory support. Communication skills of health-care professionals are mandatory to manage the inevitability of death. Palliative sedation has peculiar aspects in this population, particularly with the decision of withdrawing ventilatory support.}, } @article {pmid37382103, year = {2023}, author = {Benatar, M and Turner, MR and Wuu, J}, title = {Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {360-364}, pmid = {37382103}, issn = {1473-6551}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; RF1 NS105479/NS/NINDS NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/prevention & control ; *Frontotemporal Dementia/genetics ; Longitudinal Studies ; Biomarkers ; Asymptomatic Diseases ; }, abstract = {PURPOSE OF REVIEW: Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)].

RECENT FINDINGS: The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1 -ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk.

SUMMARY: The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.}, } @article {pmid37383106, year = {2023}, author = {Wu, C and Feng, Y}, title = {Exploring the potential of mindfulness-based therapy in the prevention and treatment of neurodegenerative diseases based on molecular mechanism studies.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1097067}, pmid = {37383106}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (ND) have received increasing attention due to their irreversibility, but there is still no means to completely cure ND in clinical practice. Mindfulness therapy (MT), including Qigong, Tai Chi, meditation, and yoga, etc., has become an effective complementary treatment modality in solving clinical and subclinical problems due to its advantages of low side effects, less pain, and easy acceptance by patients. MT is primarily used to treat mental and emotional disorders. In recent years, evidence has shown that MT has a certain therapeutic effect on ND with a potential molecular basis. In this review, we summarize the pathogenesis and risk factors of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), relating to telomerase activity, epigenetics, stress, and the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) mediated inflammatory response, and analyze the molecular mechanism basis of MT to prevent and treat ND, to provide possible explanations for the potential of MT treatments for ND.}, } @article {pmid37385457, year = {2023}, author = {DuMont, M and Agostinis, A and Singh, K and Swan, E and Buttle, Y and Tropea, D}, title = {Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106214}, doi = {10.1016/j.nbd.2023.106214}, pmid = {37385457}, issn = {1095-953X}, mesh = {Humans ; Male ; Female ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; *Attention Deficit Disorder with Hyperactivity ; }, abstract = {Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.}, } @article {pmid37387779, year = {2021}, author = {Huang, H and Chen, L and Chopp, M and Young, W and Robert Bach, J and He, X and Sarnowaska, A and Xue, M and Chunhua Zhao, R and Shetty, A and Siniscalco, D and Guo, X and Khoshnevisan, A and Hawamdeh, Z}, title = {The 2020 Yearbook of Neurorestoratology.}, journal = {Journal of neurorestoratology}, volume = {9}, number = {1}, pages = {1-12}, pmid = {37387779}, issn = {2324-2426}, abstract = {COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020. Facing this dangerous situation, many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients, and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology. Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. Therapeutic progress during this year included advances in cell therapies, neurostimulation/neuromodulation, brain-computer interface (BCI), and pharmaceutical neurorestorative therapies, which improved neurological functions and quality of life for patients. Four clinical guidelines or standards of Neurorestoratology were published in 2020. Milestone examples include: 1) a multicenter randomized, double-blind, placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements; 2) patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis; 3) a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential (SSVEP)-based BCI to achieve accurate and speedy computer input; 4) a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions. We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.}, } @article {pmid37388502, year = {2023}, author = {Mohamed, W and Kumar, J and Alghamdi, BS and Soliman, AH and Toshihide, Y}, title = {Neurodegeneration and inflammation crosstalk: Therapeutic targets and perspectives.}, journal = {IBRO neuroscience reports}, volume = {14}, number = {}, pages = {95-110}, pmid = {37388502}, issn = {2667-2421}, abstract = {Glia, which was formerly considered to exist just to connect neurons, now plays a key function in a wide range of physiological events, including formation of memory, learning, neuroplasticity, synaptic plasticity, energy consumption, and homeostasis of ions. Glial cells regulate the brain's immune responses and confers nutritional and structural aid to neurons, making them an important player in a broad range of neurological disorders. Alzheimer's, ALS, Parkinson's, frontotemporal dementia (FTD), and epilepsy are a few of the neurodegenerative diseases that have been linked to microglia and astroglia cells, in particular. Synapse growth is aided by glial cell activity, and this activity has an effect on neuronal signalling. Each glial malfunction in diverse neurodegenerative diseases is distinct, and we will discuss its significance in the progression of the illness, as well as its potential for future treatment.}, } @article {pmid37390359, year = {2023}, author = {Sheers, NL and Howard, ME and Rochford, PD and Rautela, L and Chao, C and McKim, DA and Berlowitz, DJ}, title = {A Randomized Controlled Clinical Trial of Lung Volume Recruitment in Adults with Neuromuscular Disease.}, journal = {Annals of the American Thoracic Society}, volume = {20}, number = {10}, pages = {1445-1455}, pmid = {37390359}, issn = {2325-6621}, mesh = {Female ; Humans ; Adult ; Middle Aged ; Adolescent ; *Quality of Life ; Prospective Studies ; Lung Volume Measurements ; Lung ; *Neuromuscular Diseases/complications ; }, abstract = {Rationale: Clinical care guidelines advise that lung volume recruitment (LVR) be performed routinely by people with neuromuscular disease (NMD) to maintain lung and chest wall flexibility and slow lung function decline. However, the evidence base is limited, and no randomized controlled trials of regular LVR in adults have been published. Objectives: To evaluate the effect of regular LVR on respiratory function and quality of life in adults with NMD. Methods: A randomized controlled trial with assessor blinding was conducted between September 2015 and May 2019. People (>14 years old) with NMD and vital capacity <80% predicted were eligible, stratified by disease subgroup (amyotrophic lateral sclerosis/motor neuron disease or other NMDs), and randomized to 3 months of twice-daily LVR or breathing exercises. The primary outcome was change in maximum insufflation capacity (MIC) from baseline to 3 months, analyzed using a linear mixed model approach. Results: Seventy-six participants (47% woman; median age, 57 [31-68] years; mean baseline vital capacity, 40 ± 18% predicted) were randomized (LVR, n = 37). Seventy-three participants completed the study. There was a statistically significant difference in MIC between groups (linear model interaction effect P = 0.002, observed mean difference, 0.19 [0.00-0.39] L). MIC increased by 0.13 (0.01-0.25) L in the LVR group, predominantly within the first month. No interaction or treatment effects were observed in secondary outcomes of lung volumes, respiratory system compliance, and quality of life. No adverse events were reported. Conclusions: Regular LVR increased MIC in a sample of LVR-naive participants with NMD. We found no direct evidence that regular LVR modifies respiratory mechanics or slows the rate of lung volume decline. The implications of increasing MIC are unclear, and the change in MIC may represent practice. Prospective long-term clinical cohorts with comprehensive follow-up, objective LVR use, and clinically meaningful outcome data are needed. Clinical trial registered with anzctr.org.au (ACTRN12615000565549).}, } @article {pmid37390744, year = {2023}, author = {Eskandari, S and Rezayof, A and Asghari, SM and Hashemizadeh, S}, title = {Neurobiochemical characteristics of arginine-rich peptides explain their potential therapeutic efficacy in neurodegenerative diseases.}, journal = {Neuropeptides}, volume = {101}, number = {}, pages = {102356}, doi = {10.1016/j.npep.2023.102356}, pmid = {37390744}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Arginine ; Oxidative Stress ; Peptides/metabolism ; *Nucleic Acids/metabolism/therapeutic use ; *Alzheimer Disease/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer̕ s disease (AD), Parkinson̕ s disease (PD), Huntington̕ s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) require special attention to find new potential treatment methods. This review aims to summarize the current knowledge of the relationship between the biochemical properties of arginine-rich peptides (ARPs) and their neuroprotective effects to deal with the harmful effects of risk factors. It seems that ARPs have portrayed a promising and fantastic landscape for treating neurodegeneration-associated disorders. With multimodal mechanisms of action, ARPs play various unprecedented roles, including as the novel delivery platforms for entering the central nervous system (CNS), the potent antagonists for calcium influx, the invader molecules for targeting mitochondria, and the protein stabilizers. Interestingly, these peptides inhibit the proteolytic enzymes and block protein aggregation to induce pro-survival signaling pathways. ARPs also serve as the scavengers of toxic molecules and the reducers of oxidative stress agents. They also have anti-inflammatory, antimicrobial, and anti-cancer properties. Moreover, by providing an efficient nucleic acid delivery system, ARPs can play an essential role in developing various fields, including gene vaccines, gene therapy, gene editing, and imaging. ARP agents and ARP/cargo therapeutics can be raised as an emergent class of neurotherapeutics for neurodegeneration. Part of the aim of this review is to present recent advances in treating neurodegenerative diseases using ARPs as an emerging and powerful therapeutic tool. The applications and progress of ARPs-based nucleic acid delivery systems have also been discussed to highlight their usefulness as a broad-acting class of drugs.}, } @article {pmid37391647, year = {2023}, author = {Karati, D and Mukherjee, S and Roy, S}, title = {Molecular and Structural Insight into Adenosine A2A Receptor in Neurodegenerative Disorders: A Significant Target for Efficient Treatment Approach.}, journal = {Molecular neurobiology}, volume = {60}, number = {10}, pages = {5987-6000}, pmid = {37391647}, issn = {1559-1182}, mesh = {Humans ; *Adenosine/pharmacology ; Receptor, Adenosine A2A/metabolism ; Ligands ; *Neurodegenerative Diseases/drug therapy ; Purinergic P1 Receptor Antagonists/therapeutic use ; Receptors, Purinergic P1 ; }, abstract = {All biological tissues and bodily fluids include the autacoid adenosine. The P1 class of purinergic receptors includes adenosine receptors. Four distinct G-protein-coupled receptors on the cellular membrane mediate the effects of adenosine, whose cytoplasmic content is regulated by producing/degrading enzymes and nucleoside transporters. A2A receptor has received a great deal of attention in recent years because it has a wide range of potential therapeutic uses. A2B and, more significantly, A2A receptors regulate numerous physiological mechanisms in the central nervous system (CNS). The inferior targetability of A2B receptors towards adenosine points that they might portray a promising medicinal target since they are triggered only under pharmacological circumstances (when adenosine levels rise up to micromolar concentrations). The accessibility of specific ligands for A2B receptors would permit the exploration of such a theory. A2A receptors mediate both potentially neurotoxic and neuroprotective actions. Hence, it is debatable to what extent they play a role in neurodegenerative illnesses. However, A2A receptor blockers have demonstrated clear antiparkinsonian consequences, and a significant attraction exists in the role of A2A receptors in other neurodegenerative disorders. Amyloid peptide extracellular accumulation and tau hyperphosphorylation are the pathogenic components of AD that lead to neuronal cell death, cognitive impairment, and memory loss. Interestingly, in vitro and in vivo research has shown that A2A adenosine receptor antagonists may block each of these clinical symptoms, offering a crucial new approach to combat a condition for which, regrettably, only symptomatic medications are currently available. At least two requirements must be met to determine whether such receptors are a target for diseases of the CNS: a complete understanding of the mechanisms governing A2A-dependent processes and the availability of ligands that can distinguish between the various receptor populations. This review concisely summarises the biological effects mediated by A2A adenosine receptors in neurodegenerative disorders and discusses the chemical characteristics of A2A adenosine receptor antagonists undergoing clinical trials. Selective A2A receptor blocker against neurodegenerative disorders.}, } @article {pmid37396808, year = {2023}, author = {Vucic, S and Menon, P and Huynh, W and Mahoney, C and Ho, KS and Hartford, A and Rynders, A and Evan, J and Evan, J and Ligozio, S and Glanzman, R and Hotchkin, MT and Kiernan, MC}, title = {Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.}, journal = {EClinicalMedicine}, volume = {60}, number = {}, pages = {102036}, pmid = {37396808}, issn = {2589-5370}, abstract = {BACKGROUND: CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS).

METHODS: RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N = 45) were randomised 1:1 to receive 30 mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively.

FINDINGS: In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI: -11.9 to 27.3%, p = 0.43), total MUNIX score change (18.8, 95% CI: -56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI: -12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio = 0.408 (95% Wald CI: 0.166 to 1.001, log-rank p = 0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed.

INTERPRETATION: CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS.

FUNDING: The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.}, } @article {pmid37399802, year = {2023}, author = {Pannek, J and Mahler, J and Wöllner, J and Krebs, J}, title = {Satisfaction with Homeopathic Service and Care for Persons with Spinal Cord Injury.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {408-414}, doi = {10.1159/000531658}, pmid = {37399802}, issn = {2504-2106}, mesh = {Humans ; Cross-Sectional Studies ; *Homeopathy ; Surveys and Questionnaires ; Switzerland ; }, abstract = {BACKGROUND: The aim of the study was to investigate the satisfaction of individuals with spinal cord injury (SCI) with a homeopathic service at an SCI rehabilitation center.

PATIENTS AND METHODS: A cross-sectional questionnaire study was performed at an SCI rehabilitation center in Switzerland. It included patients with chronic SCI who presented themselves to a homeopathic service offered by the hospital in a 12-months period. The participants filled in standardized questionnaires in German: "Measure Yourself Medical Outcome Profile" (MYMOP), Treatment Satisfaction Questionnaire for Medication (TSQM-9), the European Project on Patient Evaluation of General Practice Care (EUROPEP) questionnaire, and a self-administered questionnaire.

RESULTS: The data of 14 patients were analyzed. Symptom severity as well as bother by the symptoms that led to homeopathic treatment decreased under homeopathic treatment (severity: from 4.3 to 3.3; bother: from 4.2 to 2.9) and remained lower over time (severity: 2.6; bother: 2.7), suggesting a sustained effect. Irrespective of the test instrument used, satisfaction rates were higher for homeopathic service than for homeopathic medication, which was rated as successful by 50% of the participants.

CONCLUSION: Persons with SCI suffering from secondary complications of SCI who accessed homeopathic care reported high satisfaction rates with the service. Therefore, homeopathic service can be considered as an additive measure in persons with SCI suffering from recurrent symptoms.

UNLABELLED: HintergrundEvaluierung der Zufriedenheit von Personen mit Querschnittlähmung (QSL) mit einer homöopathischen Betreuung an einem Rehabilitationszentrum für QSL.Patient*innen und MethodikAn einem Rehabilitationszentrum für QSL in der Schweiz wurde eine Querschnittserhebung mittels Fragebögen durchgeführt. Eingeschlossen wurden Personen mit chronischer QSL, die sich in einer von der Klinik angebotenen homöopathischen Sprechstunde in einem 12-Monats-Intervall vorstellten. Die Teilnehmenden füllten standardisierte Fragebogen in deutscher Sprache aus: "Measure Yourself Medical Outcome Profile" (MYMOP), Treatment Satisfaction Questionnaire for Medication (TSQM-9), den "European Project on Patient Evaluation of General Practice Care (EUROPEP)" Fragebogen sowie einen selbst-erstellten Fragebogen.ErgebnisseDie Daten von 14 Teilnehmenden wurden ausgewertet. Der Schweregrad der Symptome sowie die Belastung durch die Symptome die zur homöopathischen Behandlung geführt haben, wurden unter der homöopathischen Therapie geringer (Schweregrad: von 4.3 auf 3.3; Belastung: von 4.2 auf 2.9) und blieben über den Untersuchungszeitraum geringer (Schweregrad: 2.6; Belastung 2.7), was einen anhaltenden Effekt nahelegt. Unabhängig von dem verwendeten Testinstrument waren die Zufriedenheitsraten für die homöopathische Betreuung höher als diejenigen für die homöopathische Medikation, die von 50% der Teilnehmenden als erfolgreich bewertet wurde.SchlussfolgerungPersonen mit QSL, die wegen Sekundärkomplikationen eine homöopathische Sprechstunde aufsuchten, berichteten eine hohe Zufriedenheit mit dieser Betreuung. Daher kann eine homöopathische Betreuung als zusätzliche Massnahme bei Personen mit QSL mit persistierender Symptomatik in Betracht gezogen werden.}, } @article {pmid37408276, year = {2023}, author = {Hosaka, T and Tsuji, H and Kwak, S}, title = {Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets.}, journal = {Cells}, volume = {12}, number = {10}, pages = {}, pmid = {37408276}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; RNA, Circular/genetics/metabolism ; RNA Editing/genetics ; RNA/genetics/metabolism ; Aging/genetics ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca[2+] influx through Ca[2+]-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.}, } @article {pmid37422655, year = {2023}, author = {van Eijk, RPA and van den Berg, LH and Roes, KCB and Tian, L and Lai, TL and Nelson, LM and Li, C and Scowcroft, A and Garcia-Segovia, J and Lu, Y}, title = {Hybrid Controlled Clinical Trials Using Concurrent Registries in Amyotrophic Lateral Sclerosis: A Feasibility Study.}, journal = {Clinical pharmacology and therapeutics}, volume = {114}, number = {4}, pages = {883-892}, doi = {10.1002/cpt.2994}, pmid = {37422655}, issn = {1532-6535}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Feasibility Studies ; Research Design ; }, abstract = {Hybrid designs with both randomized arms and an external control cohort preserve key features of randomization and utilize external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis. The proposed methodology was evaluated in a randomized, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomized clinical trial, to identify concurrently nonparticipating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the nonparticipating patients. Augmenting the randomized controls with matched external controls could have avoided unnecessary randomization of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilizing a concurrent registry with rigorous matching can minimize bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.}, } @article {pmid37427180, year = {2023}, author = {Chapagain, S and Khati, N and Lama, R and Karki, R and Aryal, R and Pangyani, B and Koirala, A}, title = {Amyotrophic lateral sclerosis with respiratory failure and dysautonomia: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {7}, pages = {3623-3625}, pmid = {37427180}, issn = {2049-0801}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a disease that affects both upper and lower motor neurons, causing a range of symptoms beyond the motor system. Recent research has shown that the autonomic nervous system can also be affected, with symptoms such as orthostatic hypotension, fluctuations in blood pressure, and dizziness being reported.

CASE PRESENTATION: A 58-year-old male presented with left lower limb limping, difficulty climbing stairs, and left foot weakness, followed by right upper limb weakness and was diagnosed with ALS and received edaravone and riluzole treatment. He presented again with right lower limb weakness, shortness of breath, and wide fluctuations in blood pressure, leading to ICU admission with new diagnosis of ALS with dysautonomia with respiratory failure and was managed with non-invasive ventilation, physiotherapy, and gait training exercises.

CLINICAL DISCUSSION: ALS is a progressive neurodegenerative disease affecting motor neurons but non-motor symptoms can also occur, including dysautonomia, which can result in blood pressure fluctuations. Dysautonomia in ALS is caused by several mechanisms such as severe muscle atrophy, prolonged ventilatory support, and upper and lower motor neuron lesions. Management of ALS involves giving a definitive diagnosis, providing nutritional support, using disease-modifying drugs such as riluzole and non-invasive ventilation to improve survival and quality of life. Early diagnosis is essential for effective management of the disease.

CONCLUSION: Early diagnosis, use of disease-modifying drugs, non-invasive ventilation, and maintaining the patient's nutritional status are crucial for managing ALS which can have non-motor symptoms as well.}, } @article {pmid37427325, year = {2023}, author = {Najafi, S and Najafi, P and Kaffash Farkhad, N and Hosseini Torshizi, G and Assaran Darban, R and Boroumand, AR and Sahab-Negah, S and Khodadoust, MA and Tavakol-Afshari, J}, title = {Mesenchymal stem cell therapy in amyotrophic lateral sclerosis (ALS) patients: A comprehensive review of disease information and future perspectives.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {8}, pages = {872-881}, pmid = {37427325}, issn = {2008-3866}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare deadly progressive neurological disease that primarily affects the upper and lower motor neurons with an annual incidence rate of 0.6 to 3.8 per 100,000 people. Weakening and gradual atrophy of the voluntary muscles are the first signs of the disease onset affecting all aspects of patients' lives, including eating, speaking, moving, and even breathing. Only 5-10% of patients have a familial type of the disease and show an autosomal dominant pattern, but the cause of the disease is unknown in the remaining 90% of patients (Sporadic ALS). However, in both types of disease, the patient's survival is 2 to 5 years from the disease onset. Some clinical and molecular biomarkers, magnetic resonance imaging (MRI), blood or urine test, muscle biopsy, and genetic testing are complementary methods for disease diagnosis. Unfortunately, with the exception of Riluzole, the only medically approved drug for the management of this disease, there is still no definitive cure for it. In this regard, the use of mesenchymal stem cells (MSCs) for the treatment or management of the disease has been common in preclinical and clinical studies for many years. MSCs are multipotent cells having immunoregulatory, anti-inflammatory, and differentiation ability that makes them a good candidate for this purpose. This review article aims to discuss multiple aspects of ALS disease and focus on MSCs' role in disease management based on performed clinical trials.}, } @article {pmid37430314, year = {2023}, author = {Mitsumoto, H and Cheung, K and Oskarsson, B and Andrews, HF and Jang, GE and Andrews, JA and Shah, JS and Fernandes, JA and McElhiney, M and Santella, RM}, title = {Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {449}, pmid = {37430314}, issn = {1745-6215}, support = {no number//Tsumura and Company/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy ; Drug Combinations ; *Drugs, Chinese Herbal ; Muscle Cramp/diagnosis/drug therapy/etiology ; Quality of Life ; Randomized Controlled Trials as Topic ; Glycyrrhiza ; Paeonia ; }, abstract = {INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS.

METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R).

DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life.

TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.}, } @article {pmid37431079, year = {2023}, author = {Kurashige, T}, title = {[Histopathological Diagnostic Marker for ALS: Phosphorylated Transacting Response DNA-Binding Protein of 43kDa in Intramuscular Nerve Bundles].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {7}, pages = {877-887}, doi = {10.11477/mf.1416202436}, pmid = {37431079}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; Autopsy ; DNA-Binding Proteins ; Sulfur ; }, abstract = {The discovery of transacting response DNA-binding protein of 43 kDa (TDP-43) led to a deeper understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS). Since this discovery, blood and cerebrospinal fluid biomarkers of ALS have been reported. However, these biomarkers do not exhibit sufficient specificity for ALS. Our case-control postmortem and retrospective muscle biopsy cohort studies revealed phosphorylated TDP-43 in intramuscular nerve bundles, which precedes the clinical fulfillment of the Gold Coast criteria. We attempted to establish a histopathological biomarker for ALS and identify molecular targets for the treatment of lower motor dysfunction in patients with ALS.}, } @article {pmid37432640, year = {2024}, author = {Maurya, S and Gaur, M and Yadav, AB}, title = {Staphylococcus aureus Biofilm Destabilization by Tween-80 and Lung Surfactants to Overcome Biofilm-Imposed Drug Resistance.}, journal = {Applied biochemistry and biotechnology}, volume = {196}, number = {3}, pages = {1558-1569}, pmid = {37432640}, issn = {1559-0291}, mesh = {Animals ; *Staphylococcus aureus ; Anti-Bacterial Agents/pharmacology ; Polysorbates/pharmacology ; Biofilms ; *Staphylococcal Infections/microbiology ; Surface-Active Agents/pharmacology ; Drug Resistance ; Lung ; }, abstract = {This study is aimed to evaluating the potential of tween-80 and artificial lung surfactant (ALS) to destabilize S. aureus biofilm. The biofilm destabilization was studied by crystal violet staining, bright field microscopy, and scanning electron microscopy (SEM). During the study, S. aureus biofilm was exposed with tween-80 along various concentrations (1%, 0.1%, and 0.05%) or LS (lung surfactant) at (2.5%, 5%, and 15%) for 2 hrs. It was observed that 0.1% of tween-80 destabilized 63.83 ± 4.35% and 15% ALS 77 ± 1.7% biofilm in comparison to without treatment. The combination of tween-80 and ALS was used and showed a synergistic effect to destabilize 83.4 ± 1.46% biofilm. These results showed the potential of tween-80 and ALS as biofilm disruptors, which further needs to explore in an in-vivo animal model to access the actual potential of biofilm disruption in natural conditions. This study could play a pivotal role to overcome the problem of antibiotic resistance imposed due to biofilm formation to combat antibiotic resistance imposed by bacteria.}, } @article {pmid37433091, year = {2023}, author = {Lynch, K}, title = {Pathogenesis and presentation of ALS: examining reasons for delayed diagnosis and identifying opportunities for improvement.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S104-S111}, doi = {10.37765/ajmc.2023.89390}, pmid = {37433091}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; Quality of Life ; Brain ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. As upper and lower motor neurons fail, inability to transmit messages to the muscles causes muscle stiffness, atrophy, and wasting. The incidence of this incurable disease is increasing in the United States, and its prognosis is grim. On average, patients survive about 3 to 5 years from symptom onset. Until recently, few risk factors were known, but some are newly emerging. About 10% of cases are related to genetic variants. Patients who develop ALS often experience diagnostic delays (10-16 months on average), and its heterogeneity contributes to that delay. Diagnosis is based primarily on clinical signs and symptoms and exclusion of other causes of motor neuron dysfunction. Reliable, accessible biomarkers are needed to aid early ALS diagnosis, differentiate from ALS-mimicking diseases, predict survival, and monitor disease progression and treatment response. Misdiagnosing ALS can have devastating consequences, including unnecessary emotional burden, delayed and/or inappropriate treatment, and undue financial burden. The grim prognosis and sure progression to death creates considerable burden and reduces quality of life for patients and caregivers.}, } @article {pmid37433092, year = {2023}, author = {Lynch, K}, title = {Optimizing pharmacologic treatment for ALS to improve outcomes and quality of life.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S112-S119}, doi = {10.37765/ajmc.2023.89389}, pmid = {37433092}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Quality of Life ; Riluzole ; Edaravone ; Phenylbutyrates ; }, abstract = {Just 3 disease-modifying treatments-edaravone, riluzole, and sodium phenylbutyrate and taurursodiol (PB/TURSO)-are currently FDA approved to slow progression of amyotrophic lateral sclerosis (ALS). A fourth therapy has been recently approved under accelerated approval and is contingent upon verification of clinical benefit in confirmatory trials(s). Therapy selection is based largely upon patient characteristics, as guidelines have not been updated since the recent approval of PB/TURSO or accelerated approval of tofersen. Managing ALS symptomatically is important to improve patients' quality of life. Although evidence is lacking for many pharmacologic therapies, providers use symptomatic treatments to address common symptoms including anxiety, depression, emotional lability (pseudobulbar affect), fasciculations, fatigue, insomnia, muscle cramps or spasms, musculoskeletal pain due to immobility, neuropathic type pain, excessive salivation (sialorrhea), spasticity, constipation, and urinary urgency. Emerging agents offer some hope for patients with ALS. Among the drugs, biologics, and interventions under investigation for ALS are an oral tyrosine kinase inhibitor, RIPK1 inhibition, the use of mesenchymal stem cells, antisense oligonucleotides, sequential administration of all experimental treatments in a new study design, and modification of the patient's own mesenchymal stem cells.}, } @article {pmid37433093, year = {2023}, author = {Wong, W}, title = {Managed care considerations to improve health care utilization for patients with ALS.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S120-S126}, doi = {10.37765/ajmc.2023.89388}, pmid = {37433093}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Edaravone ; Activities of Daily Living ; Quality of Life ; Patient Acceptance of Health Care ; Managed Care Programs ; Phenylbutyrates ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatally progressive degenerative disease, with many patients succumbing to the condition within 3 to 5 years after diagnosis. It is a rare, orphan disease with an estimated US prevalence of 25,000 patients. Patients with ALS and their caregivers are faced with a substantial financial burden as a result of the condition, as ALS has an estimated national financial burden of $1.03 billion. A significant driver of the patient financial burden includes the continued need for caregiver support as the weakening of muscles progresses to dysphagia and dyspnea, making it difficult to complete activities of daily living as the disease progresses. Caregivers also experience financial burdens, as well as feelings of anxiety, depression, and decreased quality of life. In addition to needed caregiver support, patients with ALS and their families also incur substantial nonmedical costs including travel expenses, home modifications such as ramps, and indirect costs such as productivity loss. Due to the wide range of clinical symptoms that patients may exhibit when first presenting with ALS symptoms, diagnosis is often delayed, which negatively affects patient outcomes and impacts missed opportunity for clinical trial recruitment aimed at developing new disease-modifying therapies. Additionally, delay in diagnosis and referral to ALS treatment centers results in increased overall health care costs. Telemedicine may be a tool used to promote timely care from an ALS treatment center in addition to clinical trial participation for those patients who cannot overcome mobility barriers for care. Currently, 4 therapies are approved for the treatment of ALS. Riluzole has demonstrated modest improvement in survival. Other recently approved therapies include oral edaravone, a combination therapy of sodium phenylbutyrate and taurursodiol (PB/TURSO), and tofersen, which is administered intrathecally and approved under an accelerated approval. Long-term studies have shown PB/TURSO to have a dual benefit on survival and function. The Institute for Clinical and Economic Review (ICER) 2022 Evidence Report for ALS does not value the high price points of edaravone and PB/TURSO as cost-effective based on the current evidence, despite valuing the need for new treatment options for this patient population.}, } @article {pmid37433768, year = {2023}, author = {Zhang, W and Xiao, D and Mao, Q and Xia, H}, title = {Role of neuroinflammation in neurodegeneration development.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {267}, pmid = {37433768}, issn = {2059-3635}, support = {UL1 TR002538/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Inflammation/genetics ; Neuroinflammatory Diseases ; *Parkinson Disease/genetics ; Protein Aggregates ; Humans ; Clinical Trials as Topic ; Disease Models, Animal ; }, abstract = {Studies in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, Huntington's disease, and so on, have suggested that inflammation is not only a result of neurodegeneration but also a crucial player in this process. Protein aggregates which are very common pathological phenomenon in neurodegeneration can induce neuroinflammation which further aggravates protein aggregation and neurodegeneration. Actually, inflammation even happens earlier than protein aggregation. Neuroinflammation induced by genetic variations in CNS cells or by peripheral immune cells may induce protein deposition in some susceptible population. Numerous signaling pathways and a range of CNS cells have been suggested to be involved in the pathogenesis of neurodegeneration, although they are still far from being completely understood. Due to the limited success of traditional treatment methods, blocking or enhancing inflammatory signaling pathways involved in neurodegeneration are considered to be promising strategies for the therapy of neurodegenerative diseases, and many of them have got exciting results in animal models or clinical trials. Some of them, although very few, have been approved by FDA for clinical usage. Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. We also summarize the current strategies, both in animal models and in the clinic, for the treatment of neurodegenerative diseases.}, } @article {pmid37440197, year = {2023}, author = {Yang, J and Li, H and Zhao, Y}, title = {Dessert or Poison? The Roles of Glycosylation in Alzheimer's, Parkinson's, Huntington's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {24}, number = {16}, pages = {e202300017}, doi = {10.1002/cbic.202300017}, pmid = {37440197}, issn = {1439-7633}, mesh = {Humans ; Aged ; *Huntington Disease ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; Glycosylation ; *Poisons ; Quality of Life ; }, abstract = {Ministry of Education and Key Laboratory of Neurons and glial cells of the central nervous system (CNS) are modified by glycosylation and rely on glycosylation to achieve normal neural function. Neurodegenerative disease is a common disease of the elderly, affecting their healthy life span and quality of life, and no effective treatment is currently available. Recent research implies that various glycosylation traits are altered during neurodegenerative diseases, suggesting a potential implication of glycosylation in disease pathology. Herein, we summarized the current knowledge about glycosylation associated with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS) pathogenesis, focusing on their promising functional avenues. Moreover, we collected research aimed at highlighting the need for such studies to provide a wealth of disease-related glycosylation information that will help us better understand the pathophysiological mechanisms and hopefully specific glycosylation information to provide further diagnostic and therapeutic directions for neurodegenerative diseases.}, } @article {pmid37442650, year = {2024}, author = {Lopez-Garcia, YK and Valdez-Carrizales, M and Nuñez-Zuno, JA and Apodaca-Chávez, E and Rangel-Patiño, J and Demichelis-Gómez, R}, title = {Are delays in diagnosis and treatment of acute leukemia in a middle-income country associated with poor outcomes? A retrospective cohort study.}, journal = {Hematology, transfusion and cell therapy}, volume = {46}, number = {4}, pages = {366-373}, pmid = {37442650}, issn = {2531-1387}, abstract = {INTRODUCTION: Acute leukemias (ALs) are aggressive diseases that lead to death without medical attention. We evaluated the association between delays in diagnosis and poor outcomes in AL by evaluating the symptom onset to treatment intervals in adults with newly diagnosed AL and their effect on an early death (ED).

METHODS: We assessed adults diagnosed with AL between 2015 and 2020 and evaluated baseline characteristics, the patient interval (PI), diagnostic interval (DI), treatment interval (TI) and the total time interval (TTI) to determine ED-associated factors.

MAIN RESULTS: We assessed 102 patients with acute lymphoblastic leukemia (ALL), 57 with acute myeloblastic leukemia (AML) and 29 with acute promyelocytic leukemia (APL). Median interval days were PI 14, DI 10, TI 4 and TTI 31.5. The TI and TTI intervals were lower in APL than in ALL and AML; TI 1 vs. 4 and 3 (p = 0.001) and TTI 21 vs. 31 and 35 (p = 0.016). The 30-day and 60-day EDs were 13.8% and 20.7%, mainly infections. ECOG > 2 (OR = 15.0) and PI < 7 days (OR = 4.06) were associated with 30-day ED; AML (OR = 2.69), high-risk (OR = 3.34), albumin < 3.5 g/dl (OR = 5) and platelets < 20 × 10[3]/uL (OR = 2.71) with a 60-day ED.

CONCLUSION: None of the interval-delays were associated with an ED. Intervals seemed to be longer in patients without an ED, except for the TI, probably because of "the waiting time paradox." Aggressive manifestations of disease may lead to shorter diagnostic intervals, but increased mortality.}, } @article {pmid37445986, year = {2023}, author = {Ciurea, AV and Mohan, AG and Covache-Busuioc, RA and Costin, HP and Glavan, LA and Corlatescu, AD and Saceleanu, VM}, title = {Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37445986}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Huntington Disease/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.}, } @article {pmid37446372, year = {2023}, author = {Alarcan, H and Vourc'h, P and Berton, L and Benz-De Bretagne, I and Piver, E and Andres, CR and Corcia, P and Veyrat-Durebex, C and Blasco, H}, title = {Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37446372}, issn = {1422-0067}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Retrospective Studies ; Sex Factors ; Delayed Diagnosis ; Central Nervous System ; }, abstract = {Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.}, } @article {pmid37450244, year = {2023}, author = {Dubowsky, M and Theunissen, F and Carr, JM and Rogers, ML}, title = {The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6330-6345}, pmid = {37450244}, issn = {1559-1182}, support = {1950//Motor Neurone Disease Australia/ ; 1950//Andrew Butcher Grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Endogenous Retroviruses ; *Motor Neuron Disease/pathology ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; *HIV Infections/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder, characterised by the death of upper and lower motor neurons. The aetiology of ALS remains unknown, and treatment options are limited. Endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the propagation of neurodegeneration in ALS. ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. A hallmark of ALS pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In ALS, TDP-43 aggregates within the cytoplasm and facilitates neurodegeneration. The involvement of ERVs in ALS pathology is thought to occur through TDP-43 and neuroinflammatory mediators. In this review, the proposed involvement of TDP-43, HERV-K and immune regulators on the onset and progression of ALS will be discussed. Furthermore, the evidence supporting a therapy based on targeting ERVs in ALS will be reviewed.}, } @article {pmid37451615, year = {2023}, author = {Yen, H and Yen, H and Huang, CH and Huang, IH and Hung, WK and Su, HJ and Tai, CC and Haw, WWY and Flohr, C and Yiu, ZZN and Chi, CC}, title = {Systematic Review and Critical Appraisal of Urticaria Clinical Practice Guidelines: A Global Guidelines in Dermatology Mapping Project (GUIDEMAP).}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {11}, number = {10}, pages = {3213-3220.e11}, doi = {10.1016/j.jaip.2023.07.002}, pmid = {37451615}, issn = {2213-2201}, mesh = {Humans ; Australia ; Databases, Factual ; *Dermatology ; Stakeholder Participation ; *Urticaria/diagnosis/therapy ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: Management of urticaria can be optimized with clinical practice guidelines (CPGs). However, the quality of recent urticaria CPGs remains unclear.

OBJECTIVE: To identify and appraise urticaria CPGs worldwide published in the last 5 years.

METHODS: A search for relevant urticaria CPGs was conducted between January 1, 2017, and May 31, 2022, using the following databases: MEDLINE, Embase, National Institute for Health and Care Excellence (NICE) Evidence Search, Guidelines International Network, ECRI Guidelines Trust, Australian Clinical Practice Guidelines, Trip Medical Database, and DynaMed. The included CPGs were critically appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et al's red flags, and the Institute of Medicine (IOM) criteria of trustworthiness.

RESULTS: We included 21 urticaria CPGs. Most guidelines reviewed treatment recommendations of chronic spontaneous urticaria. The majority of guidelines were from European and Asian countries with high and high-middle sociodemographic index, written in English, and openly accessible. Seventeen guidelines (81%) had at least 1 AGREE II domain rated poor quality. Applicability, rigor of development, and stakeholder involvement were the 3 AGREE II domains that scored the lowest across guidelines. Appraisal with Lenzer et al's red flags showed that 18 guidelines (86%) raised at least 1 red flag indicating potential bias. The top 3 domains raising red flags were: no inclusion of nonphysician experts/patient representative/community stakeholders, no or limited involvement of a methodologist in the evaluation of evidence, and lack of external review. Based on IOM's criteria of trustworthiness, 20 guidelines (95%) had 1 or more criteria that did not meet best practice standards. The 3 domains with the highest number of best practice standards not met were updating procedures, rating strength of recommendations, and external review. Guidelines scored highest for the AGREE II domains of defining scope and purpose and clarity of presentation, and had the most fully met IOM's best practice standard for articulation of recommendations. However, only 1 urticaria CPG by NICE was identified as rigorously developed across all 3 appraisal tools.

CONCLUSIONS: The quality of urticaria CPGs in the last 5 years varied widely. Only the NICE urticaria guideline consistently demonstrated excellent quality, high trustworthiness, and low risk of bias. Use of a rigorous framework to rate certainty of evidence and grade strength of recommendation, involvement of methodologists, stakeholder engagement with external review, and clear guidance for updating can help improve the quality of future CPGs.}, } @article {pmid37460332, year = {2023}, author = {Lacroix, C and Guilhaumou, R and Micallef, J and Bruneteau, G and Desnuelle, C and Blin, O}, title = {Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients' view?.}, journal = {Revue neurologique}, volume = {179}, number = {9}, pages = {967-974}, doi = {10.1016/j.neurol.2023.03.018}, pmid = {37460332}, issn = {0035-3787}, mesh = {Humans ; *Cannabis/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Quality of Life ; *Cannabinoids/adverse effects ; Pain ; }, abstract = {Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects…), most of the participants reported "rational" consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.}, } @article {pmid37460793, year = {2023}, author = {Gawlik-Dziki, U and Wrzesińska-Krupa, B and Nowak, R and Pietrzak, W and Zyprych-Walczak, J and Obrępalska-Stęplowska, A}, title = {Herbicide resistance status impacts the profile of non-anthocyanin polyphenolics and some phytomedical properties of edible cornflower (Centaurea cyanus L.) flowers.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {11538}, pmid = {37460793}, issn = {2045-2322}, mesh = {*Herbicide Resistance ; *Herbicides/pharmacology ; Flowers ; Centaurea ; Plant Weeds ; }, abstract = {To ensure sufficient food supply worldwide, plants are treated with pesticides to provide protection against pathogens and pests. Herbicides are the most commonly utilised pesticides, used to reduce the growth of weeds. However, their long-term use has resulted in the emergence of herbicide-resistant biotypes in many weed species. Cornflower (Centaurea cyanus L., Asteraceae) is one of these plants, whose biotypes resistant to herbicides from the group of acetolactate synthase (ALS) inhibitors have begun to emerge in recent years. Some plants, although undesirable in crops and considered as weeds, are of great importance in phytomedicine and food production, and characterised by a high content of health-promoting substances, including antioxidants. Our study aimed to investigate how the acquisition of herbicide resistance affects the health-promoting properties of plants on the example of cornflower, as well as how they are affected by herbicide treatment. To this end, we analysed non-anthocyanin polyphenols and antioxidant capacity in flowers of C. cyanus from herbicide-resistant and susceptible biotypes. Our results indicated significant compositional changes associated with an increase in the content of substances and activities that have health-promoting properties. High antioxidant activity and higher total phenolic and flavonoid compounds as well as reducing power were observed in resistant biotypes. The latter one increased additionally after herbicide treatment which might also suggest their role in the resistance acquisition mechanism. Overall, these results show that the herbicide resistance development, although unfavourable to crop production, may paradoxically have very positive effects for medicinal plants such as cornflower.}, } @article {pmid37461167, year = {2023}, author = {Berger, A and Locatelli, M and Arcila-Londono, X and Hayat, G and Olney, N and Wymer, J and Gwathmey, K and Lunetta, C and Heiman-Patterson, T and Ajroud-Driss, S and Macklin, EA and Bind, MA and Goslin, K and Stuchiner, T and Brown, L and Bazan, T and Regan, T and Adamo, A and Ferment, V and Schroeder, C and Somers, M and Manousakis, G and Faulconer, K and Sinani, E and Mirochnick, J and Yu, H and Sherman, AV and Walk, D and , }, title = {The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {7-8}, pages = {625-633}, doi = {10.1080/21678421.2023.2232812}, pmid = {37461167}, issn = {2167-9223}, support = {R01 FD007630/FD/FDA HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed.

METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal.

RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database.

CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.}, } @article {pmid37461717, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, M}, title = {lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37461717}, issn = {2693-5015}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Fused-in Sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered expression profiles of mRNAs and lncRNAs in iPSCs. We identified key differentially regulated TAR pairs, including LMO3, TMEM132D, ERMN, GPR149, CRACD, and ZNF404 in mutant FUS iPSCs. We performed reverse transcription PCR (RT-PCR) validation in iPSCs and iMNs. Validation confirmed RNA-Seq findings and suggested that mutant FUS-induced transcriptional alterations persisted from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis that were likely altered by FUS mutations. Ingenuity Pathway Analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations related to RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into the molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, } @article {pmid37465304, year = {2023}, author = {Kargbo, RB}, title = {Microbiome-Gut-Brain Axis Modulation: New Approaches in Treatment of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {ACS medicinal chemistry letters}, volume = {14}, number = {7}, pages = {886-888}, pmid = {37465304}, issn = {1948-5875}, abstract = {Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by symptoms like resting tremor, rigidity, bradykinesia, and postural instability, mainly due to dopamine depletion and degeneration of dopaminergic neurons. Mitochondrial dysfunction plays a critical role in the disease's progression, while amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig's disease, is a fatal progressive neurodegenerative disease characterized by significant motor neuron loss in the primary motor cortex, brainstem, and spinal cord. This loss results in impaired movements such as breathing, leading to death within 2-5 years of diagnosis. Patients experience muscle weakness in the hands, arms, legs, and swallowing muscles and may require breathing aids. This Patent Highlight describes blends, such as microbiome compositions, that can be used to treat various diseases or conditions, particularly those affecting the nervous system, like neurodegenerative diseases (PD and ALS).}, } @article {pmid37466825, year = {2024}, author = {Poppe, C and Elger, BS}, title = {Brain-Computer Interfaces, Completely Locked-In State in Neurodegenerative Diseases, and End-of-Life Decisions.}, journal = {Journal of bioethical inquiry}, volume = {21}, number = {1}, pages = {19-27}, pmid = {37466825}, issn = {1872-4353}, mesh = {Humans ; *Brain-Computer Interfaces/ethics ; *Terminal Care/ethics ; *Neurodegenerative Diseases ; *Quality of Life ; *Decision Making/ethics ; Suicide, Assisted/ethics ; Locked-In Syndrome ; Mental Competency ; }, abstract = {In the future, policies surrounding end-of-life decisions will be faced with the question of whether competent people in a completely locked-in state should be enabled to make end-of-life decisions via brain-computer interfaces (BCI). This article raises ethical issues with acting through BCIs in the context of these decisions, specifically self-administration requirements within assisted suicide policies. We argue that enabling patients to end their life even once they have entered completely locked-in state might, paradoxically, prolong and uphold their quality of life.}, } @article {pmid37467213, year = {2023}, author = {Oey, A and McClure, M and Symons, JA and Chanda, S and Fry, J and Smith, PF and Luciani, K and Fayon, M and Chokephaibulkit, K and Uppala, R and Bernatoniene, J and Furuno, K and Stanley, T and Huntjens, D and Witek, J and , }, title = {Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results.}, journal = {PloS one}, volume = {18}, number = {7}, pages = {e0288271}, pmid = {37467213}, issn = {1932-6203}, mesh = {Adult ; Child ; Humans ; Infant ; Infant, Newborn ; Antiviral Agents/adverse effects ; *Neutropenia/complications ; Nucleosides/therapeutic use ; *Respiratory Syncytial Virus Infections ; *Respiratory Syncytial Virus, Human ; }, abstract = {Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b).}, } @article {pmid37470509, year = {2023}, author = {Strnad, P and San Martin, J}, title = {RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {7}, pages = {571-581}, doi = {10.1080/13543784.2023.2239707}, pmid = {37470509}, issn = {1744-7658}, mesh = {Humans ; *Protein Aggregates ; RNA Interference ; RNAi Therapeutics ; *alpha 1-Antitrypsin Deficiency/complications/genetics/therapy ; RNA, Small Interfering ; }, abstract = {INTRODUCTION: Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism.

AREAS COVERED: This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases.

EXPERT OPINION: Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.}, } @article {pmid37474587, year = {2023}, author = {Zilio, F and Gomez-Pilar, J and Chaudhary, U and Fogel, S and Fomina, T and Synofzik, M and Schöls, L and Cao, S and Zhang, J and Huang, Z and Birbaumer, N and Northoff, G}, title = {Altered brain dynamics index levels of arousal in complete locked-in syndrome.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {757}, pmid = {37474587}, issn = {2399-3642}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Locked-In Syndrome ; Electroencephalography/methods ; Brain/physiology ; Wakefulness ; Biomarkers ; }, abstract = {Complete locked-in syndrome (CLIS) resulting from late-stage amyotrophic lateral sclerosis (ALS) is characterised by loss of motor function and eye movements. The absence of behavioural indicators of consciousness makes the search for neuronal correlates as possible biomarkers clinically and ethically urgent. EEG-based measures of brain dynamics such as power-law exponent (PLE) and Lempel-Ziv complexity (LZC) have been shown to have explanatory power for consciousness and may provide such neuronal indices for patients with CLIS. Here, we validated PLE and LZC (calculated in a dynamic way) as benchmarks of a wide range of arousal states across different reference states of consciousness (e.g., awake, sleep stages, ketamine, sevoflurane). We show a tendency toward high PLE and low LZC, with high intra-subject fluctuations and inter-subject variability in a cohort of CLIS patients with values graded along different arousal states as in our reference data sets. In conclusion, changes in brain dynamics indicate altered arousal in CLIS. Specifically, PLE and LZC are potentially relevant biomarkers to identify or diagnose the arousal level in CLIS and to determine the optimal time point for treatment, including communication attempts.}, } @article {pmid37480846, year = {2023}, author = {Ziff, OJ and Harley, J and Wang, Y and Neeves, J and Tyzack, G and Ibrahim, F and Skehel, M and Chakrabarti, AM and Kelly, G and Patani, R}, title = {Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is restored by VCP ATPase inhibition.}, journal = {Neuron}, volume = {111}, number = {19}, pages = {3011-3027.e7}, doi = {10.1016/j.neuron.2023.06.019}, pmid = {37480846}, issn = {1097-4199}, support = {FC010110/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; FC010110/MRC_/Medical Research Council/United Kingdom ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; MC_PC_19038/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Adenosine Triphosphatases/genetics/metabolism ; RNA, Messenger/metabolism ; Motor Neurons/metabolism ; RNA-Binding Proteins/metabolism ; Valosin Containing Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by nucleocytoplasmic mislocalization of the RNA-binding protein (RBP) TDP-43. However, emerging evidence suggests more widespread mRNA and protein mislocalization. Here, we employed nucleocytoplasmic fractionation, RNA sequencing, and mass spectrometry to investigate the localization of mRNA and protein in induced pluripotent stem cell-derived motor neurons (iPSMNs) from ALS patients with TARDBP and VCP mutations. ALS mutant iPSMNs exhibited extensive nucleocytoplasmic mRNA redistribution, RBP mislocalization, and splicing alterations. Mislocalized proteins exhibited a greater affinity for redistributed transcripts, suggesting a link between RBP mislocalization and mRNA redistribution. Notably, treatment with ML240, a VCP ATPase inhibitor, partially restored mRNA and protein localization in ALS mutant iPSMNs. ML240 induced changes in the VCP interactome and lysosomal localization and reduced oxidative stress and DNA damage. These findings emphasize the link between RBP mislocalization and mRNA redistribution in ALS motor neurons and highlight the therapeutic potential of VCP inhibition.}, } @article {pmid37483353, year = {2023}, author = {Shi, Y and Zhao, Y and Lu, L and Gao, Q and Yu, D and Sun, M}, title = {CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1223777}, pmid = {37483353}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.}, } @article {pmid37484758, year = {2023}, author = {Chen, TY and Hsu, CW and Chang, YP and Wang, MT and Wu, YJ and Wang, CH and Wang, KY and Chu, TH and Lee, YK}, title = {Percutaneous transhepatic duodenal drainage is good option for afferent loop syndrome for obstructive colorectal cancer patient with history of Billroth's operation II: A case report of a rare postoperative complication.}, journal = {Clinical case reports}, volume = {11}, number = {7}, pages = {e7725}, pmid = {37484758}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: Temporal percutaneous transhepatic duodenum drainage (PTDD) seems to be effective in the treatment of postoperative afferent loop syndrome (ALS) following transverse loop colostomy for obstructive colorectal cancer.

ABSTRACT: Management of obstructive colorectal cancer still remains a challenge. There are various options with different risks of mortality and mobility for obstructive colorectal cancer. A rare unexpected postoperative ALS following a low anterior resection and transverse loop colostomy for obstructive colorectal cancer is presented in this report. A 64-year-old man had the acute ALS had been noted 10 days after transverse loop colostomy. An option was temporal PTDD treatment in the patient with history of Billroth's operation II for upper gastrointestinal bleeding 30 years ago. Acute ALS was treated by temporal PTDD. The drainage tube for PTDD was not removed until closure of the transverse colostomy 2 months later. The patient recovered uneventfully. Acute ALS after transverse loop colostomy for obstructive colorectal cancer is rare and has never been reported in the literature. The mechanism of acute ALS after construction of a loop colostomy and the treatment strategy of PTDD for acute ALS is presented.}, } @article {pmid37488208, year = {2023}, author = {Aly, A and Laszlo, ZI and Rajkumar, S and Demir, T and Hindley, N and Lamont, DJ and Lehmann, J and Seidel, M and Sommer, D and Franz-Wachtel, M and Barletta, F and Heumos, S and Czemmel, S and Kabashi, E and Ludolph, A and Boeckers, TM and Henstridge, CM and Catanese, A}, title = {Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.}, journal = {Acta neuropathologica}, volume = {146}, number = {3}, pages = {451-475}, pmid = {37488208}, issn = {1432-0533}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Proteomics ; Superoxide Dismutase-1/genetics ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.}, } @article {pmid37489441, year = {2023}, author = {Ramakrishna, K and Nalla, LV and Naresh, D and Venkateswarlu, K and Viswanadh, MK and Nalluri, BN and Chakravarthy, G and Duguluri, S and Singh, P and Rai, SN and Kumar, A and Singh, V and Singh, SK}, title = {WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.}, journal = {Diseases (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {37489441}, issn = {2079-9721}, abstract = {Wnt/β-catenin (WβC) signaling pathway is an important signaling pathway for the maintenance of cellular homeostasis from the embryonic developmental stages to adulthood. The canonical pathway of WβC signaling is essential for neurogenesis, cell proliferation, and neurogenesis, whereas the noncanonical pathway (WNT/Ca[2+] and WNT/PCP) is responsible for cell polarity, calcium maintenance, and cell migration. Abnormal regulation of WβC signaling is involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and spinal muscular atrophy (SMA). Hence, the alteration of WβC signaling is considered a potential therapeutic target for the treatment of neurodegenerative disease. In the present review, we have used the bibliographical information from PubMed, Google Scholar, and Scopus to address the current prospects of WβC signaling role in the abovementioned neurodegenerative diseases.}, } @article {pmid37489926, year = {2023}, author = {Greensmith, L and Bryson, JB}, title = {The cholesterol depleting agent, (2-Hydroxypropyl)-ß-cyclodextrin, does not affect disease progression in SOD1[G93A] mice.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {7-8}, pages = {756-762}, doi = {10.1080/21678421.2023.2239867}, pmid = {37489926}, issn = {2167-9223}, abstract = {OBJECTIVE: Previously, we demonstrated that Amyloid Precursor Protein (APP) contributes to pathology in the SOD1[G93A] mouse model of ALS and that genetic ablation of APP in SOD1[G93A] mice significantly improved multiple disease parameters, including muscle innervation and motor neuron survival. We also observed elevated levels of potentially neurotoxic Aß peptides that have been implicated in Alzheimer's Disease (AD) pathogenesis, within motor neurons and astrocytes in SOD1[G93A] mice. More recently, it has been shown that blocking Aß production improves outcome measures in SOD1[G93A] mice. The cyclodextrin, (2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD), has previously been shown to deplete intraneuronal unesterified cholesterol, resulting in effective reduction of Aß production and amelioration of disease progression in mouse models of AD and Niemann Pick Type C (NPC) disease. Here, we tested whether HP-β-CD could also improve phenotypic progression in SOD1[G93A] mice.

METHODS: Pre-symptomatic male SOD1[G93A] mice were randomly assigned to the following treatment groups: HP-β-CD (4000mg/kg, n = 9) or vehicle (saline; n = 10), delivered by weekly subcutaneous injection, commencing at 67 days of age. Longitudinal grip-strength and body mass analysis was performed until late-stage disease (120 days of age), followed by in vivo bilateral isometric muscle tension analysis of tibialis anterior (TA) and extensor digitorum longus (EDL) muscles. Results: HP-β-CD administration had no effect on body mass or grip-strength compared to vehicle treated SOD1[G93A] mice. Similarly, HP-β-CD treatment had no effect on muscle force, contractile properties or motor unit number estimates (MUNE) at late-stage disease in SOD1[G93A] mice.

CONCLUSION: This study shows that HP-β-CD does not confer any therapeutic benefit in SOD1[G93A] mice. However, the absence of detrimental effects is informative, given the common use of cyclodextrins as complexing agents for other pharmaceutical products, their standalone therapeutic potential and the emerging association between dyslipidaemia and ALS progression.}, } @article {pmid37490673, year = {2023}, author = {Kovrazhkina, EA and Serdyuk, AV and Razinskaya, OD and Shurdumova, MH and Vyatkina, NV and Baranova, EA}, title = {[Myasthenic syndrome in a patient with end-stage amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {123}, number = {7}, pages = {102-107}, doi = {10.17116/jnevro2023123071102}, pmid = {37490673}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Myasthenia Gravis/complications/diagnosis ; *Lambert-Eaton Myasthenic Syndrome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and myasthenia gravis are diseases with similar clinical features but different prognosis and approach to treatment. It is possible as an extremely rare combination of these diseases, as well as myasthenia gravis with signs of ALS (MuSK-positive), as well as ALS, accompanied by myasthenic syndrome. Latter option is the most common. Myasthenic syndrome accompanying the ALS characterized by pathological muscle fatigue signs, symptoms variability during the day, partial sensitivity to neostigmine, M-wave decrements detection during electromyographyc study. We present a case of a patient with terminal ALS and myasthenic syndrome. The main pathogenesis theories of this condition and the differential diagnosis of ALS and myasthenia gravis are discussed.}, } @article {pmid37493197, year = {2024}, author = {Sun, Y and Benatar, M and Mascías Cadavid, J and Ennist, D and Wicks, P and Staats, K and Beauchamp, M and Jhooty, S and Pattee, G and Brown, A and Bertorini, T and Barkhaus, P and Bromberg, M and Carter, G and Bedlack, R and Li, X}, title = {ALSUntangled #71: Nuedexta.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {218-222}, doi = {10.1080/21678421.2023.2239292}, pmid = {37493197}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Dextromethorphan/therapeutic use ; Drug Combinations ; *Quinidine/therapeutic use ; }, abstract = {Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.}, } @article {pmid37494786, year = {2023}, author = {Jin, S and Zhang, L and Wang, L}, title = {Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {165}, number = {}, pages = {115215}, doi = {10.1016/j.biopha.2023.115215}, pmid = {37494786}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy ; Kaempferols/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.}, } @article {pmid37500993, year = {2023}, author = {Ludolph, A and Dupuis, L and Kasarskis, E and Steyn, F and Ngo, S and McDermott, C}, title = {Nutritional and metabolic factors in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {9}, pages = {511-524}, pmid = {37500993}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; Energy Metabolism ; Prognosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.}, } @article {pmid37508478, year = {2023}, author = {La Cognata, V and D'Amico, AG and Maugeri, G and Morello, G and Guarnaccia, M and Magrì, B and Aronica, E and D'Agata, V and Cavallaro, S}, title = {CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508478}, issn = {2073-4409}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Apoptosis ; Chemokine CXCL2/metabolism ; Ligands ; Mice, Transgenic ; Motor Neurons/pathology ; *Neurodegenerative Diseases/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Receptors, Interleukin-8B ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.}, } @article {pmid37508548, year = {2023}, author = {Morello, G and La Cognata, V and Guarnaccia, M and La Bella, V and Conforti, FL and Cavallaro, S}, title = {A Diagnostic Gene-Expression Signature in Fibroblasts of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508548}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Transcriptome/genetics ; *Neurodegenerative Diseases/metabolism ; Gene Expression Profiling/methods ; Fibroblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease with limited treatment options. Diagnosis can be difficult due to the heterogeneity and non-specific nature of the initial symptoms, resulting in delays that compromise prompt access to effective therapeutic strategies. Transcriptome profiling of patient-derived peripheral cells represents a valuable benchmark in overcoming such challenges, providing the opportunity to identify molecular diagnostic signatures. In this study, we characterized transcriptome changes in skin fibroblasts of sporadic ALS patients (sALS) and controls and evaluated their utility as a molecular classifier for ALS diagnosis. Our analysis identified 277 differentially expressed transcripts predominantly involved in transcriptional regulation, synaptic transmission, and the inflammatory response. A support vector machine classifier based on this 277-gene signature was developed to discriminate patients with sALS from controls, showing significant predictive power in both the discovery dataset and in six independent publicly available gene expression datasets obtained from different sALS tissue/cell samples. Taken together, our findings support the utility of transcriptional signatures in peripheral cells as valuable biomarkers for the diagnosis of ALS.}, } @article {pmid37508574, year = {2023}, author = {Malhotra, S and Miras, MCM and Pappolla, A and Montalban, X and Comabella, M}, title = {Liquid Biopsy in Neurological Diseases.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508574}, issn = {2073-4409}, mesh = {Humans ; Liquid Biopsy/methods ; *Cell-Free Nucleic Acids ; *MicroRNAs ; *Central Nervous System Neoplasms ; Biomarkers ; }, abstract = {The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.}, } @article {pmid37510999, year = {2023}, author = {Halder, SK and Milner, R}, title = {Spinal Cord Blood Vessels in Aged Mice Show Greater Levels of Hypoxia-Induced Vascular Disruption and Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37510999}, issn = {1422-0067}, support = {RF1 NS119477/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Hypoxia ; Microglia/pathology ; *Spinal Cord/pathology ; *White Matter/pathology ; *Aging/pathology ; }, abstract = {In response to chronic mild hypoxia (CMH, 8% O2), spinal cord blood vessels launch a robust angiogenic response that is associated with transient disruption of the blood-spinal cord barrier (BSCB) which, in turn, triggers a microglial vasculo-protective response. Because hypoxia occurs in many age-related conditions, the goal of this study was to define how aging influences these responses by comparing events in young (8-10 weeks) and aged (20 months) mice. This revealed that aged mice had much greater (3-4-fold) levels of hypoxic-induced BSCB disruption than young mice and that, while the early stage of the angiogenic response in aged mice was no different to young mice, the maturation of newly formed vessels was significantly delayed. Interestingly, microglia in the spinal cords of aged mice were much more activated than young mice, even under normoxic conditions, and this was further enhanced by CMH, though, surprisingly, this resulted in reduced microglial clustering around leaky blood vessels and diminished vasculo-protection. Vascular disruption was associated with loss of myelin in spinal cord white matter (WM) in both young and aged mice. Furthermore, it was notable that the spinal cord of aged mice contained a lower density of Olig2+ oligodendroglial cells even under normoxic conditions and that CMH significantly reduced the density of Olig2+ cells in spinal cord WM of the aged, but not the young, mice. These results demonstrate that spinal cord blood vessels of aged mice are much more vulnerable to the damaging effects of hypoxia than young mice, in part due to the reduced vasculo-protection conferred by chronically activated microglial cells. These observations may have implications for the pathogenesis and/or treatment of spinal cord diseases such as amyotrophic lateral sclerosis (ALS) and suggest that an improvement in microglial function could offer therapeutic potential for treating these age-related conditions.}, } @article {pmid37511037, year = {2023}, author = {Xiang, L and Wang, Y and Liu, S and Liu, B and Jin, X and Cao, X}, title = {Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511037}, issn = {1422-0067}, support = {32000387//National Natural Science Foundation of China/ ; LY23C060001//Zhejiang Provincial Natural Science Foundation/ ; 2021LFR053//Scientific Research Foundation of Zhejiang A&F University/ ; 19 0069//Swedish Cancer Society/ ; VR 2019-03604//Swedish Research Council/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; *Biological Products/pharmacology/therapeutic use ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.}, } @article {pmid37516663, year = {2023}, author = {Ahmed, M and Spicer, C and Harley, J and Taylor, JP and Hanna, M and Patani, R and Greensmith, L}, title = {Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models.}, journal = {Molecular neurobiology}, volume = {60}, number = {12}, pages = {6896-6915}, pmid = {37516663}, issn = {1559-1182}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Frontotemporal Dementia/drug therapy/genetics/pathology ; Hydroxylamines/therapeutic use ; Heat-Shock Response ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now known as parts of a disease spectrum with common pathological features and genetic causes. However, as both conditions are clinically heterogeneous, patient groups may be phenotypically similar but pathogenically and genetically variable. Despite numerous clinical trials, there remains no effective therapy for these conditions, which, in part, may be due to challenges of therapy development in a heterogeneous patient population. Disruption to protein homeostasis is a key feature of different forms of ALS and FTD. Targeting the endogenous protein chaperone system, the heat shock response (HSR) may, therefore, be a potential therapeutic approach. We conducted a preclinical study of a known pharmacological amplifier of the HSR, called arimoclomol, in mice with a mutation in valosin-containing protein (VCP) which causes both ALS and FTD in patients. We demonstrate that amplification of the HSR ameliorates the ALS/FTD-like phenotype in the spinal cord and brain of mutant VCP mice and prevents neuronal loss, replicating our earlier findings in the SOD1 mouse model of ALS. Moreover, in human cell models, we demonstrate improvements in pathology upon arimoclomol treatment in mutant VCP patient fibroblasts and iPSC-derived motor neurons. Our findings suggest that targeting of the HSR may have therapeutic potential, not only in non-SOD1 ALS, but also for the treatment of FTD.}, } @article {pmid37516990, year = {2023}, author = {Tröger, J and Baltes, J and Baykara, E and Kasper, E and Kring, M and Linz, N and Robin, J and Schäfer, S and Schneider, A and Hermann, A}, title = {PROSA-a multicenter prospective observational study to develop low-burden digital speech biomarkers in ALS and FTD.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {7-8}, pages = {589-598}, doi = {10.1080/21678421.2023.2239312}, pmid = {37516990}, issn = {2167-9223}, abstract = {OBJECTIVE: There is a need for novel biomarkers that can indicate disease state, project disease progression, or assess response to treatment for amyotrophic lateral sclerosis (ALS) and associated neurodegenerative diseases such as frontotemporal dementia (FTD). Digital biomarkers are especially promising as they can be collected non-invasively and at low burden for patients. Speech biomarkers have the potential to objectively measure cognitive, motor as well as respiratory symptoms at low-cost and in a remote fashion using widely available technology such as telephone calls.

METHODS: The PROSA study aims to develop and evaluate low-burden frequent prognostic digital speech biomarkers. The main goal is to create a single, easy-to-perform battery that serves as a valid and reliable proxy for cognitive, respiratory, and motor domains in ALS and FTD. The study will be a multicenter 12-months observational study aiming to include 75 ALS and 75 FTD patients as well as 50 healthy controls and build on three established longitudinal cohorts: DANCER, DESCRIBE-ALS and DESCRIBE-FTD. In addition to the extensive clinical phenotyping in DESCRIBE, PROSA collects a comprehensive speech protocol in fully remote and automated fashion over the telephone at four time points. This longitudinal speech data, together with gold standard measures, will allow advanced speech analysis using artificial intelligence for the development of speech-based phenotypes of ALS and FTD patients measuring cognitive, motor and respiratory symptoms.

CONCLUSION: Speech-based phenotypes can be used to develop diagnostic and prognostic models predicting clinical change. Results are expected to have implications for future clinical trial stratification as well as supporting innovative trial designs in ALS and FTD.}, } @article {pmid37517821, year = {2023}, author = {Huang, Y and Yang, H and Yang, B and Zheng, Y and Hou, X and Chen, G and Zhang, W and Zeng, X and DU, B}, title = {Ginsenoside-Rg1 combined with a conditioned medium from induced neuron-like hUCMSCs alleviated the apoptosis in a cell model of ALS through regulating the NF-κB/Bcl-2 pathway.}, journal = {Chinese journal of natural medicines}, volume = {21}, number = {7}, pages = {540-550}, doi = {10.1016/S1875-5364(23)60445-5}, pmid = {37517821}, issn = {1875-5364}, mesh = {Humans ; NF-kappa B/genetics/metabolism ; *Ginsenosides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Culture Media, Conditioned/pharmacology ; Superoxide Dismutase-1 ; *Neurodegenerative Diseases ; Neurons/metabolism ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain and spinal cord. One important aspect of ALS pathogenesis is superoxide dismutase 1 (SOD1) mutant-mediated mitochondrial toxicity, leading to apoptosis in neurons. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on a mutational SOD1 cell model, and to explore the underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were exposed to neuron differentiation reagents for seven days. CM or G-Rg1 decreased the apoptotic rate of SOD1[G93A]-NSC34 cells to a certain extent, but their combination brought about the least apoptosis, compared with CM or G-Rg1 alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all the treatment groups. Proteins associated with mitochondrial apoptotic pathways, such as Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. Furthermore, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the phosphorylation of p65 and IκBα. CM/G-Rg1 or their combination also reduced the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF-κB signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1[G93A]-NSC34 cells through suppressing the NF-κB/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract).}, } @article {pmid37520009, year = {2023}, author = {Gouveia, D and Correia, J and Cardoso, A and Carvalho, C and Oliveira, AC and Almeida, A and Gamboa, Ó and Ribeiro, L and Branquinho, M and Sousa, A and Lopes, B and Sousa, P and Moreira, A and Coelho, A and Rêma, A and Alvites, R and Ferreira, A and Maurício, AC and Martins, Â}, title = {Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy.}, journal = {Frontiers in veterinary science}, volume = {10}, number = {}, pages = {1192744}, pmid = {37520009}, issn = {2297-1769}, abstract = {INTRODUCTION: Degenerative myelopathy (DM) is a neurodegenerative spinal cord disease with upper motor neurons, with progressive and chronic clinical signs, similar to amyotrophic lateral sclerosis (ALS). DM has a complex etiology mainly associated with SOD1 gene mutation and its toxic role, with no specific treatment. Daily intensive rehabilitation showed survival time near 8 months but most animals are euthanized 6-12 months after clinical signs onset.

METHODS: This prospective controlled blinded cohort clinical study aims to evaluate the neural regeneration response ability of DM dogs subjected to an intensive neurorehabilitation protocol with mesenchymal stem cells (MSCs) transplantation. In total, 13 non-ambulatory (OFS 6 or 8) dogs with homozygous genotype DM/DM and diagnosed by exclusion were included. All were allocated to the intensive neurorehabilitation with MSCs protocol (INSCP) group (n = 8) or to the ambulatory rehabilitation protocol (ARP) group (n = 5), which differ in regard to training intensity, modalities frequency, and MSCs transplantation. The INSCP group was hospitalized for 1 month (T0 to T1), followed by MSCs transplantation (T1) and a second month (T2), whereas the ARP group was under ambulatory treatment for the same 2 months.

RESULTS: Survival mean time of total population was 375 days, with 438 days for the INSCP group and 274 for the ARP group, with a marked difference on the Kaplan-Meier survival analysis. When comparing the literature's results, there was also a clear difference in the one-sample t-test (p = 0.013) with an increase in time of approximately 70%. OFS classifications between groups at each time point were significantly different (p = 0.008) by the one-way ANOVA and the independent sample t-test.

DISCUSSION: This INSCP showed to be safe, feasible, and a possibility for a long progression of DM dogs with quality of life and functional improvement. This study should be continued.}, } @article {pmid37522557, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A}, title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023047235}, pmid = {37522557}, issn = {2162-6472}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.}, } @article {pmid37522558, year = {2023}, author = {Chen, PC and Kaur, K and Ko, MW and Huerta-Yepez, S and Jain, Y and Jewett, A}, title = {Regulation of Cytotoxic Immune Effector Function by AJ3 Probiotic Bacteria in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {13-26}, doi = {10.1615/CritRevImmunol.2023047231}, pmid = {37522558}, issn = {2162-6472}, mesh = {Humans ; Interleukin-10/pharmacology ; *Amyotrophic Lateral Sclerosis/therapy ; Leukocytes, Mononuclear ; Interleukin-2 ; Cytokines ; Interferon-gamma ; *Antineoplastic Agents/pharmacology ; Antibodies, Monoclonal ; }, abstract = {Our recent studies indicated that amyotrophic lateral sclerosis (ALS) patients suffer from significantly elevated levels of interferon-gamma (IFN-γ) secretion by natural killer (NK) and CD8+ T cells, which may be responsible for the immune-pathologies seen in central nervous system and in peripheral organs of the patients. In order to counter such elevated induction of IFN-γ in patients we designed a treatment strategy to increase anti-inflammatory cytokine interleukin-10 (IL-10) by the use of probiotic strains which significantly increase the levels of IL-10. Therefore, in this paper we demonstrate disease specific functions of Al-Pro (AJ3) formulated for the adjunct treatment of auto-immune diseases including ALS, and compared the function with CA/I-Pro (AJ4) for the treatment of cancer and viral diseases, and NK-CLK (AJ2) for maintenance of immune balance and promotion of disease prevention. The three different formulations of probiotic bacteria have distinct profiles of activation of peripheral blood mononuclear cells (PBMCs), NK, and CD8+ T cells, and their induced activation is different from those mediated by either IL-2 or IL-2 + anti-CD16 monoclonal antibodies (mAbs) or IL-2 + anti-CD3/CD28 mAbs. IL-2 + anti-CD16 mAb activation of PBMCs and NK cells had the highest IFN-γ/IL-10 ratio, whereas IL-2 combination with sAJ4 had the next highest followed by IL-2 + sAJ2 and the lowest was seen with IL-2 + sAJ3. Accordingly, the highest secretion of IFN-γ was seen when the PBMCs and NK cells were treated with IL-2 + sAJ4, intermediate for IL-2 + sAJ2 and the lowest with IL-2 + sAJ3. The levels of IFN-γ induction and the ratio of IFN-γ to IL-10 induced by different probiotic bacteria formulation in the absence of IL-2 treatment remained much lower when compared to those treated in the presence of IL-2. Of note is the difference between NK cells and CD8+ T cells in which synergistic induction of IFN-y by IL-2 + sAJ4 was significantly higher in NK cells than those seen by CD8+ T cells. Based on these results, sAJ3 should be effective in alleviating auto-immunity seen in ALS since it will greatly regulate the levels and function of IFN-γ negatively, decreasing overactivation of cytotoxic immune effectors and prevention of death in motor neurons.}, } @article {pmid37525592, year = {2023}, author = {Brooks, BR and Pioro, EP and Sakata, T and Takahashi, F and Hagan, M and Apple, S}, title = {The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {4}, pages = {397-403}, doi = {10.1002/mus.27946}, pmid = {37525592}, issn = {1097-4598}, mesh = {Humans ; Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Tracheostomy ; Proportional Hazards Models ; Survival Analysis ; }, abstract = {INTRODUCTION/AIMS: Intravenous (IV) edaravone is a US Food and Drug Administration-approved treatment for amyotrophic lateral sclerosis (ALS), shown in clinical trials to slow physical functional decline. In this study we compared the effect of IV edaravone (edaravone-first group) versus placebo followed by IV edaravone (placebo-first group) on survival and additional milestone events.

METHODS: This work is a post hoc analysis of Study 19/MCI186-19, which was a randomized, placebo-controlled, phase 3 study investigating IV edaravone versus placebo. Study 19 and its 24-week extension have been described previously (NCT01492686). Edaravone-first versus placebo-first group time to events for specific milestone(s) were analyzed post hoc. Time-to-event composite endpoints were time to death; time to death, tracheostomy, or permanent assisted ventilation (PAV); and time to death, tracheostomy, PAV, or hospitalization.

RESULTS: The risk for death, tracheostomy, PAV, or hospitalization was 53% lower among patients in the edaravone-first vs placebo-first groups (hazard ratio = 0.47 [95% confidence interval 0.25 to 0.88], P = .02). The overall effect of IV edaravone on ALS progression could be seen in the significant separation of time-to-event curves for time to death, tracheostomy, PAV, or hospitalization. ALS survival composite endpoint analyses (ALS/SURV) suggested a treatment benefit (least-squares mean difference) for the edaravone-first versus the placebo-first group at week 24 (0.15 ± 0.05 [95% confidence interval 0.06 to 0.25], P < .01) and week 48 (0.11 ± 0.05 [95% confidence interval 0.02 to 0.21], P = .02).

DISCUSSION: These analyses illustrate the value of timely and continued IV edaravone treatment, as earlier initiation was associated with a lower risk of death, tracheostomy, PAV, or hospitalization in patients with ALS.}, } @article {pmid37527390, year = {2023}, author = {Firnberg, MT and Lerner, EB and Nan, N and Ma, CX and Shah, MI and Mann, NC and Dayan, PS}, title = {National Variation in EMS Response and Antiepileptic Medication Administration for Children with Seizures in the Prehospital Setting.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {4}, pages = {805-813}, pmid = {37527390}, issn = {1936-9018}, mesh = {Male ; Female ; Humans ; Child ; United States/epidemiology ; Anticonvulsants/therapeutic use ; Midazolam/therapeutic use ; *Emergency Medical Services ; *Emergency Medical Technicians ; Seizures/drug therapy ; Retrospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Prehospital Advanced Life Support (ALS) is important to improve patient outcomes in children with seizures, yet data is limited regarding national prehospital variation in ALS response for these children. We aimed to determine the variation in ALS response and prehospital administration of antiepileptic medication for children with seizures across the United States.

METHODS: We analyzed children <19 years with 9-1-1 dispatch codes for seizure in the 2019 National Emergency Medical Services Information System dataset. We defined ALS response as ALS-paramedic, ALS-Advanced Emergency Medical Technician, or ALS-intermediate responses. We conducted regression analyses to identify associations between ALS response (primary outcome), antiepileptic administration (secondary outcome) and age, gender, location, and US census regions.

RESULTS: Of 147,821 pediatric calls for seizures, 88% received ALS responses. Receipt of ALS response was associated with urbanicity, with wilderness (adjusted odds ratio [aOR] 0.44, 0.39-0.49) and rural (aOR 0.80, 0.75-0.84) locations less likely to have ALS responses than urban areas. Of 129,733 emergency medical service (EMS) activations with an ALS responder's impression of seizure, antiepileptic medications were administered in 9%. Medication administration was independently associated with age (aOR 1.008, 95% confidence interval [CI] 1.005-1.010) and gender (aOR 1.22, 95% CI 1.18-1.27), with females receiving medications more than males. Of the 11,698 children who received antiepileptic medications, midazolam was the most commonly used (83%).

CONCLUSION: The majority of children in the US receive ALS responses for seizures. Although medications are infrequently administered, the majority who received medications had midazolam given, which is the current standard of care. Further research should determine the proportion of children who are continuing to seize upon EMS arrival and would most benefit from immediate treatment.}, } @article {pmid37532350, year = {2023}, author = {Zhao, B and Xu, X and Li, B and Qi, Z and Huang, J and Hu, A and Wang, G and Liu, X}, title = {Target-site mutation and enhanced metabolism endow resistance to nicosulfuron in a Digitaria sanguinalis population.}, journal = {Pesticide biochemistry and physiology}, volume = {194}, number = {}, pages = {105488}, doi = {10.1016/j.pestbp.2023.105488}, pmid = {37532350}, issn = {1095-9939}, mesh = {Digitaria/genetics ; Sulfonylurea Compounds/pharmacology ; Pyridines ; Mutation ; *Acetolactate Synthase/metabolism ; Enzyme Inhibitors/pharmacology ; *Herbicides/pharmacology ; Herbicide Resistance/genetics ; }, abstract = {Digitaria sanguinalis is a competitive and annual grass weed that commonly infests crops across the world. In recent years, the control of D. sanguinalis by nicosulfuron has declined in Hebei Province, China. To determine the resistance mechanisms of D. sanguinalis to nicosulfuron, a population of D. sanguinalis where nicosulfuron had failed was collected from a maize field of Hebei Province, China. Whole-plant dose-response experiments demonstrated that the resistant population (HBMT-15) displayed 6.9-fold resistance to nicosulfuron compared with the susceptible population (HBMT-5). Addition of the glutathione S-transferase (GSTs) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) significantly reduced the resistance level of the HBMT-15 population to nicosulfuron, and the GSTs activity of the HBMT-15 population was higher than the HBMT-5 population after nicosulfuron treatment. In vitro acetolactate synthase (ALS) enzyme experiments revealed that the nicosulfuron I50 value for the HBMT-15 population was 41 times higher than that of the HBMT-5 population. An Asp376 to Glu substitution in the ALS gene was identified in the HBMT-15 population. The HBMT-15 population had a moderate (2- to 4-fold) level of cross-resistance to three other ALS inhibitors (imazethapyr, pyroxsulam, and flucarbazone‑sodium), but was susceptible to pyrithiobac‑sodium. This study demonstrated that both an Asp376 to Glu substitution in the ALS gene and GSTs-involved metabolic resistance to ALS inhibitors coexisted in a D. sanguinalis population.}, } @article {pmid37535076, year = {2023}, author = {Yang, X and Zhang, Y and Luo, JX and Zhu, T and Ran, Z and Mu, BR and Lu, MH}, title = {Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {396}, number = {12}, pages = {3503-3528}, pmid = {37535076}, issn = {1432-1912}, mesh = {Animals ; Humans ; Mitophagy/physiology ; Mitochondria/metabolism ; *Parkinson Disease/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.}, } @article {pmid37540049, year = {2023}, author = {Ko, JI and Choi, SJ and Yoo, SH and Cho, B and Kim, MS and Kim, KH and Lee, SY}, title = {Epidemiology and characteristics of emergency department utilization by patients with amyotrophic lateral sclerosis in Korea from 2016 to 2020: A nationwide study.}, journal = {Muscle & nerve}, volume = {68}, number = {4}, pages = {451-459}, doi = {10.1002/mus.27952}, pmid = {37540049}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; Cross-Sectional Studies ; Emergency Service, Hospital ; *Respiratory Insufficiency/epidemiology/etiology/therapy ; Dyspnea ; Republic of Korea/epidemiology ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Patients with amyotrophic lateral sclerosis (ALS) inevitably visit the emergency department (ED) due to their increased risk of respiratory failure and mobility limitations. However, nationwide data on ED visits by patients with ALS are limited. This study investigated the characteristics of patients with ALS-related ED visits.

METHODS: We conducted a cross-sectional study from 2016 to 2020, utilizing a nationwide ED database. The total number of patients with ALS who visited the ED and their primary reasons for visiting/diagnoses were analyzed.

RESULTS: In total, 6036 visits to the ED were made by patients with ALS. Of these, 41.8% arrived by ambulance and 27.7% spent >9 h in the ED. Following ED treatment, 57.4% were hospitalized, including 19.3% admitted to the intensive care unit (ICU) and 5.4% who died in the hospital. The primary reasons for ALS-related ED visits were dyspnea (35.2%), feeding tube problems (10.1%), fever (7.8%), and mental status changes (3.6%). The most common diagnoses were pneumonia (14.5%), respiratory failure (5.7%), dyspnea (5.5%), aspiration pneumonia (4.3%), and tracheostomy complications (3.4%).

DISCUSSION: Reasons for ED visits for patients with ALS include acute respiratory distress, as well as concerns related to tube feeding and tracheostomy. To reduce the risk of patients with ALS requiring ED visits, it is essential to ensure the provision of timely respiratory support and high-quality home-based medical care teams that can support and address patients before their condition deteriorates.}, } @article {pmid37545536, year = {2023}, author = {Ramachandran, S and Grozdanov, V and Leins, B and Kandler, K and Witzel, S and Mulaw, M and Ludolph, AC and Weishaupt, JH and Danzer, KM}, title = {Low T-cell reactivity to TDP-43 peptides in ALS.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1193507}, pmid = {37545536}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; DNA-Binding Proteins/metabolism ; Interleukin-2 ; }, abstract = {BACKGROUND: Dysregulation of the immune system in amyotrophic lateral sclerosis (ALS) includes changes in T-cells composition and infiltration of T cells in the brain and spinal cord. Recent studies have shown that cytotoxic T cells can directly induce motor neuron death in a mouse model of ALS and that T cells from ALS patients are cytotoxic to iPSC-derived motor neurons from ALS patients. Furthermore, a clonal expansion to unknown epitope(s) was recently found in familial ALS and increased peripheral and intrathecal activation of cytotoxic CD8[+] T cells in sporadic ALS.

RESULTS: Here, we show an increased activation of peripheral T cells from patients with sporadic ALS by IL-2 treatment, suggesting an increase of antigen-experienced T cells in ALS blood. However, a putative antigen for T-cell activation in ALS has not yet been identified. Therefore, we investigated if peptides derived from TDP-43, a key protein in ALS pathogenesis, can act as epitopes for antigen-mediated activation of human T cells by ELISPOT and flow cytometry. We found that TDP-43 peptides induced only a weak MHCI or MHCII-restricted activation of both naïve and antigen-experienced T cells from healthy controls and ALS patients. Interestingly, we found less activation in T cells from ALS patients to TDP-43 and control stimuli. Furthermore, we found no change in the levels of naturally occurring auto-antibodies against full-length TDP-43 in ALS.

CONCLUSION: Our data suggests a general increase in antigen-experienced T cells in ALS blood, measured by in-vitro culture with IL-2 for 14 days. Furthermore, it suggests that TDP-43 is a weak autoantigen.}, } @article {pmid37548234, year = {2023}, author = {Notarstefano, V and Belloni, A and Mariani, P and Orilisi, G and Orsini, G and Giorgini, E and Byrne, HJ}, title = {Multivariate curve Resolution-Alternating least squares coupled with Raman microspectroscopy: new insights into the kinetic response of primary oral squamous carcinoma cells to cisplatin.}, journal = {The Analyst}, volume = {148}, number = {18}, pages = {4365-4372}, doi = {10.1039/d3an01182h}, pmid = {37548234}, issn = {1364-5528}, mesh = {Humans ; *Cisplatin/pharmacology ; Least-Squares Analysis ; Spectrum Analysis, Raman/methods ; *Carcinoma, Squamous Cell/drug therapy ; Multivariate Analysis ; }, abstract = {Raman MicroSpectroscopy (RMS) is a powerful label-free tool to probe the effects of drugs at a cellular/subcellular level. It is important, however, to be able to extract relevant biochemical and kinetic spectroscopic signatures of the specific cellular responses. In the present study, a combination of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis (PCA) is used to analyse the RMS data for the example of exposure of primary Oral Squamous Carcinoma Cells (OSCC) to the chemotherapeutic agent cisplatin. Dosing regimens were established by cytotoxicity assays, and the effects of the drug on cellular spectral profiles were monitored from 16 to 72 hours post-exposure using an apoptosis assay, to establish the relative populations of viable (V), early (EA) and late apoptotic/dead (LA/D) cells after the drug treatment. Based on a kinetic model of the progression from V > EA > D, MCR-ALS regression analysis of the RMS responses was able to extract spectral profiles associated with each stage of the cellular responses, enabling a quantitative comparison of the response rates for the respective drug treatments. Moreover, PCA was used to compare the spectral profiles of the viable cells exposed to the drug. Spectral differences were highlighted in the early stages (16 hours exposure), indicative of the initial cellular response to the drug treatment, and also in the late stages (48-72 hours exposure), representing the cell death pathway. The study demonstrates that RMS coupled with multivariate analysis can be used to quantitatively monitor the progression of cellular responses to different drugs, towards future applications for label-free, in vitro, pre-clinical screening.}, } @article {pmid37550578, year = {2024}, author = {Maksymowicz, S and Siwek, T}, title = {Diagnostic odyssey in amyotrophic lateral sclerosis: diagnostic criteria and reality.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {1}, pages = {191-196}, pmid = {37550578}, issn = {1590-3478}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Quality of Life ; *Physicians ; Rare Diseases ; }, abstract = {BACKGROUND: Diagnosing a rare disease, such as amyotrophic lateral sclerosis, is a major challenge for physicians and patients. Despite detailed diagnostic criteria, this process often does not proceed as it should, exacerbating the problems of patients. In the following study, we show how the process, which in medical sciences has been called the "diagnostic odyssey", proceeds and how it affects patients.

MATERIALS AND METHODS: Participants were recruited via a neurology clinic. Twenty-four patients with the diagnosed disease were interviewed using in-depth interviews and an author questionnaire: 9 females and 15 males ages ranging from 30-39 to 60-69.

RESULTS: The median time from 1st symptoms to diagnosis was almost 12 months and mean almost 20 months (min. 3, max 106). Only 5 patients waited less than 6 months for being diagnosed. Over 80% of patients received an alternative diagnosis on the first attempt.

CONCLUSION: ALS is a fast-paced fatal disease, which requires immediate action to slow down the course of the disease and improve patients' quality of life. However, in many cases, the disease is diagnosed too late. It also happens that a wrong diagnosis causes inaccurate treatment, which accelerates the development of ALS. For this reason, it is necessary to expand the clinical and communication competences of medical personnel already at the stage of medical studies. In addition, the diagnostic criteria should highlight the common problem with diagnosing ALS.}, } @article {pmid37550954, year = {2023}, author = {Weemering, DN and Midei, M and Milner, P and Gopalakrishnan, V and Kumar, A and Dannenberg, AJ and Bunte, TM and Foucher, J and Ingre, C and Ķēniņa, V and Rallmann, K and van den Berg, LH and van Eijk, RPA}, title = {A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {12}, pages = {3722-3731}, doi = {10.1111/ene.16020}, pmid = {37550954}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Linoleic Acids/therapeutic use ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.

RESULTS: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.

CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.}, } @article {pmid37553906, year = {2023}, author = {Runacres, F and Mathers, S and Lee, SC and Hearn, R and Gregory, S and Bear, N and Aoun, S}, title = {Motor neurone disease: A point-prevalence study of patient reported symptom prevalence, severity and palliative care needs.}, journal = {Palliative medicine}, volume = {37}, number = {9}, pages = {1402-1412}, doi = {10.1177/02692163231191545}, pmid = {37553906}, issn = {1477-030X}, mesh = {Humans ; *Palliative Care ; Prevalence ; Cross-Sectional Studies ; Syndrome ; *Motor Neuron Disease/epidemiology/therapy ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND: Motor neurone disease is a rare but debilitating illness with incomplete evidence regarding patients' symptom burden. Palliative care and generalist clinicians are often in-experienced in caring for these patients and assessing their needs.

AIM: To identify the symptom prevalence and severity experienced by patients with motor neurone disease. Secondary objectives were to examine differences in symptom burden and clusters according to phenotype, functional status, palliative care provision and those in their last months of life.

DESIGN: A point prevalence study assessing patient-reported symptoms using a modified IPOS-Neuro assessment tool, incorporating 41 symptom items.

SETTING/PARTICIPANTS: Patients with motor neurone disease attending the State-wide Progressive Neurological Disease Service or inpatient unit at Calvary Health Care Bethlehem, Melbourne Australia, from March to December 2021.

RESULTS: A total of 102 patients participated, the majority diagnosed with lumber-onset (30.4%), bulbar-onset (28.4%) and cervical-onset (25.5%) phenotypes. Patients experienced a median of 17 symptoms (range 2-32) with a median of 3 symptoms rated as severe/overwhelming (range 0-13). Motor and functional symptoms predominated, with differences in symptom clusters present according to phenotype. Patients had a higher number of severe/overwhelming symptoms if they were accessing palliative care services (p = 0.005), in their last 6 months of life (p = 0.003) and experiencing moderate or severe functional impairment (p < 0.001).

CONCLUSIONS: Patients with motor neurone disease report high symptom burden. A validated motor neurone disease-specific symptom assessment tool is needed to accurately assess patients, including important variations in symptom clusters according to phenotype. Further research must focus on evidence-based treatment guidelines for symptoms experienced commonly and severely.}, } @article {pmid37555646, year = {2023}, author = {Ribeiro, SS and Gnutt, D and Azoulay-Ginsburg, S and Fetahaj, Z and Spurlock, E and Lindner, F and Kuz, D and Cohen-Erez, Y and Rapaport, H and Israelson, A and Gruzman, AL and Ebbinghaus, S}, title = {Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel.}, journal = {Biological chemistry}, volume = {404}, number = {10}, pages = {909-930}, pmid = {37555646}, issn = {1437-4315}, mesh = {Humans ; Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; Protein Folding ; Mutation ; Molecular Chaperones ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.}, } @article {pmid37558009, year = {2023}, author = {Monteiro Neto, JR and Ribeiro, GD and Magalhães, RSS and Follmer, C and Outeiro, TF and Eleutherio, ECA}, title = {Glycation modulates superoxide dismutase 1 aggregation and toxicity in models of sporadic amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1869}, number = {8}, pages = {166835}, doi = {10.1016/j.bbadis.2023.166835}, pmid = {37558009}, issn = {1879-260X}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/pathology ; Superoxide Dismutase/metabolism ; Maillard Reaction ; Magnesium Oxide ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.}, } @article {pmid37559423, year = {2023}, author = {Kim, S and An, S and Lee, J and Jeong, Y and You, CL and Kim, H and Bae, JH and Yun, CE and Ryu, D and Bae, GU and Kang, JS}, title = {Cdon ablation in motor neurons causes age-related motor neuron degeneration and impaired sciatic nerve repair.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {14}, number = {5}, pages = {2239-2252}, pmid = {37559423}, issn = {2190-6009}, support = {NRF-2016R1A5A2945889//National Research Foundation Grant funded by the Korean Government (MSIP)/ ; NRF-2022R1A2B5B02001482//National Research Foundation Grant funded by the Korean Government (MSIP)/ ; }, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; Mice ; *Sciatic Nerve/pathology/metabolism ; Nerve Regeneration ; Disease Models, Animal ; *Cell Adhesion Molecules/metabolism/genetics ; *Nerve Degeneration/pathology ; *Aging ; }, abstract = {BACKGROUND: The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.

METHODS: Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1[G93A]) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.

RESULTS: Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.

CONCLUSIONS: Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.}, } @article {pmid37564731, year = {2023}, author = {Kudritzki, V and Howard, IM}, title = {Telehealth-based exercise in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1238916}, pmid = {37564731}, issn = {1664-2295}, abstract = {The Veterans Health Administration (VHA) has served as a leader in the implementation of telerehabilitation technologies and continues to expand utilization of non-traditional patient encounters to better serve a geographically and demographically diverse population. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease impacting Veterans at a higher rate than the civilian population and associated with high levels of disability and limited access to subspecialized care. There is growing evidence supporting exercise-based interventions as an independent or adjunctive treatment to maintain or restore function for this patient population; many of these interventions can be delivered remotely by telehealth. The recent advancements in disease-modifying therapies for neuromuscular disorders will likely increase the importance of rehabilitation interventions to maximize functional outcomes. Here, we review the evidence for specific exercise interventions in ALS and the evidence for telehealth-based exercise in neuromuscular disorders. We then use this existing literature to propose a framework for telehealth delivery of these treatments, including feasible exercise interventions and remote outcome measures, recommended peripheral devices, and an example of a current remote group exercise program offered through VHA.}, } @article {pmid37565183, year = {2023}, author = {Sheers, NL and O'Sullivan, R and Howard, ME and Berlowitz, DJ}, title = {The role of lung volume recruitment therapy in neuromuscular disease: a narrative review.}, journal = {Frontiers in rehabilitation sciences}, volume = {4}, number = {}, pages = {1164628}, pmid = {37565183}, issn = {2673-6861}, abstract = {Respiratory muscle weakness results in substantial discomfort, disability, and ultimately death in many neuromuscular diseases. Respiratory system impairment manifests as shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing, and chronic ventilatory failure. Ventilatory support (i.e., non-invasive ventilation) is an established and key treatment for the latter. As survival outcomes improve for people living with many neuromuscular diseases, there is a shift towards more proactive and preventative chronic disease multidisciplinary care models that aim to manage symptoms, improve morbidity, and reduce mortality. Clinical care guidelines typically recommend therapies to improve cough effectiveness and mobilise mucus, with the aim of averting acute respiratory compromise or respiratory tract infections. Moreover, preventing recurrent infective episodes may prevent secondary parenchymal pathology and further lung function decline. Regular use of techniques that augment lung volume has similarly been recommended (volume recruitment). It has been speculated that enhancing lung inflation in people with respiratory muscle weakness when well may improve respiratory system "flexibility", mitigate restrictive chest wall disease, and slow lung volume decline. Unfortunately, clinical care guidelines are based largely on clinical rationale and consensus opinion rather than level A evidence. This narrative review outlines the physiological changes that occur in people with neuromuscular disease and how these changes impact on breathing, cough, and respiratory tract infections. The biological rationale for lung volume recruitment is provided, and the clinical trials that examine the immediate, short-term, and longer-term outcomes of lung volume recruitment in paediatric and adult neuromuscular diseases are presented and the results synthesised.}, } @article {pmid37566027, year = {2023}, author = {Bagyinszky, E and Hulme, J and An, SSA}, title = {Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy.}, journal = {Cells}, volume = {12}, number = {15}, pages = {}, pmid = {37566027}, issn = {2073-4409}, mesh = {Humans ; Child ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Neurodegenerative Diseases ; Proteomics ; DNA-Binding Proteins/metabolism ; Superoxide Dismutase-1 ; Biomarkers ; Risk Factors ; DNA Helicases ; RNA Helicases ; Multifunctional Enzymes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5-10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially "at risk" individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.}, } @article {pmid37566177, year = {2024}, author = {Meyer, M and Meijer, O and Hunt, H and Belanoff, J and Lima, A and de Kloet, ER and Gonzalez Deniselle, MC and De Nicola, AF}, title = {Stress-induced Neuroinflammation of the Spinal Cord is Restrained by Cort113176 (Dazucorilant), A Specific Glucocorticoid Receptor Modulator.}, journal = {Molecular neurobiology}, volume = {61}, number = {1}, pages = {1-14}, pmid = {37566177}, issn = {1559-1182}, support = {PIP 11220170100002CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PIP 11220210100091CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT 2021 00389//Ministerio de Ciencia, Tecnología e Innovación Productiva/ ; Ubacyt 20020170100224BA//Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires/ ; }, mesh = {Male ; Mice ; Humans ; Animals ; Receptors, Glucocorticoid/metabolism ; Corticosterone ; *HMGB1 Protein/metabolism ; Neuroinflammatory Diseases ; Gliosis/metabolism ; Toll-Like Receptor 4/metabolism ; Glucocorticoids/pharmacology ; Spinal Cord/metabolism ; *Neurodegenerative Diseases/metabolism ; *Isoquinolines ; *Pyrazoles ; }, abstract = {Glucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing´ syndrome and neurodegenerative disorders of humans and models of human diseases. ."The Wobbler mouse model of amyotrophic lateral sclerosis shows hypercorticoidism and neuroinflammation which subsided by treatment with the glucocorticoid receptor (GR) modulator Dazucorilant (CORT113176). This effect suggests that GR mediates the chronic glucocorticoid unwanted effects. We now tested this hypothesis using a chronic stress model resembling the condition of the Wobbler mouse Male NFR/NFR mice remained as controls or were subjected to a restraining / rotation stress protocol for 3 weeks, with a group of stressed mice receiving CORT113176 also for 3 weeks. We determined the mRNAS or reactive protein for the proinflamatory factors HMGB1, TLR4, NFkB, TNFα, markers of astrogliosis (GFAP, SOX9 and acquaporin 4), of microgliosis (Iba, CD11b, P2RY12 purinergic receptor) as well as serum IL1β and corticosterone. We showed that chronic stress produced high levels of serum corticosterone and IL1β, decreased body and spleen weight, produced microgliosis and astrogliosis and increased proinflammatory mediators. In stressed mice, modulation of the GR with CORT113176 reduced Iba + microgliosis, CD11b and P2RY12 mRNAs, immunoreactive HMGB1 + cells, GFAP + astrogliosis, SOX9 and acquaporin expression and TLR4 and NFkB mRNAs vs. stress-only mice. The effects of CORT113176 indicate that glucocorticoids are probably involved in neuroinflammation. Thus, modulation of the GR would become useful to dampen the inflammatory component of neurodegenerative disorders.}, } @article {pmid37570771, year = {2023}, author = {Liu, X and Zhao, X and He, J and Wang, S and Shen, X and Liu, Q and Wang, S}, title = {Advances in the Structure of GGGGCC Repeat RNA Sequence and Its Interaction with Small Molecules and Protein Partners.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {15}, pages = {}, pmid = {37570771}, issn = {1420-3049}, support = {22274050//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics ; Base Sequence ; DNA Repeat Expansion ; RNA/genetics/chemistry ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC)n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC)n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC)n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC)n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC)n. In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC)n, its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC)n and its influence on partner binding. Given the crucial role of r(GGGGCC)n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC)n RNA.}, } @article {pmid37573101, year = {2023}, author = {Queral-Beltran, A and Marín-García, M and Lacorte, S and Tauler, R}, title = {UV-Vis absorption spectrophotometry and LC-DAD-MS-ESI(+)-ESI(-) coupled to chemometrics analysis of the monitoring of sulfamethoxazole degradation by chlorination, photodegradation, and chlorination/photodegradation.}, journal = {Analytica chimica acta}, volume = {1276}, number = {}, pages = {341563}, doi = {10.1016/j.aca.2023.341563}, pmid = {37573101}, issn = {1873-4324}, mesh = {*Sulfamethoxazole ; *Chemometrics ; Halogenation ; Photolysis ; Chlorine ; Spectrophotometry/methods ; Mass Spectrometry/methods ; Chromatography, Liquid ; }, abstract = {Sulfamethoxazole (SMX) is one of the most widely used antibiotics worldwide and has been detected at high concentrations in wastewater treatment plant effluents and river waters. In this study, the SMX degradation process combining the simultaneous chlorine oxidation and UV photodegradation is assessed and compared with both photodegradation and chlorine oxidation processes individually. Photodegradation and Chlorine/UV tests were performed using Suntest CPS equipment. Different experimental techniques, including UV-Visible spectrophotometry and liquid chromatography coupled to a diode array detector and positive and negative ionization mass spectrometry (LC-DAD-MS-ESI(+)-ESI(-)), were used to evaluate the degradation reaction of SMX. All the analytical data generated have been processed with the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to monitor, resolve, and identify the several transformation products generated during the studied degradation processes. A new data fusion analysis strategy is proposed to examine the three processes simultaneously (with only photodegradation, only chlorination, and simultaneous chlorination+photodegradation). Combined with the analysis of different analytical techniques individually (spectrophotometry, LC-DAD, and LC-MS), the fusion of all generated data improved the description of the degradation processes. Detection using DAD allowed a better correspondence among the species monitored spectrophotometrically (UV-Vis) with those analyzed chromatographically. On the other side, detection using MS in both positive and negative acquisition modes allowed resolving a larger number of chemical compounds (specially SMX degradation subproducts) that could not be detected by UV-Vis spectrometry. The results obtained permitted the comparison of the effects produced by the three different degradation processes.}, } @article {pmid37573779, year = {2023}, author = {Zhang, Z and Zhu, Y and Zhu, C and Li, S and Zhao, Y and Yang, J and Qin, Y and Hou, J and Zhang, J and Han, C}, title = {Effects of Dihuang Yinzi Decoction on Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {440-452}, doi = {10.1159/000531931}, pmid = {37573779}, issn = {2504-2106}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Treatment Outcome ; *Medicine ; Medicine, Chinese Traditional ; China ; }, abstract = {OBJECTIVE: The aim of this study was to systematically evaluate the therapeutic effects of Dihuang Yinzi decoction on Alzheimer's disease (AD) and provide a medical evidence-based clinical application of traditional Chinese medicine (TCM).

METHODS: A comprehensive search was conducted across multiple databases, including PubMed, Embase, Cochrane Library, China National Journals Full-text Database, VIP Database for Chinese Technical Periodicals, Wan Fang database, and SinoMed database, to collect clinical randomized controlled trials of Dihuang Yinzi decoction in the treatment of AD. Strict literature screening was performed based on predefined inclusion and exclusion criteria. The Cochrane Collaboration risk of bias assessment tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system recommendation-level method was used to assess the quality of the included studies. Review Manager 5.4 and Stata 17 software were used for data synthesis and processing, while GRADE Profiler 3.6 software was used to evaluate the quality of evidence for outcome indicators (risk ratio, standardized mean difference, and weighted mean difference).

RESULTS: A total of 11 studies involving 798 patients met the inclusion criteria. Dihuang Yinzi decoction, whether used alone or in combination with conventional Western medicine, demonstrated superior efficacy compared to conventional Western medicine alone in improving the clinical effective rate, TCM syndrome score, activity of daily living score, Mini-Mental State Examination score, and Hasegawa Dementia Scale score in AD treatment. Furthermore, it exhibited a favorable safety profile. However, the GRADE evidence quality rating for the included studies was low.

CONCLUSIONS: Dihuang Yinzi decoction, either used alone or in combination with conventional Western medicine, shows promising results in enhancing cognitive and memory functions as well as the self-care ability of patients with AD. However, the low GRADE evidence quality rating highlights the need for focused advancements in the planning and execution of clinical randomized controlled trials during future research attempts.

UNLABELLED: ZIELZiel dieser Studie ist es, die therapeutischen Effekte von Dihuang Yinzi-Dekokt auf die Alzheimer-Krankheit systematisch zu bewerten und eine evidenzbasierte klinische Anwendung der traditionellen chinesischen Medizin (TCM) bereitzustellen.MethodenEs wurde eine umfassende Suche in mehreren Datenbanken, darunter PubMed, Embase, Cochrane Library, China National Journals Volltext-Datenbank, VIP Database for Chinese Technical Periodicals, Wan Fang Datenbank und SinoMed-Datenbank durchgeführt, um randomisierte, kontrollierte klinische Studien zu Dihuang Yinzi-Dekokt in der Behandlung der Alzheimer-Krankheit zu erfassen. Die strenge Literatursuche erfolgte auf Grundlage von vordefinierten Ein-und Ausschlusskriterien. Zur Bewertung der Qualität der eingeschlossenen Studien wurden das Risk-of-Bias-Tool von Cochrane und das GRADE (Grading of Recommendations Assessment, Development, and Evaluation)-System zur Beurteilung der Empfehlungsgrade herangezogen. Die Datensynthese und -verarbeitung erfolgten mithilfe der Review Manager 5.4- und der Stata 17-Software, während für die Bewertung der Evidenzqualität der Outcome-Indikatoren (Risikoverhältnis, standardisierte Mittelwertdifferenz und gewichtete Mittelwertdifferenz) die Software GRADE Profiler 3.6 verwendet wurde.ErgebnisseInsgesamt erfüllten 11 Studien, an denen 798 Patienten teilnahmen, die Einschlusskriterien. Dihuang Yinzi-Dekokt zeigte allein oder in Kombination mit konventioneller westlicher Medizin eine überlegene Wirksamkeit gegenüber der alleinigen Verwendung von konventioneller westlicher Medizin in Bezug auf die klinische Gesamtwirksamkeitsrate, den TCM-Syndrom-Score, den Score für die Alltagsaktivitäten, den Mini-Mental State Examination-Score und den Score der Hasegawa-Demenz-Skala in der Behandlung der Alzheimer-Krankheit. Darüber hinaus wies es ein günstiges Sicherheitsprofil auf. Die Evidenzqualität der eingeschlossenen Studien gemäß GRADE wurde jedoch als gering eingestuft.SchlussfolgerungenDihuang Yinzi-Dekokt zeigt allein oder in Kombination mit konventioneller westlicher Medizin vielversprechende Ergebnisse in Bezug auf die Verbesserung der kognitiven und Gedächtnisfunktionen sowie die Selbstversorgungsfähigkeit von Alzheimer-Patienten. Die niedrige Bewertung der Evidenzqualität gemäß GRADE unterstreicht jedoch die Notwendigkeit von zielgerichteten Weiterentwicklungen bei der Planung und Durchführung von randomisierten, kontrollierten klinischen Studien in zukünftigen Forschungsunternehmungen.}, } @article {pmid37576491, year = {2023}, author = {Seidel, M and Rajkumar, S and Steffke, C and Noeth, V and Agarwal, S and Roger, K and Lipecka, J and Ludolph, A and Guerrera, CI and Boeckers, T and Catanese, A}, title = {Propranolol reduces the accumulation of cytotoxic aggregates in C9orf72-ALS/FTD in vitro models.}, journal = {Current research in neurobiology}, volume = {5}, number = {}, pages = {100105}, pmid = {37576491}, issn = {2665-945X}, abstract = {Mutations in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathogenetic mechanisms linked to this gene are a direct consequence of an aberrant intronic expansion of a GGGGCC hexanucleotide located between the 1a and 1b non-coding exons, which can be transcribed to form cytotoxic RNA foci or even translated into aggregation-prone dipeptide repeat proteins. Importantly, the abnormal length of these repeats affects also the expression levels of C9orf72 itself, which suggests haploinsufficiency as additional pathomechanism. Thus, it appears that both toxic gain of function and loss of function are distinct but still coexistent features contributing to the insurgence of the disease in case of C9orf72 mutations. In this study, we aimed at identifying a strategy to address both aspects of the C9orf72-related pathobiochemistry and provide proof-of-principle information for a better understanding of the mechanisms leading to neuronal loss. By using primary neurons overexpressing toxic poly(GA), the most abundant protein product of the GGGGCC repeats, we found that the antiarrhythmic drug propranolol could efficiently reduce the accumulation of aberrant aggregates and increase the survival of C9orf72-related cultures. Interestingly, the improved catabolism appeared to not depend on major degradative pathways such as autophagy and the proteasome. By analyzing the proteome of poly(GA)-expressing neurons after exposure to propranolol, we found that the drug increased lysosomal degradation through a mechanism directly involving C9orf72 protein, whose levels were increased after treatment. Further confirmation of the beneficial effect of the beta blocker on aggregates' accumulation and survival of hiPSC-derived C9orf72-mutant motoneurons strengthened the finding that addressing both facets of C9orf72 pathology might represent a valid strategy for the treatment of these ALS/FTD cases.}, } @article {pmid37581487, year = {2023}, author = {van Roon-Mom, W and Ferguson, C and Aartsma-Rus, A}, title = {From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of SOD1 Mutated Amyotrophic Lateral Sclerosis.}, journal = {Nucleic acid therapeutics}, volume = {33}, number = {4}, pages = {234-237}, doi = {10.1089/nat.2023.0027}, pmid = {37581487}, issn = {2159-3345}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Mutation ; *Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; United States ; United States Food and Drug Administration ; Drug Approval ; Endpoint Determination ; Oligonucleotides ; }, } @article {pmid37582053, year = {2024}, author = {Assoni, AF and Guerrero, EN and Wardenaar, R and Oliveira, D and Bakker, PL and Alves, LM and Carvalho, VM and Okamoto, OK and Zatz, M and Foijer, F}, title = {IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {1}, pages = {e13206}, pmid = {37582053}, issn = {1750-3639}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Motor Neurons/metabolism ; Mutation ; Oxidative Stress ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUS[R521H] mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUS[R521H] MNs. Furthermore, FUS[R521H] MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUS[R521H] MNs exposed to oxidative stress and partially restores the translation rates in FUS[R521H] MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.}, } @article {pmid37590829, year = {2023}, author = {Lee-Iannotti, JK}, title = {Sleep Disorders in Patients with Neurologic Disease.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {4}, pages = {1188-1204}, pmid = {37590829}, issn = {1538-6899}, mesh = {Humans ; *Neurodegenerative Diseases ; *Sleep Wake Disorders/complications/diagnosis ; *Parkinson Disease ; *Multiple Sclerosis ; *Stroke ; }, abstract = {OBJECTIVE: This article provides an overview of the growing body of evidence showing bidirectional relationships between sleep and various neurologic disorders.

LATEST DEVELOPMENTS: Mounting evidence demonstrates that disrupted sleep can negatively impact various neurologic disease processes, including stroke, multiple sclerosis, epilepsy, neuromuscular disorders including amyotrophic lateral sclerosis, and headache syndromes. Abnormal sleep can also be a precursor to Alzheimer disease and neurodegenerative disease states such as Parkinson disease and dementia with Lewy bodies. Interventions to improve sleep and treat obstructive sleep apnea may play a vital role in preventing neurologic disease development and progression.

ESSENTIAL POINTS: Sleep disorders are common among patients with neurologic disorders. To provide comprehensive care to patients with neurologic conditions, neurologists must ask patients about sleep issues that may warrant further diagnostic testing, treatment, and sleep medicine referral when indicated.}, } @article {pmid37591957, year = {2023}, author = {Mandrioli, J and D'Amico, R and Zucchi, E and De Biasi, S and Banchelli, F and Martinelli, I and Simonini, C and Lo Tartaro, D and Vicini, R and Fini, N and Gianferrari, G and Pinti, M and Lunetta, C and Gerardi, F and Tarlarini, C and Mazzini, L and De Marchi, F and Scognamiglio, A and Sorarù, G and Fortuna, A and Lauria, G and Bella, ED and Caponnetto, C and Meo, G and Chio, A and Calvo, A and Cossarizza, A}, title = {Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4970}, pmid = {37591957}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Interleukin-18 ; Quality of Life ; Ribosomal Proteins ; Autophagy ; }, abstract = {In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m[2]/day,1 mg/m[2]/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.}, } @article {pmid37600635, year = {2023}, author = {Fathi, M and Sedaghat, M and Ahadi, H}, title = {Quality of Life of Amyotrophic Lateral Sclerosis Patients in Iran.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {37}, number = {}, pages = {76}, pmid = {37600635}, issn = {1016-1430}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare disease that can bring different emotional, physical, and psychological burdens. This study aimed to investigate the quality of life in patients with ALS.

METHODS: This is a cross-sectional study. Fifty-two patients contributed in this study. The setting was an ALS clinic in Iran. A mixed method was used in this study. We applied a short form of the WHO Quality of Life questionnaire (WHOQOL) to measure the quality of life of patients. Also, all participants were interviewed through the semi-structured interview guide. To measure physical strength and functioning the Appel ALS Rating Scale (AALS) was employed in this study. To analyze the data, a two-tailed t-test and x2 test were used.

RESULTS: 42.3% of the participants were female. The age of the participants ranged between 28 to 81 (mean=57.6). The disease duration ranged from 0.07 to 14 years (mean=1.8). The overall mean QOL was 58.7 (±8.1). The overall mean of the AALS score was 74.4 (±24.2). The results of the qualitative part of the study showed four psychosocial themes: (1) internal personality traits, communicating with friends and family; (2) religion and spirituality; (3) stress, mood changes, and difficult relationship; and (4) changes in lifestyle, work, leisure time and financial situation.

CONCLUSION: Despite recent advances, ALS is still one of the diseases for which there is no effective treatment. Paying attention to psychosocial issues in patients with ALS can play a very important role in increasing the quality of life of patients.}, } @article {pmid37604125, year = {2023}, author = {Lee, SW and Lyu, YR and Yang, WK and Kim, SH and Kim, SY and Kang, W and Jung, IC and Lee, BJ and Choi, JY and Lee, MY and Park, YC}, title = {Efficacy and Safety of Yukmijihwang-Tang in the Treatment of Cough-Variant Asthma: Study Protocol for a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {424-430}, doi = {10.1159/000533252}, pmid = {37604125}, issn = {2504-2106}, mesh = {Humans ; *Cough/drug therapy ; *Asthma/drug therapy ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase II as Topic ; Drugs, Chinese Herbal ; }, abstract = {BACKGROUND: Cough-variant asthma (CVA), a precursor of typical asthma, is the main cause of chronic cough. We hypothesize that yukmijihwang-tang (YJT), which has been used for chronic cough in traditional medicine and has been reported to have an anti-inflammatory effect, could be an adjuvant to asthma treatment.

METHODS: We plan a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial to investigate the efficacy and safety of YJT in CVA patients. A total of 60 patients with CVA will be recruited and randomly assigned to either a high-dose YJT group, standard-dose YJT group, or control group (placebo) in a 1:1:1 allocation ratio after a 2-week run-in period. For the run-in period, only inhaled corticosteroids (ICSs) will be used, and the investigational drug will be administered once a day with concomitant ICS for 6 weeks. Data will be collected at baseline, week 3, and week 6, and the primary outcome measure will be the mean cough symptom score (CSS) change before and after medication. The secondary outcome measures will include the Leicester cough questionnaire-Korean version (LCQ-K) score, eosinophil count and eosinophil cationic protein level, pulmonary function test, and the number of uses of rescue medication, and so on.

CONCLUSION: This study aimed to evaluate the efficacy and safety of YJT in concomitant treatment with ICS in patients with CVA and to determine the optimal dosage of YJT. The results are expected to provide evidence for the use of YJT as an adjuvant treatment for CVA.

UNLABELLED: HintergrundCough-Variant-Asthma (CVA), eine Frühform von typischem Asthma, ist die Hauptursache von chronischem Husten. Unserer Vermutung nach könnte Yukmijihwang-Tang (YJT), das in der traditionellen Medizin zur Behandlung von chronischem Husten eingesetzt wird und das Berichten zufolge einen entzündungshemmenden Effekt hat, unterstützend in der Asthma-Therapie wirken.Methoden: Wir planen eine randomisierte, doppelblinde, placebokontrollierte, multizentrische Phase-2-Studie, um die Wirksamkeit und Sicherheit von YJT bei Patienten mit CVA zu untersuchen. Insgesamt werden 60 CVA-Patienten für die Studie rekrutiert und nach einer zweiwöchigen Run-in-Phase randomisiert im Verhältnis 1:1:1 einer Gruppe mit hochdosiertem YJT, einer Gruppe, die YJT in der Standarddosierung erhält oder einer Kontrollgruppe (Placebo) zugewiesen. Während der Run-in-Phase werden nur inhalative Corticosteroide (ICS) verwendet, und das Prüfpräparat wird über 6 Wochen einmal täglich gleichzeitig mit den ICS angewendet. Die Datenerhebung erfolgt bei Studienbeginn, in Woche 3 sowie in Woche 6, und das primäre Zielkriterium ist die Änderung des mittleren Hustenscores (cough symptom score, CSS) vor und nach der Anwendung der Medikamente. Zu den sekundären Zielkriterien gehören der Score des Leicester Hustenfragebogens - koreanische Version (LCQ-K), die Eosinophilenzahl und der Spiegel an eosinophilem kationischen Protein, Lungenfunktionstests sowie die Anzahl der Anwendungen von Bedarfsmedikation usw.SchlussfolgerungZiel dieser Studie ist es, die Wirksamkeit und Sicherheit von YJT bei gleichzeitiger Behandlung mit ICS bei Patienten mit CVA zu bewerten und die optimale YJT-Dosis zu ermitteln. Es wird erwartet, dass die Ergebnisse Belege für die Anwendung von YJT als adjuvante Therapie bei CVA liefern werden.Registrierung der StudieWHO International Clinical Trials Registry Platform, Clinical Research Information Service (CRIS), KCT0006994, registriert am 10. Februar 2022, https://cris.nih.go.kr/cris/search/detailSearch.do/21743.}, } @article {pmid37605404, year = {2024}, author = {De, SK}, title = {New Pyrrolopyrimidines as LRRK2 Inhibitors for Treating Parkinson's Disease.}, journal = {Current medicinal chemistry}, volume = {31}, number = {33}, pages = {5477-5480}, pmid = {37605404}, issn = {1875-533X}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; *Pyrimidines/chemistry/pharmacology/therapeutic use ; *Pyrroles/chemistry/pharmacology/therapeutic use ; Patents as Topic ; }, abstract = {This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).}, } @article {pmid37607205, year = {2023}, author = {Keifer, OP and Gutierrez, J and Butt, MT and Cramer, SD and Bartus, R and Tansey, M and Deaver, D and Betourne, A and Boulis, NM}, title = {Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0277718}, pmid = {37607205}, issn = {1932-6203}, mesh = {Humans ; Animals ; Dogs ; *Amyotrophic Lateral Sclerosis/drug therapy ; Riluzole/therapeutic use ; Brain ; Administration, Oral ; *Drug-Related Side Effects and Adverse Reactions ; }, abstract = {Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."}, } @article {pmid37610446, year = {2023}, author = {Bombaci, A and Lupica, A and Pozzi, FE and Remoli, G and Manera, U and Di Stefano, V}, title = {Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review.}, journal = {Journal of neurology}, volume = {270}, number = {12}, pages = {5677-5691}, pmid = {37610446}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Neurodegenerative Diseases ; Quality of Life ; Motor Neurons/physiology ; Electromyography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and non-motor symptoms. Recent evidence suggests that ALS is indeed a multisystem disorder, associated with cognitive impairment, dysautonomia, pain and fatigue, excess of secretions, and sensory symptoms. To evaluate whether sensory neuropathy could broaden its spectrum, we systematically reviewed its presence and characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, and genetic features. Sensory neuropathy can be found in up to 20% of ALS patients, affecting both large and small fibers, although there is a great heterogeneity related to different techniques used for its detection (electromyography vs skin biopsy vs nerve biopsy). Moreover, the association between CIDP-like neuropathy and ALS needs to be better explored, although it could be interpreted as part of the neuroinflammatory process in the latter disease. Sensory neuropathy in ALS may be associated with a spinal onset and might be more frequent in SOD1 patients. Moreover, it seems mutually exclusive with cognitive impairment. No associations with sex and other genetic mutation were observed. All these data in the literature reveal the importance of actively looking for sensory neuropathy in ALS patients, and suggest including sensory neuropathy among ALS non-motor features, as it may explain sensory symptoms frequently reported throughout the course of the disease. Its early identification could help avoid diagnostic delays and improve patients' treatment and quality of life.}, } @article {pmid37610866, year = {2023}, author = {Kołodziej, D and Sobczak, Ł and Łączkowski, KZ}, title = {New opportunities for treatment and prevention of neurodegenerative diseases with PTP1B inhibitors.}, journal = {Future medicinal chemistry}, volume = {15}, number = {16}, pages = {1443-1447}, doi = {10.4155/fmc-2023-0187}, pmid = {37610866}, issn = {1756-8927}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/prevention & control ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, } @article {pmid37619554, year = {2023}, author = {Cheesbrough, A and Harley, P and Riccio, F and Wu, L and Song, W and Lieberam, I}, title = {A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds.}, journal = {Biofabrication}, volume = {15}, number = {4}, pages = {}, pmid = {37619554}, issn = {1758-5090}, support = {BB/M009513/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; MR/W006251/1/MRC_/Medical Research Council/United Kingdom ; MR/N026063/1/MRC_/Medical Research Council/United Kingdom ; 108874/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; WT098503/WT_/Wellcome Trust/United Kingdom ; MR/N025865/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Induced Pluripotent Stem Cells ; *Nanofibers ; Elastomers ; *Neuromuscular Diseases ; }, abstract = {Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image (HCI) analysis. This study describes the development of a scalable human induced pluripotent stem cell (iPSC)-neuromuscular disease model, whereby suspended elastomer nanofibers support long-term stability, alignment, maturation, and repeated contractions of iPSC-myofibers, innervated by iPSC-motor neurons in 96-well assay plates. In this platform, optogenetic stimulation of the motor neurons elicits robust myofiber-contractions, providing a functional readout of neuromuscular transmission. Additionally, HCI analysis provides rapid and automated quantification of axonal outgrowth, myofiber morphology, and neuromuscular synapse number and morphology. By incorporating amyotrophic lateral sclerosis (ALS)-related TDP-43[G298S]mutant motor neurons and CRISPR-corrected controls, key neuromuscular disease phenotypes are recapitulated, including weaker myofiber contractions, reduced axonal outgrowth, and reduced number of neuromuscular synapses. Treatment with a candidate ALS drug, the receptor-interacting protein kinase-1 (RIPK1)-inhibitor necrostatin-1, rescues these phenotypes in a dose-dependent manner, highlighting the potential of this platform to screen novel treatments for neuromuscular diseases.}, } @article {pmid37619619, year = {2023}, author = {Wang, Y and Lv, MN and Zhao, WJ}, title = {Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {91}, number = {}, pages = {102035}, doi = {10.1016/j.arr.2023.102035}, pmid = {37619619}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Ferroptosis ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease ; }, abstract = {Ferroptosis is an iron- and lipid peroxidation (LPO)-mediated programmed cell death type. Recently, mounting evidence has indicated the involvement of ferroptosis in neurodegenerative diseases, especially in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and so on. Treating ferroptosis presents opportunities as well as challenges for neurodegenerative diseases. This review provides a comprehensive overview of typical features of ferroptosis and the underlying mechanisms that contribute to its occurrence, as well as their implications in the pathogenesis and advancement of major neurodegenerative disorders. Meanwhile, we summarize the utilization of ferroptosis inhibition in both experimental and clinical approaches for the treatment of major neurodegenerative disorders. In addition, we specifically summarize recent advances in developing therapeutic means targeting ferroptosis in these diseases, which may guide future approaches for the effective management of these devastating medical conditions.}, } @article {pmid37620070, year = {2023}, author = {Younger, DS and Brown, RH}, title = {Amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {203-229}, doi = {10.1016/B978-0-323-98817-9.00031-4}, pmid = {37620070}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Motor Neurons ; Syndrome ; }, abstract = {The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a comprehensive review of the genetic basis of amyotrophic lateral sclerosis, highlighting factors that contribute to its heritability and phenotypic manifestations, and an overview of past, present, and upcoming therapeutic strategies.}, } @article {pmid37620092, year = {2023}, author = {Fink, JK}, title = {The hereditary spastic paraplegias.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {59-88}, doi = {10.1016/B978-0-323-98817-9.00022-3}, pmid = {37620092}, issn = {0072-9752}, mesh = {Child, Preschool ; Humans ; *Spastic Paraplegia, Hereditary/genetics ; Biological Transport ; *Cerebral Palsy ; Exercise ; Family ; }, abstract = {The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments ("uncomplicated HSP") or when accompanied by other neurologic deficits ("complicated HSP"), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, autosomal recessive, X-linked, and maternal (mitochondrial) traits. Symptoms that begin in early childhood may be nonprogressive and resemble spastic diplegic cerebral palsy. Symptoms that begin later, typically progress insidiously over a number of years. Genetic testing is able to confirm the diagnosis for many subjects. Insights from gene discovery indicate that abnormalities in diverse molecular processes underlie various forms of HSP, including disturbance in axon transport, endoplasmic reticulum morphogenesis, vesicle transport, lipid metabolism, and mitochondrial function. Pathologic studies in "uncomplicated" HSP have shown axon degeneration particularly involving the distal ends of corticospinal tracts and dorsal column fibers. Treatment is limited to symptom reduction including amelioration of spasticity, reducing urinary urgency, proactive physical therapy including strengthening, stretching, balance, and agility exercise.}, } @article {pmid37627315, year = {2023}, author = {Kandeel, M and Morsy, MA and Alkhodair, KM and Alhojaily, S}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627315}, issn = {2218-273X}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Mesenchymal Stem Cells ; *Adult Stem Cells ; *Alzheimer Disease ; *Extracellular Vesicles ; *Huntington Disease ; *Multiple Sclerosis ; *Parkinson Disease/diagnosis/therapy ; }, abstract = {Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.}, } @article {pmid37632964, year = {2023}, author = {Wang, T and Yang, X and Du, R and Zheng, S and Cui, H}, title = {Acupuncture in the Treatment of Amyotrophic Lateral Sclerosis: A Research Progress in Clinical Trials.}, journal = {Alternative therapies in health and medicine}, volume = {29}, number = {7}, pages = {114-118}, pmid = {37632964}, issn = {1078-6791}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Acupuncture Therapy/methods ; Quality of Life ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Acupuncture, a complementary and alternative medicine (CAM) modality, shows promise as an integrative therapy for Amyotrophic Lateral Sclerosis (ALS) due to the chronic nature of the disease and its persistent symptoms. Many patients turn to CAM for ALS treatment.

OBJECTIVE: This review assesses acupuncture's efficacy in treating Amyotrophic Lateral Sclerosis.

METHODS: We searched China National Knowledge Network (CNKI) and PubMed databases for Chinese and English articles, including clinical trials, case studies, cohorts, and randomized controlled trials. The search, performed on March 31, 2023, encompassed literature published up to that date. Keywords used in titles and abstracts were (acupuncture) OR (electro-acupuncture)) AND (Amyotrophic Lateral Sclerosis).

RESULTS: Among the 45 articles studied, 34 were included in this research. Acupuncture's benefits primarily lie in neuro-immune system regulation, enhanced quality of life, reduced fatigue, disease progression delay, and fewer relapses.

CONCLUSIONS: Recent clinical trials highlight the potential of traditional Chinese acupuncture in improving Amyotrophic Lateral Sclerosis symptoms (e.g., fatigue, neural functional deficits) and curtailing relapses. Consequently, acupuncture holds promise as an integrative therapy for ALS patients.}, } @article {pmid37636024, year = {2023}, author = {Nouri Nojadeh, J and Bildiren Eryilmaz, NS and Ergüder, BI}, title = {CRISPR/Cas9 genome editing for neurodegenerative diseases.}, journal = {EXCLI journal}, volume = {22}, number = {}, pages = {567-582}, pmid = {37636024}, issn = {1611-2156}, abstract = {Gene therapy has emerged as a promising therapeutic strategy for various conditions, including blood disorders, ocular disease, cancer, and nervous system disorders. The advent of gene editing techniques has facilitated the ability of researchers to specifically target and modify the eukaryotic cell genome, making it a valuable tool for gene therapy. This can be performed through either in vivo or ex vivo approaches. Gene editing tools, such as zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR-Cas-associated nucleases, can be employed for gene therapy purposes. Among these tools, CRISPR-Cas-based gene editing stands out because of its ability to introduce heritable genome changes by designing short guide RNAs. This review aims to provide an overview of CRISPR-Cas technology and summarizes the latest research on the application of CRISPR/Cas9 genome editing technology for the treatment of the most prevalent neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Spinocerebellar ataxia.}, } @article {pmid37641579, year = {2024}, author = {Shefner, JM and Jacobsen, B and Kupfer, S and Malik, FI and Meng, L and Wei, J and Wolff, AA and Rudnicki, SA}, title = {Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {162-169}, doi = {10.1080/21678421.2023.2252468}, pmid = {37641579}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Hand Strength ; Quality of Life ; Surveys and Questionnaires ; Muscle Strength ; Disease Progression ; }, abstract = {OBJECTIVE: To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial.

METHODS: In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman's rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis.

RESULTS: Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores.

CONCLUSIONS: In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.}, } @article {pmid37642362, year = {2023}, author = {Bireley, JD and Morren, JA}, title = {CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {8}, pages = {677-683}, doi = {10.1080/13543784.2023.2252738}, pmid = {37642362}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Quality of Life ; Drugs, Investigational/therapeutic use ; Phenylbutyrates ; }, abstract = {INTRODUCTION: Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment.

AREAS COVERED: In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment.

EXPERT OPINION: Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.}, } @article {pmid37645251, year = {2023}, author = {Rojas, F and Aguilar, R and Almeida, S and Fritz, E and Corvalán, D and Ampuero, E and Abarzúa, S and Garcés, P and Amaro, A and Diaz, I and Arredondo, C and Cortes, N and Sanchez, M and Mercado, C and Varela-Nallar, L and Gao, FB and Montecino, M and van Zundert, B}, title = {Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43[A90V] mutation display a mild reactive state and release polyP toxic to motoneurons.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1226604}, pmid = {37645251}, issn = {2296-634X}, support = {R01 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A growing number of studies have shown that soluble toxic factor(s) in the ACM cause non-cell autonomous MN death, including our recent identification of inorganic polyphosphate (polyP) that is excessively released from mouse primary astrocytes (SOD1, TARDBP, and C9ORF72) and human induced pluripotent stem cells (iPSC)-derived astrocytes (TARDBP) to kill MNs. However, others have reported that astrocytes carrying mutant TDP43 do not produce detectable MN toxicity. This controversy is likely to arise from the findings that human iPSC-derived astrocytes exhibit a rather immature and/or reactive phenotype in a number of studies. Here, we have succeeded in generating a highly homogenous population of functional quiescent mature astrocytes from control subject iPSCs. Using identical conditions, we also generated mature astrocytes from an ALS/FTD patient carrying the TDP43[A90V] mutation. These mutant TDP43 patient-derived astrocytes exhibit key pathological hallmarks, including enhanced cytoplasmic TDP-43 and polyP levels. Additionally, mutant TDP43 astrocytes displayed a mild reactive signature and an aberrant function as they were unable to promote synaptogenesis of hippocampal neurons. The polyP-dependent neurotoxic nature of the TDP43[A90V] mutation was further confirmed as neutralization of polyP in ACM derived from mutant TDP43 astrocytes prevented MN death. Our results establish that human astrocytes carrying the TDP43[A90V] mutation exhibit a cell-autonomous pathological signature, hence providing an experimental model to decipher the molecular mechanisms underlying the generation of the neurotoxic phenotype.}, } @article {pmid37646130, year = {2023}, author = {Pattee, GL and Genge, A and Couratier, P and Lunetta, C and Sobue, G and Aoki, M and Yoshino, H and Jackson, CE and Wymer, J and Salah, A and Nelson, S}, title = {Oral Edaravone - Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {23}, number = {10}, pages = {859-866}, doi = {10.1080/14737175.2023.2251687}, pmid = {37646130}, issn = {1744-8360}, mesh = {Humans ; Edaravone/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/drug therapy ; Free Radical Scavengers/pharmacology ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications.

AREAS COVERED: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed.

EXPERT OPINION: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.}, } @article {pmid37650499, year = {2023}, author = {Morichon, L and Hirtz, C and Tiers, L and Mezghrani, A and Raoul, C and Esselin, F and La Cruz, E and Julien, JP and Camu, W and Lehmann, S}, title = {Ultrasensitive digital immunoassays for SOD1 conformation in amyotrophic lateral sclerosis.}, journal = {Bioanalysis}, volume = {15}, number = {15}, pages = {927-936}, doi = {10.4155/bio-2023-0103}, pmid = {37650499}, issn = {1757-6199}, support = {misSOD1//ARSLA: Association pour la recherche sur la SLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Superoxide Dismutase-1 ; Biological Assay ; Immunoassay ; Molecular Conformation ; }, abstract = {Aim: The aim of this study was to detect misfolded Cu/Zn SOD1 as a potential biomarker for amyotrophic lateral sclerosis (ALS). Materials & methods: Two ultrasensitive immunodetection assays were developed for the quantification of total and misfolded SOD1. Results: The detection of total and misfolded SOD1 was possible in human serum and cerebrospinal fluid. Total SOD1 was increased in cerebrospinal fluid from ALS patients. Misfolded SOD1 had low and variable expression in both control and ALS patient samples. Conclusion: These assays hold promise for improving our understanding of ALS and its detection, and could lead to more effective treatment options in the future. Further studies in larger cohorts are now required.}, } @article {pmid37651612, year = {2023}, author = {Sadžak, A and Eraković, M and Šegota, S}, title = {Kinetics of Flavonoid Degradation and Controlled Release from Functionalized Magnetic Nanoparticles.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {10}, pages = {5148-5159}, doi = {10.1021/acs.molpharmaceut.3c00478}, pmid = {37651612}, issn = {1543-8392}, mesh = {*Flavonoids/chemistry ; Kinetics ; *Magnetite Nanoparticles/chemistry ; Drug Liberation ; *Delayed-Action Preparations/chemistry ; Quercetin/chemistry ; Oxidation-Reduction ; Solubility ; Antioxidants/chemistry ; Drug Carriers/chemistry ; }, abstract = {Flavonoids are naturally occurring antioxidants that have been shown to protect cell membranes from oxidative stress and have a potential use in photodynamic cancer treatment. However, they degrade at physiological pH values, which is often neglected in drug release studies. Kinetic study of flavonoid oxidation can help to understand the mechanism of degradation and to correctly analyze flavonoid release data. Additionally, the incorporation of flavonoids into magnetic nanocarriers can be utilized to mitigate degradation and overcome their low solubility, while the release can be controlled using magnetic fields (MFs). An approach that combines alternating least squares (ALS) and multilinear regression to consider flavonoid autoxidation in release studies is presented. This approach can be used in general cases to account for the degradation of unstable drugs released from nanoparticles. The oxidation of quercetin, myricetin (MCE), and myricitrin (MCI) was studied in PBS buffer (pH = 7.4) using UV-vis spectrophotometry. ALS was used to determine the kinetic profiles and characteristic spectra, which were used to analyze UV-vis data of release from functionalized magnetic nanoparticles (MNPs). MNPs were selected for their unique magnetic properties, which can be exploited for both targeted drug delivery and control over the drug release. MNPs were prepared and characterized by X-ray diffraction, infrared spectroscopy, scanning electron microscopy, superconducting quantum interference device magnetometer, and electrophoretic mobility measurements. Autoxidation of all three flavonoids follows a two-step first-order kinetic model. MCE showed the fastest degradation, while the oxidation of MCI was the slowest. The flavonoids were successfully loaded into the prepared MNPs, and the drug release was described by the first-order and Korsmeyer-Peppas models. External MFs were utilized to control the release mechanism and the cumulative mass of the flavonoids released.}, } @article {pmid37657764, year = {2023}, author = {Zhou, S and Zhou, Y and Zhong, W and Su, Z and Qin, Z}, title = {Involvement of protein L-isoaspartyl methyltransferase in the physiopathology of neurodegenerative diseases: Possible substrates associated with synaptic function.}, journal = {Neurochemistry international}, volume = {170}, number = {}, pages = {105606}, doi = {10.1016/j.neuint.2023.105606}, pmid = {37657764}, issn = {1872-9754}, mesh = {Humans ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/metabolism ; *Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; Isoaspartic Acid/metabolism ; Aspartic Acid/metabolism ; }, abstract = {Synaptic dysfunction is a typical pathophysiologic change in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Hintington's disease (HD) and amyotrophic lateral sclerosis (ALS), which involves protein post-translational modifications (PTMs) including L-isoaspartate (L-isoAsp) formed by isomerization of aspartate or deamidation of asparagine. The formation of L-isoAsp could be repaired by protein L-isoaspartyl methyltransferase (PIMT). Some synaptic proteins have been identified as PIMT potential substrates and play an essential role in ensuring synaptic function. In this review, we discuss the role of certain synaptic proteins as PIMT substrates in neurodegenerative disease, thus providing therapeutic synapse-centered targets for the treatment of NDs.}, } @article {pmid37657967, year = {2023}, author = {Ryan, SK and Ugalde, CL and Rolland, AS and Skidmore, J and Devos, D and Hammond, TR}, title = {Therapeutic inhibition of ferroptosis in neurodegenerative disease.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {10}, pages = {674-688}, doi = {10.1016/j.tips.2023.07.007}, pmid = {37657967}, issn = {1873-3735}, support = {MC_PC_19032/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/drug therapy ; Iron ; }, abstract = {Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.}, } @article {pmid37658972, year = {2023}, author = {Singh, S and Shukla, R}, title = {Nanovesicular-Mediated Intranasal Drug Therapy for Neurodegenerative Disease.}, journal = {AAPS PharmSciTech}, volume = {24}, number = {7}, pages = {179}, pmid = {37658972}, issn = {1530-9932}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Nose ; Drug Delivery Systems ; Brain ; *Glioblastoma ; }, abstract = {Numerous neurodegenerative conditions, such as Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and glioblastoma multiform are now becoming significant concerns of global health. Formulation-related issues, physiological and anatomical barriers, post-administration obstacles, physical challenges, regulatory limitations, environmental hurdles, and health and safety issues have all hindered successful delivery and effective outcomes despite a variety of treatment options. In the current review, we covered the intranasal route, an alternative strategic route targeting brain for improved delivery across the BBB. The trans-nasal pathway is non-invasive, directing therapeutics directly towards brain, circumventing the barrier and reducing peripheral exposure. The delivery of nanosized vesicles loaded with drugs was also covered in the review. Nanovesicle systems are organised in concentric bilayered lipid membranes separated with aqueous layers. These carriers surmount the disadvantages posed by intranasal delivery of rapid mucociliary clearance and enzymatic degradation, and enhance retention of drug to reach the site of target. In conclusion, the review covers in-depth conclusions on numerous aspects of formulation of drug-loaded vesicular system delivery across BBB, current marketed nasal devices, significant jeopardies, potential therapeutic aids, and current advancements followed by future perspectives.}, } @article {pmid37660686, year = {2023}, author = {Bhakta, P and Dutta, A}, title = {Homeopathic Treatment of Ramsay Hunt Syndrome: A Case Report.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {544-552}, doi = {10.1159/000533849}, pmid = {37660686}, issn = {2504-2106}, mesh = {Female ; Humans ; Young Adult ; Adult ; *Facial Paralysis ; *Homeopathy ; *Herpes Zoster Oticus/therapy ; *Deglutition Disorders ; Quality of Life ; Ulcer ; }, abstract = {INTRODUCTION: Ramsay Hunt syndrome (RHS) is an uncommon neurological complication resulting from the reactivation of latent herpes zoster virus. The condition often presents with facial paralysis, palatal ulcers, dysphagia, and altered taste sensation, leading to reduced quality of life. Standard therapeutic options for RHS have limitations, prompting the exploration of alternative treatments with improved prognostic outcomes. This case report aims to present a noteworthy clinical observation of RHS managed with individualized homeopathic treatment, emphasizing its potential therapeutic effect.

CASE DESCRIPTION: A 24-year-old female patient exhibited left-sided facial weakness, along with palatal ulcers, dysphagia, and ageusia, prompting the diagnosis of RHS. Following the principles of homeopathy, a personalized therapeutic regimen was formulated, consisting tailored administration of Rhus toxicodendron, Spigelia anthelmia, and Sulfur. The House-Brackmann scale was employed to objectively assess the severity of facial palsy, while photographic documentation tracked the progression of palatal ulcers and facial paralysis. Over a carefully monitored observation period of 14 days, the patient demonstrated notable therapeutic response. There was a significant reduction in the extent of palatal ulceration and left-sided facial palsy exhibited marked improvement. Subsequent days of follow-up witnessed a consistent amelioration of the patient's condition, substantiating the effect of the individualized homeopathic treatment.

CONCLUSION: This case report highlights an exceptional instance of RHS recovery within a relatively short timeframe, achieved through the administration of individualized homeopathic therapy. The favorable outcomes observed in this case underscore the potential of homeopathy as a promising intervention for RHS management. Nevertheless, further systematic investigations are imperative to comprehensively evaluate the scope and applicability of homeopathy in the treatment of RHS.

UNLABELLED: EinleitungDas Ramsay‐Hunt‐Syndrom (RHS) ist eine seltene neurologische Komplikation, die durch die Reaktivierung einer latenten Herpes‐Zoster‐Virusinfektion verursacht wird. Die Krankheit manifestiert sich häufig mit Gesichtslähmung, Ulcerationen am Gaumen, Dysphagie und verändertem Geschmacksempfinden und ist mit einer Einschränkung der Lebensqualität verbunden. Die Standardtherapieoptionen für RHS sind begrenzt, weshalb nach alternativen Behandlungsmöglichkeiten mit besseren prognostischen Ergebnissen gesucht wird. Im vorliegenden Fallbericht wird eine interessante klinische Beobachtung bei RHS vorgestellt, das mit individualisierter Homöopathie behandelt wurde, und deren potenzielle therapeutische Wirksamkeit wird hervorgehoben.Der FallEine 24-jährige Patientin zeigte eine linksseitige Gesichtsschwäche in Verbindung mit Ulcerationen am Gaumen, Dysphagie und Ageusie, so dass die Diagnose RHS gestellt wurde. Gemäß den Prinzipien der Homöopathie wurde ein personalisiertes Therapieschema formuliert, das die individuell zugeschnittene Gabe von Rhus toxicodendron, Spigelia anthelmia, und Sulphur umfasste. Die objektive Bewertung des Schweregrads der Gesichtslähmung erfolgte mithilfe der House-Brackmann-Skala, wohingegen das Fortschreiten der Gaumenulcerationen und der Gesichtslähmung fotografisch dokumentiert wurde. Während eines sorgfältig überwachten Beobachtungszeitraums von 14 Tagen zeigte die Patientin ein deutliches therapeutisches Ansprechen. Das Ausmaß der Gaumenulcerationen ging signifikant zurück, und die linksseitige Gesichtslähmung besserte sich deutlich. In den folgenden Tagen besserte sich der Zustand der Patientin kontinuierlich, was die Wirkung der individualisierten homöopathischen Behandlung untermauert.SchlussfolgerungDieser Fallbericht beleuchtet einen ungewöhnlichen Fall von Genesung nach einem RHS innerhalb relativ kurzer Zeit, die durch Verabreichung einer individualisierten homöopathischen Therapie erreicht wurde. Die im vorliegenden Fall beobachteten günstigen Ergebnisse unterstreichen das Potenzial der Homöopathie als vielversprechende Intervention zur Behandlung von RHS. Allerdings sind weitere systematische Untersuchungen unabdingbar, um den Umfang und die Anwendbarkeit der Homöopathie bei der Behandlung von RHS umfassend zu beurteilen.}, } @article {pmid37664456, year = {2023}, author = {Garodia, P and Hegde, M and Kunnumakkara, AB and Aggarwal, BB}, title = {Curcumin, inflammation, and neurological disorders: How are they linked?.}, journal = {Integrative medicine research}, volume = {12}, number = {3}, pages = {100968}, pmid = {37664456}, issn = {2213-4220}, abstract = {BACKGROUND: Despite the extensive research in recent years, the current treatment modalities for neurological disorders are suboptimal. Curcumin, a polyphenol found in Curcuma genus, has been shown to mitigate the pathophysiology and clinical sequalae involved in neuroinflammation and neurodegenerative diseases.

METHODS: We searched PubMed database for relevant publications on curcumin and its uses in treating neurological diseases. We also reviewed relevant clinical trials which appeared on searching PubMed database using 'Curcumin and clinical trials'.

RESULTS: This review details the pleiotropic immunomodulatory functions and neuroprotective properties of curcumin, its derivatives and formulations in various preclinical and clinical investigations. The effects of curcumin on neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumors, epilepsy, Huntington's disorder (HD), ischemia, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI) with a major focus on associated signalling pathways have been thoroughly discussed.

CONCLUSION: This review demonstrates curcumin can suppress spinal neuroinflammation by modulating diverse astroglia mediated cascades, ensuring the treatment of neurological disorders.}, } @article {pmid37666395, year = {2023}, author = {Atiya, A and Muhsinah, AB and Alrouji, M and Alhumaydhi, FA and Al Abdulmonem, W and Aljasir, MA and Sharaf, SE and Furkan, M and Khan, RH and Shahwan, M and Shamsi, A}, title = {Unveiling promising inhibitors of superoxide dismutase 1 (SOD1) for therapeutic interventions.}, journal = {International journal of biological macromolecules}, volume = {253}, number = {Pt 2}, pages = {126684}, doi = {10.1016/j.ijbiomac.2023.126684}, pmid = {37666395}, issn = {1879-0003}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; Molecular Docking Simulation ; *Amyotrophic Lateral Sclerosis/metabolism ; Oxidation-Reduction ; *Neoplasms ; Superoxide Dismutase/metabolism ; Mutation ; }, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer pathogenesis and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Among the inhibitors known to be effective against SOD1, LCS-1 stands out; however, its efficacy, specificity, and safety profiles are somewhat restricted. In this study, we used PubChem library to retrieve compounds that exhibited a structural similarity of at least 90 % with LCS-1. These compounds underwent molecular docking analyses to examine their interaction patterns and binding affinities with SOD1. Further, we applied filters based on physicochemical and ADMET properties, refining the selection process. Our analysis revealed that selected compounds interact with crucial residues of SOD1 active site. To gain further insights into conformational stability and dynamics of the SOD1-ligand complexes, we conducted all-atom molecular dynamics (MD) simulations for 100 ns. We identified two compounds, CID:133306073 and CID:133446715, as potential scaffolds with promising inhibitory properties against SOD1. Both compounds hold significant potential for further exploration as therapeutic SOD1 inhibitors. Further studies are warranted to fully harness their therapeutic potential in targeting SOD1 for cancer and ALS treatment, offering new avenues for improved patient outcomes and disease management.}, } @article {pmid37669876, year = {2023}, author = {Quinn, L and Bird, P and Remsing, S and Reeves, K and Lilford, R}, title = {Unintended consequences of the 18-week referral to treatment standard in NHS England: a threshold analysis.}, journal = {BMJ quality & safety}, volume = {32}, number = {12}, pages = {712-720}, pmid = {37669876}, issn = {2044-5423}, mesh = {Humans ; *State Medicine ; *Hospitals ; Patients ; England ; Referral and Consultation ; }, abstract = {OBJECTIVE: In 2012, an '18-week referral to treatment standard' was introduced in England. Among people on the list of those waiting for hospital treatment at a point in time, the standard states that at least '92% of patients should have been waiting for less than 18 weeks'. Targets can have unintended consequences, where patients are prioritised based on the target rather than clinical need. Such an effect will be evident as a spike in the number of hospital trusts at the target threshold, referred to as a threshold effect. This study examines for threshold effects across all non-specialist acute NHS England hospital trusts by financial year.

METHODS: A retrospective observational study of publicly available data examined waiting times for patients on the waiting list. We examined trust performance against the 92% target by financial year, from 2015/16 to 2021/22, using Cattaneo et al's manipulation density test (test for discontinuity/spike in data around target threshold) for all patients and by type of treatment.

RESULTS: The proportion of NHS hospital trusts meeting the 92% target deteriorated over time. From 2015/16 to 2019/20, there was strong evidence of a threshold effect at the 92% target (p<0.001). There was no evidence of a threshold effect in 2020/21 (p=0.063) or 2021/22 (p=0.090). Threshold effects were present across most types of treatment in 2016/17 and fewer types from 2017/18 onwards.

CONCLUSION: We observed striking evidence of a threshold effect suggesting that while targets change behaviour, they do so in a selective way, focusing on the threshold rather than a pervasive improvement in practice. However, at the height of the pandemic, as almost no trusts could reach the target, the threshold effect disappeared.}, } @article {pmid37670160, year = {2023}, author = {Devalckeneer, A and Bourgeois, P and Caudron, Y and Estrade, L and Obled, L and Leclerc, X and Assaker, R and Lejeune, JP and Aboukais, R}, title = {Surgical evolution in spinal dural arteriovenous fistula treatment-a 7 years monocentric experience.}, journal = {Neurosurgical review}, volume = {46}, number = {1}, pages = {225}, pmid = {37670160}, issn = {1437-2320}, mesh = {Adult ; Humans ; *Central Nervous System Vascular Malformations ; Cerebrospinal Fluid Leak ; Laminectomy ; Retrospective Studies ; *Spinal Cord Diseases ; }, abstract = {Accounting for 70% of all spinal vascular malformations, spinal dural arteriovenous fistulas (SDAVF) are the most common type of malformation. Interruption of the fistulous arterialized vein point is the goal of surgical treatment. The aim of the study was to compare open surgery (laminectomy) versus minimal invasive surgery (MIS) in SDAVF treatment. Between March 2013 and March 2020, we retrospectively collected 21 consecutive adult patients with SDAVF. Since March 2017, MIS has been routinely used for surgical treatment. Pre- and post-operative clinical evaluations used Aminoff-Logue score (ALS). Complication rate was noted. Post-operative occlusion of the malformation was confirmed by digital subtraction angiography (DSA) in all patients. MIS was compared to open surgery in terms of efficacy and complications with statistical evaluation. Standard laminectomy was performed in 12 patients and MIS technique in 9 patients. No difference was noted on pre-operative parameters. ALS and MRI signs of myelopathy were improved in all cases except for 1 patient in each group. All SDAVFs were excluded based on post-operative DSA. Significant differences were noted between the 2 groups in terms of perioperative blood loss (p<0.001), post-operative pain visual analog scale values (p<0.001), and first time out of bed (p<0.001). Wrong level surgery occurred in one patient in each group; patients were re-operated using the same technique. No infection or cerebrospinal fluid (CSF) leak was noted. In our experience, MIS is a safe alternative to open laminectomy for SDAVF treatment. MIS contributes to patient comfort and minimizes blood loss without increasing complication rate.}, } @article {pmid37672770, year = {2023}, author = {Naveed, M and Aqib Shabbir, M and Aziz, T and Hurraira, HM and Fatima Zaidi, S and Athar, R and Chattha, HA and Alharbi, M and Alshammari, A and Alasmari, AF}, title = {CRISPR-Cas9 guided rna based model for the treatment of Amyotrophic Lateral Sclerosis: A progressive neurodegenerative disorder.}, journal = {Acta biochimica Polonica}, volume = {70}, number = {3}, pages = {643-653}, doi = {10.18388/abp.2020_6789}, pmid = {37672770}, issn = {1734-154X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; CRISPR-Cas Systems/genetics ; Gene Editing ; Muscles ; RNA, Guide, CRISPR-Cas Systems ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to the degeneration of motor neurons and the weakening of muscles. Despite extensive research efforts, there is currently no cure for ALS and existing treatments only address its symptoms. To address this unmet medical need, genome editing technologies, such as CRISPR-Cas9, have emerged as a promising solution for the development of new treatments for ALS. Studies have shown that CRISPR-Cas9-guided RNAs have the potential to provide accurate and effective silencing in the genetic disease of ALS. Results have demonstrated a 67% on-target score and a 98% off-target score with GC content within the range of 40-60%. This is further validated by the correlation between the gRNA's structural accuracy and the minimum free energy. The use of CRISPR-Cas9 provides a unique opportunity to target this disease at the molecular level, offering hope for the development of a more effective treatment. In silico and computational therapeutic approaches for ALS suggest that the CRISPR-Cas9 protein holds promise as a future treatment candidate. The CRISPR mechanism and the specificity of gRNA provide a novel therapeutic approach for this genetic disease, offering new hope to those affected by ALS. This study highlights the potential of CRISPR-Cas9 as a promising solution for the development of new treatments for ALS. Further research is required to validate these findings in preclinical and clinical trials and to establish the safety and efficacy of this approach in the treatment of ALS.}, } @article {pmid37674720, year = {2023}, author = {Chen, S and Puri, A and Bell, B and Fritsche, J and Palacios, H and Balch, M and Sprunger, M and Howard, M and Patterson, J and Patti, G and Davis, A and Jackrel, M}, title = {HtrA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37674720}, issn = {2693-5015}, support = {K08 NS101118/NS/NINDS NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; }, abstract = {Parkinson disease (PD) is closely linked to the misfolding and accumulation of α-synuclein (α-syn) into Lewy bodies. HtrA1 is a PDZ serine protease that degrades fibrillar tau, which is associated with Alzheimer disease (AD). Further, inactivating mutations to mitochondrial HtrA2 have been implicated in PD. Here, we establish that HtrA1 inhibits the aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We demonstrate that the protease domain of HtrA1 is necessary and sufficient for inhibition of aggregation, yet this activity is independent of HtrA1 proteolytic activity. Further, we find that HtrA1 also disaggregates preformed α-syn fibrils, which may promote their clearance. Treatment of α-syn fibrils with HtrA1 renders α-syn incapable of seeding the aggregation of endogenous α-syn in mammalian biosensor cells. We find that HtrA1 remodels α-syn by specifically targeting the NAC domain, which is the key domain that catalyzes α-syn oligomerization and fibrillization. Finally, in a primary neuron model of α-syn aggregation, we show that HtrA1 and its proteolytically inactive form both detoxify α-syn and prevent the formation of hyperphosphorylated α-syn accumulations. Our findings suggest that HtrA1 prevents aggregation and promotes disaggregation of multiple disease-associated proteins, and may be a therapeutic target for treating a range of neurodegenerative disorders.}, } @article {pmid37680538, year = {2023}, author = {Dunn, E and Zhang, B and Sahota, VK and Augustin, H}, title = {Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1230467}, pmid = {37680538}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.}, } @article {pmid37682161, year = {2023}, author = {Tang, X and Zhan, Y and Yang, B and Du, B and Huang, J}, title = {Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology.}, journal = {Medicine}, volume = {102}, number = {36}, pages = {e35101}, pmid = {37682161}, issn = {1536-5964}, mesh = {Humans ; *Semen ; *Amyotrophic Lateral Sclerosis/drug therapy ; Network Pharmacology ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; }, abstract = {Semen Strychni (SS), known as an agonist of central nervous system, is a traditional herb widely used in treating amyotrophic lateral sclerosis (ALS) in small doses to relieve muscle weakness and improve muscle strength. However, the potential mechanisms and the main components of SS in treating ALS remain unclear. To explore the underlying mechanism of SS in treating ALS based on network pharmacology and molecular docking. The active components of SS were obtained using TCMSP, Herb, ETCM, and BATMAN-TCM. The targets of SS were gained from PharmMapper. The targets of ALS were searched on Genecards, Drugbank, DisGeNET, OMIM, TTD and GEO database. After obtaining the coincidence targets, we submitted them to the STRING database to build a protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed subsequently. The active components and targets were further investigated using molecular docking technology. 395 targets of SS and 1925 targets of ALS were obtained with 125 common targets. The protein-protein interaction analysis indicated that SRC, AKT1, MAPK1, EGFR, and HSP90AA1 received the higher degree value and were considered the central genes. The Ras, PI3K-Akt, and MAPK signaling pathway could be involved in the treatment of ALS. Brucine-N-oxide obtained the lowest binding energy in molecular docking. This study explored the mechanism of SS in the treatment of ALS and provides a new perspective for future study. However, further experimental studies are needed to validate the therapeutic effect.}, } @article {pmid37686322, year = {2023}, author = {Badu-Mensah, A and Guo, X and Mendez, R and Parsaud, H and Hickman, JJ}, title = {The Effect of Skeletal Muscle-Specific Creatine Treatment on ALS NMJ Integrity and Function.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37686322}, issn = {1422-0067}, support = {R01 NS050452/NS/NINDS NIH HHS/United States ; R01NS050452/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Creatine/pharmacology/therapeutic use ; Muscle Fatigue ; Muscle, Skeletal ; Neuromuscular Junction ; }, abstract = {Although skeletal muscle (hSKM) has been proven to be actively involved in Amyotrophic Lateral Sclerosis (ALS) neuromuscular junction (NMJ) dysfunction, it is rarely considered as a pharmacological target in preclinical drug discovery. This project investigated how improving ALS hSKM viability and function effects NMJ integrity. Phenotypic ALS NMJ human-on-a-chip models developed from patient-derived induced pluripotent stem cells (iPSCs) were used to study the effect of hSKM-specific creatine treatment on clinically relevant functional ALS NMJ parameters, such as NMJ numbers, fidelity, stability, and fatigue index. Results indicated comparatively enhanced NMJ numbers, fidelity, and stability, as well as reduced fatigue index, across all hSKM-specific creatine-treated systems. Immunocytochemical analysis of the NMJs also revealed improved post-synaptic nicotinic Acetylcholine receptor (AChR) clustering and cluster size in systems supplemented with creatine relative to the un-dosed control. This work strongly suggests hSKM as a therapeutic target in ALS drug discovery. It also demonstrates the need to consider all tissues involved in multi-systemic diseases, such as ALS, in drug discovery efforts. Finally, this work further establishes the BioMEMs NMJ platform as an effective means of performing mutation-specific drug screening, which is a step towards personalized medicine for rare diseases.}, } @article {pmid37686737, year = {2023}, author = {Zhou, J and Zhang, W and Cao, Z and Lian, S and Li, J and Nie, J and Huang, Y and Zhao, K and He, J and Liu, C}, title = {Association of Selenium Levels with Neurodegenerative Disease: A Systemic Review and Meta-Analysis.}, journal = {Nutrients}, volume = {15}, number = {17}, pages = {}, pmid = {37686737}, issn = {2072-6643}, support = {81903294//National Natural Science Foundation of China/ ; 202102020120//Guangzhou Basic and Applied Basic Research Foundation/ ; A2022080//Medical Scientific Research Foundation of Guangdong Province of China/ ; }, mesh = {Humans ; *Selenium ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Databases, Factual ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) have posed significant challenges to public health, and it is crucial to understand their mechanisms in order to develop effective therapeutic strategies. Recent studies have highlighted the potential role of selenium in ND pathogenesis, as it plays a vital role in maintaining cellular homeostasis and preventing oxidative damage. However, a comprehensive analysis of the association between selenium and NDs is still lacking.

METHOD: Five public databases, namely PubMed, Web of Science, EMBASE, Cochrane and Clinical Trials, were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I[2]), Cochrane's Q test and Tau2 were calculated to evaluate the heterogeneity.

RESULT: The association of selenium in ND patients with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) was studied. A statistically significant relationship was only found for AD patients (SMD = -0.41, 95% CI (-0.64, -0.17), p < 0.001), especially for erythrocytes. However, no significant relationship was observed in the analysis of the other four diseases.

CONCLUSION: Generally, this meta-analysis indicated that AD patients are strongly associated with lower selenium concentrations compared with healthy people, which may provide a clinical reference in the future. However, more studies are urgently needed for further study and treatment of neurodegenerative diseases.}, } @article {pmid37689321, year = {2023}, author = {Donini, L and Tanel, R and Zuccarino, R and Basso, M}, title = {Protein biomarkers for the diagnosis and prognosis of Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {31-41}, doi = {10.1016/j.neures.2023.09.002}, pmid = {37689321}, issn = {1872-8111}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Prognosis ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease, still incurable. The disease is highly heterogenous both genetically and phenotypically. Therefore, developing efficacious treatments is challenging in many aspects because it is difficult to predict the rate of disease progression and stratify the patients to minimize statistical variability in clinical studies. Moreover, there is a lack of sensitive measures of therapeutic effect to assess whether a pharmacological intervention ameliorates the disease. There is also urgency of markers that reflect a molecular mechanism dysregulated by ALS pathology and can be rescued when a treatment relieves the condition. Here, we summarize and discuss biomarkers tested in multicentered studies and across different laboratories like neurofilaments, the most used marker in ALS clinical studies, neuroinflammatory-related proteins, p75[ECD], p-Tau/t-Tau, and UCHL1. We also explore the applicability of muscle proteins and extracellular vesicles as potential biomarkers.}, } @article {pmid37692101, year = {2023}, author = {Stansberry, WM and Pierchala, BA}, title = {Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1238453}, pmid = {37692101}, issn = {1662-5099}, support = {R01 NS089585/NS/NINDS NIH HHS/United States ; }, abstract = {The discovery of the neurotrophins and their potent survival and trophic effects led to great enthusiasm about their therapeutic potential to rescue dying neurons in neurodegenerative diseases. The further discovery that brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) had potent survival-promoting activity on motor neurons led to the proposal for their use in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). In this review we synthesize the literature pertaining to the role of NGF, BDNF, CNTF and GDNF on the development and physiology of spinal motor neurons, as well as the preclinical studies that evaluated their potential for the treatment of ALS. Results from the clinical trials of these molecules will also be described and, with the aid of decades of hindsight, we will discuss what can reasonably be concluded and how this information can inform future clinical development of neurotrophic factors for ALS.}, } @article {pmid37695446, year = {2024}, author = {Yang, EJ}, title = {Combined Treatment with Bojungikgi-tang (Buzhong Yiqi Decoction) and Riluzole Attenuates Cell Death in TDP-43-Expressing Cells.}, journal = {Chinese journal of integrative medicine}, volume = {30}, number = {7}, pages = {616-622}, pmid = {37695446}, issn = {1993-0402}, mesh = {*Drugs, Chinese Herbal/pharmacology ; *DNA-Binding Proteins/metabolism ; *Cell Death/drug effects ; *Riluzole/pharmacology ; Cell Line ; Autophagy/drug effects ; Animals ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; Drug Therapy, Combination ; Humans ; }, abstract = {OBJECTIVE: To examine the effect of combined treatment with Bojungikgi-tang (BJIGT, Buzhong Yiqi Decoction) and riluzole (RZ) in transactive response DNA-binding protein 43 (TDP-43) stress granule (SG) cells, a amyotrophic lateral sclerosis (ALS) cell line using transcriptomic and molecular techniques.

METHODS: TDP-43 SG cells were pretreated with BJIGT (100 µg/mL), RZ (50 µmol/L), and combined BJIGT (100 µg/mL)/RZ (50 µmol/L) for 6 h before treatment with lipopolysaccharide (LPS, 200 µmol/L). Cell viability assay was performed to elucidate cell toxicity in TDP-43 SC cells using a cell-counting kit-8 (CCK8) assay kit. The expression levels of cell death-related proteins, including Bax, caspase 1, cleaved caspase 3 and DJ1 in TDP-43 SG cells were examined by Western blot analysis. The autophagy-related proteins, including pmTOR/mTOR, LC3b, P62, ATG7 and Bcl-2-associated athanogene 3 (Bag3) were investigated using immunofluorescence and immunoblotting assays.

RESULTS: Cell viability assay and Western blot analysis showed that combined treatment with BJIGT and RZ suppressed LPS-induced cell death and expression of cell death-related proteins, including Bax, caspase 1, and DJ1 (P<0.05 or P<0.01). Immunofluorescence and immunoblotting assays showed that combined treatment with BJIGT and RZ reduced LPS-induced formation of TDP-43 aggregates and regulated autophagy-related protein levels, including p62, light chain 3b, Bag3, and ATG7, in TDP-43-expressing cells (P<0.05 or P<0.01).

CONCLUSION: The combined treatment of BJIGT and RZ might reduce inflammation and regulate autophagy dysfunction in TDP-43-induced ALS.}, } @article {pmid37695623, year = {2023}, author = {Genge, A and van den Berg, LH and Frick, G and Han, S and Abikoff, C and Simmons, A and Lin, Q and Patra, K and Kupperman, E and Berry, JD}, title = {Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {80}, number = {10}, pages = {1089-1097}, pmid = {37695623}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration & dosage ; Middle Aged ; Double-Blind Method ; Aged ; Adult ; Complement Inactivating Agents/therapeutic use/adverse effects/administration & dosage ; Treatment Outcome ; Complement C5/antagonists & inhibitors ; }, abstract = {IMPORTANCE: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression.

OBJECTIVE: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS.

This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month.

INTERVENTIONS: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment.

MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS).

RESULTS: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]).

CONCLUSIONS AND RELEVANCE: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04248465.}, } @article {pmid37695947, year = {2024}, author = {Sanson, G and Antonaglia, V and Buttignon, G and Caggegi, GD and Pegani, C and Peratoner, A}, title = {Dynamic Course of Clinical State Transitions in Patients Undergoing Advanced Life Support after Out-of-Hospital Cardiac Arrest.}, journal = {Prehospital emergency care}, volume = {28}, number = {3}, pages = {461-469}, doi = {10.1080/10903127.2023.2258192}, pmid = {37695947}, issn = {1545-0066}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/complications ; *Cardiopulmonary Resuscitation ; Retrospective Studies ; *Emergency Medical Services ; Ventricular Fibrillation/therapy/complications ; *Tachycardia, Ventricular/complications ; Arrhythmias, Cardiac ; }, abstract = {OBJECTIVES: Studies of out-of-hospital cardiac arrest generally document the presenting (pulseless electrical activity [PEA], ventricular fibrillation/tachycardia (VF/VT), asystole), and the final states (resuming stable spontaneous circulation [s-ROSC], being declared dead). Only a few studies described the transitions between clinical states during advanced life support (ALS). The aim of this study was to describe and analyze the dynamics of state transitions during ALS.

METHODS: A retrospective analysis of 464 OHCA events was conducted. Any observed state and its corresponding changing time were documented through continuous electrocardiographic and trans-thoracic impedance recording.

RESULTS: When achieved, most s-ROSCs were obtained by 30 min, regardless of the presenting state. After this time point, the persistence of any transient state was associated with a great probability of being declared dead. The most probable change for VF/VT or PEA at any time was the transition to asystole (36.4% and 34.4%, respectively); patients in asystole at any time had a 70% probability of death. Patients achieving s-ROSC mostly came from a VF/VT state.In most cases, the presenting rhythm tended to persist over time during ALS. Asystole was the most stable state; a higher degree of instability was observed when the presenting rhythms were VF/VT or PEA. Transient ROSC episodes occurred mainly as the first transition after the presenting state, especially for initial PEA.

CONCLUSIONS: An understanding of the dynamic course of clinical state transitions during ALS may allow treatment strategies to be tailored in patients affected by OHCA.}, } @article {pmid37703175, year = {2023}, author = {Runfola, V and Giambruno, R and Caronni, C and Pannese, M and Andolfo, A and Gabellini, D}, title = {MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.}, journal = {Cell reports}, volume = {42}, number = {9}, pages = {113120}, pmid = {37703175}, issn = {2211-1247}, support = {R21 CA249378/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics ; Gene Expression Regulation ; Genes, Homeobox ; *Homeodomain Proteins/genetics/metabolism ; Muscle, Skeletal/metabolism ; *Muscular Dystrophy, Facioscapulohumeral/genetics/metabolism ; Neurodegenerative Diseases/genetics ; Nuclear Matrix-Associated Proteins/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.}, } @article {pmid37704056, year = {2023}, author = {Tang, J and Kang, Y and Zhou, Y and Chen, Q and Lan, J and Liu, X and Peng, Y}, title = {Umbilical cord mesenchymal stem cell-conditioned medium inhibits microglial activation to ameliorate neuroinflammation in amyotrophic lateral sclerosis mice and cell models.}, journal = {Brain research bulletin}, volume = {202}, number = {}, pages = {110760}, doi = {10.1016/j.brainresbull.2023.110760}, pmid = {37704056}, issn = {1873-2747}, mesh = {Mice ; Animals ; Microglia ; Neuroinflammatory Diseases ; *Amyotrophic Lateral Sclerosis ; Culture Media, Conditioned/pharmacology ; *Neurodegenerative Diseases ; Superoxide Dismutase-1 ; *Mesenchymal Stem Cells ; Mice, Transgenic ; Cytokines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease for which few effective therapeutic strategies are available. Increasing evidence indicates that neuroinflammation plays a significant role in ALS pathogenesis. Mesenchymal stem cell (MSC)-based therapy has been proposed for the treatment of neurodegenerative diseases, including ALS. In this study, we first demonstrated that systemic administration of conditioned medium derived from umbilical cord MSCs (UCMSC-CM) extends the lifespan of transgenic SOD1-G93A mice, a well-characterized model of familial ALS. Moreover, UCMSC-CM inhibits microglial activation and astrogliosis and alleviates the inflammatory milieu by reducing the release of proinflammatory cytokines and the expression of iNOS in the spinal cord. Using BV-2 cells overexpressing the SOD1-G93A mutant as an ALS cellular model, we uncovered that UCMSC-CM also suppresses the lipopolysaccharide (LPS)-induced inflammatory response, including reduced expression of proinflammatory cytokines and iNOS. Importantly, by culturing astrocytes alone in microglia-conditioned medium (MCM) or together with microglia in a transwell coculture system, we found that UCMSC-CM modulates the secretome of microglia exposed to inflammatory stimuli, thereby preventing the conversion of astrocytes to the A1 neurotoxic phenotype. This study revealed the anti-inflammatory properties of UCMSC-CM and its regulatory effect on glial activation in the treatment of neuroinflammation in ALS, providing strong evidence for the clinical application of UCMSC-CM.}, } @article {pmid37709589, year = {2023}, author = {Jin, J and Zhong, XB}, title = {ASO drug Qalsody (tofersen) targets amyotrophic lateral sclerosis.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {12}, pages = {1043-1044}, pmid = {37709589}, issn = {1873-3735}, support = {R35 GM140862/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oligonucleotides ; }, } @article {pmid37711011, year = {2023}, author = {Rodrigues, RB and Orsini, M and Neves, SV and de Rezende Pinto, WBV and da Silva Catarino, AM and Pereira, DA and Oliveira, ASB}, title = {Differential Diagnosis or Etiology: A Case Report on Amyotrophic Lateral Sclerosis-like Neuropathy Associated with HIV Infection.}, journal = {Current HIV research}, volume = {21}, number = {5}, pages = {323-329}, doi = {10.2174/1570162X21666230914104220}, pmid = {37711011}, issn = {1873-4251}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/drug therapy ; *HIV Infections/complications/drug therapy ; Diagnosis, Differential ; }, abstract = {BACKGROUND: Retroviruses are described as a risk factor for chronic neuropathy. However, it is still unknown if they can work as amyotrophic lateral sclerosis triggers. Over the years, some cases of this association have been described with heterogenous disclosures.

CASE REPRESENTATION: This study aimed to report a case of HIV and ALS-like neuropathy and briefly discuss peculiarities of clinical aspects, such as physiopathology and treatment options. The patient underwent neurological examination associated with blood tests, electromyography, analysis of cerebrospinal fluid, and imaging studies.

DISCUSSION: A non-systematic review was performed in major databases regarding the topic. The case presented mixed upper and lower motor neuron signs and was framed as a probable case of ALS following the present criteria.

CONCLUSION: After a short follow-up and viral load cleansing, neurological stabilization was achieved.}, } @article {pmid37711512, year = {2023}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1211486}, pmid = {37711512}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN β) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1[G93A] transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT-qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation.}, } @article {pmid37720931, year = {2023}, author = {Martínez-Camarena, Á and Sour, A and Faller, P}, title = {Impact of human serum albumin on Cu[II] and Zn[II] complexation by ATSM (diacetyl-bis(N4-methylthiosemicarbazone)) and a water soluble analogue.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {52}, number = {38}, pages = {13758-13768}, doi = {10.1039/d3dt02380j}, pmid = {37720931}, issn = {1477-9234}, mesh = {Humans ; *Coordination Complexes ; *Organometallic Compounds/chemistry ; Diacetyl ; Serum Albumin, Human ; Ligands ; Zinc ; *Thiosemicarbazones/chemistry ; Copper Radioisotopes ; Radiopharmaceuticals ; }, abstract = {The chelator diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) and its complexes with Cu[II] and Zn[II] are becoming increasingly investigated for medical applications such as PET imaging for anti-tumour therapy and the treatment of amyotrophic lateral sclerosis. However, the solubility in water of both the ligand and the complexes presents certain limitations for in vitro studies. Moreover, the stability of the Cu[II] and Zn[II] complexes and their metal exchange reaction against the potential biological competitor human serum albumin (HSA) has not been studied in depth. In this work it was observed that the ATSM with an added carboxylic group into the structure increases its solubility in aqueous solutions without altering the coordination mode and the conjugated system of the ligand. The poorly water-soluble Cu[II]- and Zn[II]-ATSM complexes were prevented from precipitating due to the binding to HSA. Both HSA and ATSM show a similar thermodynamic affinity for Zn[II]. Finally, the Cu[II]-competition experiments with EDTA and the water-soluble ATSM ligands yielded an apparent log Kd at pH 7.4 of about -19. When ATSM was added to Cu[II]- and Zn[II]-loaded HSA, withdrawing of Zn[II] was kinetically favoured, but this metal is slowly substituted by the Cu[II] afterwards taken from HSA so that this protein could be considered as a source of Cu[II] for ATSM.}, } @article {pmid37735683, year = {2023}, author = {Sołek, P and Czechowska, E and Sowa-Kućma, M and Stachowicz, K and Kaczka, P and Tabęcka-Łonczyńska, A}, title = {Elucidating the molecular mechanisms underlying the induction of autophagy by antidepressant-like substances in C57BL/6J mouse testis model upon LPS challenge.}, journal = {Cell communication and signaling : CCS}, volume = {21}, number = {1}, pages = {251}, pmid = {37735683}, issn = {1478-811X}, mesh = {Animals ; Male ; Mice ; Antidepressive Agents/pharmacology ; Autophagy ; *Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Testis ; }, abstract = {The treatment of depression with pharmaceuticals is associated with many adverse side effects, including male fertility problems. The precise mechanisms by which these agents affect testicular cells remain largely unknown, but they are believed to induce cellular stress, which is sensed by the endoplasmic reticulum (ER) and the Golgi apparatus. These organelles are responsible for maintaining cellular homeostasis and regulating signal pathways that lead to autophagy or apoptosis. Therefore, in this study, we aimed to investigate the autophagy, ER, and Golgi stress-related pathways in mouse testis following treatment with antidepressant-like substances (ALS) and ALS combined with lipopolysaccharide (LPS). We found that most ALS and activated proteins are associated with the induction of apoptosis. However, when imipramine (IMI) was combined with NS-398 (a cyclooxygenase-2 inhibitor) after LPS administration, we observed a marked increase in the BECLIN1, Bcl-2, ATG16L, and LC3 expression, which are marker proteins of autophagosome formation. The expression of the BECN1 and ATG16L genes was also high compared to the control, indicating the induction of autophagy processes that may potentially protect mouse testicular cells from death and regulate metabolism in the testis. Our findings may provide a better understanding of the stress-related effects of specific ALS on the testis. Video Abstract.}, } @article {pmid37739033, year = {2023}, author = {Tanaka, Y and Ito, SI and Honma, Y and Hasegawa, M and Kametani, F and Suzuki, G and Kozuma, L and Takeya, K and Eto, M}, title = {Dysregulation of the progranulin-driven autophagy-lysosomal pathway mediates secretion of the nuclear protein TDP-43.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {11}, pages = {105272}, pmid = {37739033}, issn = {1083-351X}, mesh = {Humans ; *Autophagy/drug effects/genetics ; *DNA-Binding Proteins/genetics/metabolism ; HeLa Cells ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; *Lysosomes/metabolism ; *Progranulins/genetics/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; Gene Expression Regulation/drug effects ; Extracellular Vesicles/metabolism ; Enzyme Inhibitors/pharmacology ; Autophagosomes/drug effects/metabolism ; Autophagy-Related Proteins/genetics/metabolism ; Leupeptins ; Macrolides ; }, abstract = {The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.}, } @article {pmid37740686, year = {2023}, author = {Vucic, S and Kiernan, MC}, title = {Nanocrystalline gold (CNM-Au8): a novel bioenergetic treatment for ALS.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {9}, pages = {783-785}, doi = {10.1080/13543784.2023.2263368}, pmid = {37740686}, issn = {1744-7658}, } @article {pmid37745304, year = {2023}, author = {Yokota, M and Yoshino, Y and Hosoi, M and Hashimoto, R and Kakuta, S and Shiga, T and Ishikawa, KI and Okano, H and Hattori, N and Akamatsu, W and Koike, M}, title = {Reduced ER-mitochondrial contact sites and mitochondrial Ca[2+] flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1171440}, pmid = {37745304}, issn = {2296-634X}, abstract = {Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca[2+] flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.}, } @article {pmid37746513, year = {2023}, author = {Singh, A and Arora, S and Chavan, M and Shahbaz, S and Jabeen, H}, title = {An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions.}, journal = {Cureus}, volume = {15}, number = {8}, pages = {e44051}, pmid = {37746513}, issn = {2168-8184}, abstract = {For both short-term and long-term treatment of bipolar disorder, lithium is a prototypical mood stabilizer. Lithium's neuroprotective properties were revealed by cumulative translational research, which opened the door to reforming the chemical as a treatment for neurodegenerative illnesses. The control of homeostatic systems such as oxidative stress, autophagy, apoptosis, mitochondrial function, and inflammation underlies lithium's neuroprotective characteristics. The fact that lithium inhibits the enzymes inositol monophosphatase (IMPase) and glycogen synthase kinase (GSK)-3 may be the cause of the various intracellular reactions. In this article, we review lithium's neurobiological properties, as demonstrated by its neurotrophic and neuroprotective capabilities, as well as translational studies in cells in culture and in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease, amyotrophic lateral sclerosis (ALS), ischemic stroke, and neuronal ceroid lipofuscinosis (NCL), discussing the justification for the drug's use in the treatment of these neurodegenerative disorders.}, } @article {pmid37752364, year = {2023}, author = {Guan, T and Zhou, T and Zhang, X and Guo, Y and Yang, C and Lin, J and Zhang, JV and Cheng, Y and Marzban, H and Wang, YT and Kong, J}, title = {Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {10}, pages = {304}, pmid = {37752364}, issn = {1420-9071}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Disease Models, Animal ; Motor Neurons ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS.

METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS.

RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice.

CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.}, } @article {pmid37756598, year = {2023}, author = {Prior-González, M and Lazo-Gómez, R and Tapia, R}, title = {Sodium butyrate does not protect spinal motor neurons from AMPA-induced excitotoxic degeneration in vivo.}, journal = {Disease models & mechanisms}, volume = {16}, number = {10}, pages = {}, pmid = {37756598}, issn = {1754-8411}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Butyric Acid/pharmacology/metabolism ; Motor Neurons/pathology ; Spinal Cord/pathology ; }, abstract = {Motor neuron (MN) loss is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS). Histone deacetylase 4 (HDAC4) is one of several factors involved in nerve-muscle communication during MN loss, hindering muscle reinnervation, as shown in humans and in animal models of ALS, and may explain the differential progression observed in patients with ALS - rapid versus slow progression. In this work, we inhibited HDAC4 activity through the administration of a pan-histone deacetylase inhibitor, sodium butyrate, in an in vivo model of chronic spinal MN death induced by AMPA-mediated excitotoxicity. We infused AMPA into the spinal cord at low and high doses, which mimic the rapid and slow progression observed in humans, respectively. We found that muscle HDAC4 expression was increased by high-dose infusion of AMPA. Treatment of animals with sodium butyrate further decreased expression of muscle HDAC4, although non-significantly, and did not prevent the paralysis or the MN loss induced by AMPA infusion. These results inform on the role of muscle HDAC4 in MN degeneration in vivo and provide insights for the search for more suitable therapeutic strategies.}, } @article {pmid37759773, year = {2023}, author = {Goto, S and Zhang, Y and Vyas, SA and Zhu, Q and Wildsoet, CF}, title = {Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia.}, journal = {Biomolecules}, volume = {13}, number = {9}, pages = {}, pmid = {37759773}, issn = {2218-273X}, support = {R01 EY012392/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; Bone Morphogenetic Protein 2/genetics ; Choroid ; *Myopia/genetics ; *Retinal Pigment Epithelium ; }, abstract = {PURPOSE: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia.

METHODS: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes.

RESULTS: Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.}, } @article {pmid37762599, year = {2023}, author = {Taneva, SG and Todinova, S and Andreeva, T}, title = {Morphometric and Nanomechanical Screening of Peripheral Blood Cells with Atomic Force Microscopy for Label-Free Assessment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762599}, issn = {1422-0067}, support = {KP-06-H31/8//Bulgarian Science Fund/ ; funding programme Open Access Publishing//Baden-Württemberg Ministry of Science, Research and Culture/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Alzheimer Disease/diagnosis ; Microscopy, Atomic Force ; Blood Cells ; }, abstract = {Neurodegenerative disorders (NDDs) are complex, multifactorial disorders with significant social and economic impact in today's society. NDDs are predicted to become the second-most common cause of death in the next few decades due to an increase in life expectancy but also to a lack of early diagnosis and mainly symptomatic treatment. Despite recent advances in diagnostic and therapeutic methods, there are yet no reliable biomarkers identifying the complex pathways contributing to these pathologies. The development of new approaches for early diagnosis and new therapies, together with the identification of non-invasive and more cost-effective diagnostic biomarkers, is one of the main trends in NDD biomedical research. Here we summarize data on peripheral biomarkers, biofluids (cerebrospinal fluid and blood plasma), and peripheral blood cells (platelets (PLTs) and red blood cells (RBCs)), reported so far for the three most common NDDs-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PLTs and RBCs, beyond their primary physiological functions, are increasingly recognized as valuable sources of biomarkers for NDDs. Special attention is given to the morphological and nanomechanical signatures of PLTs and RBCs as biophysical markers for the three pathologies. Modifications of the surface nanostructure and morphometric and nanomechanical signatures of PLTs and RBCs from patients with AD, PD, and ALS have been revealed by atomic force microscopy (AFM). AFM is currently experiencing rapid and widespread adoption in biomedicine and clinical medicine, in particular for early diagnostics of various medical conditions. AFM is a unique instrument without an analog, allowing the generation of three-dimensional cell images with extremely high spatial resolution at near-atomic scale, which are complemented by insights into the mechanical properties of cells and subcellular structures. Data demonstrate that AFM can distinguish between the three pathologies and the normal, healthy state. The specific PLT and RBC signatures can serve as biomarkers in combination with the currently used diagnostic tools. We highlight the strong correlation of the morphological and nanomechanical signatures between RBCs and PLTs in PD, ALS, and AD.}, } @article {pmid37766430, year = {2023}, author = {Cheng, W and Huang, J and Fu, XQ and Tian, WY and Zeng, PM and Li, Y and Luo, ZG}, title = {Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {31}, number = {11}, pages = {3277-3289}, pmid = {37766430}, issn = {1525-0024}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Dependovirus/genetics ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Motor Neurons/metabolism ; Nerve Growth Factors/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1[G93A] ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1[G93A] mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1[G93A] mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS.}, } @article {pmid37766843, year = {2023}, author = {Olukoya, AO and Stires, H and Bahnassy, S and Persaud, S and Guerra, Y and Ranjit, S and Ma, S and Cruz, MI and Benitez, C and Rozeboom, AM and Ceuleers, H and Berry, DL and Jacobsen, BM and Raj, GV and Riggins, RB}, title = {Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer.}, journal = {Journal of the Endocrine Society}, volume = {7}, number = {10}, pages = {bvad117}, pmid = {37766843}, issn = {2472-1972}, support = {P30 CA051008/CA/NCI NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, riluzole has shown antitumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by riluzole.

METHODS: We tested the ability of riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.

RESULTS: Single-agent riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple prosurvival signaling molecules, including Akt/mTOR, CREB, and Fak/Src family kinases. Riluzole, in combination with either fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growth in vitro. Single-agent riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of riluzole plus fulvestrant significantly reduced proliferation in ex vivo primary breast tumor explant cultures.

CONCLUSION: Riluzole may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.}, } @article {pmid37770137, year = {2023}, author = {Bivehed, E and Hellman, B and Fan, Y and Haglöf, J and Buratovic, S}, title = {DNA integrity under alkaline conditions: An investigation of factors affecting the comet assay.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {891}, number = {}, pages = {503680}, doi = {10.1016/j.mrgentox.2023.503680}, pmid = {37770137}, issn = {1879-3592}, mesh = {Humans ; *Comet Assay/methods ; DNA ; DNA Damage ; DNA Repair ; Hydrogen-Ion Concentration ; }, abstract = {The effect of pH on DNA integrity was assessed using a three-step approach. The comet assay was used on a whole genome level, with three different protocols: neutral (no alkaline unwinding), flash (pH 12.5 with 2.5 min unwinding), and the conventional alkaline protocol (pH>13 with 40 min unwinding). Real-time quantitative PCR (RT-qPCR) was then used to study the isolated DNA, revealing that gene amplification decreased with increasing pH, indicating DNA degradation. Specially designed molecular beacons were used to examine DNA at the molecular level, with or without alkali-labile site (ALS) insertions. At pH 12.5, fluorescence in the hairpins with ALS started to increase after 30 min, while at pH> 13, this increase was already observed after 5 min, indicating a significant increase in DNA strand breaks. Liquid chromatography analysis was also used, demonstrating that the hairpins remained intact up to pH 10, even after 1 h exposure, whereas, at pH 12.5, partial conversion into strand breaks occurred after 30 min. At pH> 13, the hairpins were almost completely degraded after 30 min. The flash protocol effectively detects DNA single- and double-strand breaks and identified these damages after 2.5 min of alkaline treatment at pH 12.5. When the hairpins were exposed to pH 12.5 for 60 min, ALS were converted to strand breaks, demonstrating the sensitivity of this approach to detect changes in DNA structure. These findings indicate that pH poses a substantial risk to DNA integrity, leading to significantly higher background levels of DNA damage compared to conditions closer to neutrality. Our study demonstrates the importance of understanding the influence of pH on DNA stability and provides insights into risks associated with alkaline environments, especially at pH> 13.}, } @article {pmid37773166, year = {2023}, author = {Aguilar-Vázquez, CA and Gallardo-González, LI and Raymundo-Carrillo, AD and Reyes-Sosa, LC and Martínez-Romo, ES}, title = {[Parkinson-dementia and amyotrophic lateral sclerosis association (complex of Guam). Diagnostic challenge, Mexican patient].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {61}, number = {5}, pages = {677-684}, pmid = {37773166}, issn = {2448-5667}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Parkinson Disease/complications/pathology ; *Dementia/complications/epidemiology/pathology ; *Neurodegenerative Diseases ; Guam/epidemiology ; *Parkinsonian Disorders/etiology/complications ; }, abstract = {BACKGROUND: The Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS-PDC) was first described in the islands of Guam. This pathology presented its peak incidence in the 1950s. Due to the rarity of the association, we report a clinical case with this complex. The objective was to describe the nosological and pathogenic implications of these neurodegenerative disorder, since they are not frequent to find in our population.

CLINICAL CASE: We present a case of Latinoamerican origin who initially manifested systemic symptoms of more than 6 years of evolution, with subsequent cognitive alterations. Later, patient began with gait disturbances and motor symptoms suggestive of parkinsonism with atypical data and data of motor neurone disease (MND). More studies were carried out and confirmed findings compatible with upper and lower motor neuron involvement. A mutation in the POLG gene was observed, related to mitochondrial depletion syndrome.

CONCLUSION: Despite the knowledge of this association, it is an entity whose clinical diagnosis could be very difficult to achieve. In addition, molecular mechanisms have not been fully identified, the most common genes related to Parkinsonism and ALS have been excluded, and even attempts to locate the locus were made, without achieving accurate results. Unfortunately, being a neurodegenerative disease, the prognosis is fatal, with no disease-modifying treatment.}, } @article {pmid37774774, year = {2023}, author = {Gschwendtberger, T and Thau-Habermann, N and von der Ohe, J and Luo, T and Hass, R and Petri, S}, title = {Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons.}, journal = {Neuroscience letters}, volume = {816}, number = {}, pages = {137493}, doi = {10.1016/j.neulet.2023.137493}, pmid = {37774774}, issn = {1872-7972}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Exosomes/metabolism ; Antioxidants/pharmacology ; Motor Neurons/metabolism ; *Mesenchymal Stem Cells/metabolism ; }, abstract = {In recent years, the neuroprotective potential of mesenchymal stroma-/stem-like cells (MSC) as well as of MSC-derived extracellular vesicles (EVs) like exosomes has been intensively explored. This included preclinical evaluation regarding treatment of neurodegenerative disorders such as the fatal motor neuron disease amyotrophic Lateral Sclerosis (ALS). Several studies have reported that MSC-derived exosomes can stimulate tissue regeneration and reduce inflammation. MSC release EVs and trophic factors and thereby modify cell-to-cell communication. These cell-free products may protect degenerating motor neurons (MNs) and represent a potential therapeutic approach for ALS. In the present study we investigated the effects of exosomes derived from a permanently growing MSC line on both, wild type and ALS (SOD1[G93A] transgenic) primary motor neurons. Following application in a normal and stressed environment we could demonstrate beneficial effects of MSC exosomes on neurite growth and morphology indicating the potential for further preclinical evaluation and clinical therapeutic development. Investigation of gene expression profiles detected transcripts of several antioxidant and anti-inflammatory genes in MSC exosomes. Characterization of their microRNA (miRNA) content revealed miRNAs capable of regulating antioxidant and anti-apoptotic pathways.}, } @article {pmid37781884, year = {2023}, author = {Erdag, E and Haskologlu, IC and Mercan, M and Abacioglu, N and Sehirli, AO}, title = {An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?.}, journal = {Chronobiology international}, volume = {40}, number = {10}, pages = {1395-1403}, doi = {10.1080/07420528.2023.2265476}, pmid = {37781884}, issn = {1525-6073}, mesh = {Animals ; Humans ; *Melatonin/pharmacology ; Circadian Rhythm/physiology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Chronotherapy/methods ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; }, abstract = {Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.}, } @article {pmid37783557, year = {2023}, author = {Chen, D and Huang, H and Saberi, H and Sharma, HS}, title = {Positive and negative cell therapy in randomized control trials for central nervous system diseases.}, journal = {International review of neurobiology}, volume = {171}, number = {}, pages = {241-254}, doi = {10.1016/bs.irn.2023.05.017}, pmid = {37783557}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; *Central Nervous System Diseases/therapy ; Cell- and Tissue-Based Therapy ; *Parkinson Disease/therapy ; Brain Damage, Chronic ; }, abstract = {Neurorestorative cell therapies have been tested to treat patients with nervous system diseases for over 20 years. Now it is still hard to answer which kinds of cells can really play a role on improving these patients' quality of life. Non-randomized clinical trials or studies could not provide strong evidences in answering this critical question. In this review, we summarized randomized clinical trials of cell therapies for central nervous diseases, such as stroke, spinal cord injury, cerebral palsy (CP), Parkinson's disease (PD), multiple sclerosis (MS), brain trauma, amyotrophic lateral sclerosis (ALS), etc. Most kinds of cell therapies demonstrated negative results for stoke, brain trauma and amyotrophic lateral sclerosis. A few kinds of cell therapies showed neurorestorative effects in this level of evidence-based medicine, such as olfactory ensheating cells for chronic ischemic stroke. Some kinds of cells showed positive or negative effects from different teams in the same or different diseases. We analyzed the possible failed reasons of negative results and the cellular bio-propriety basis of positive results. Based on therapeutic results of randomized control trials and reasonable analysis, we recommend: (1) to further conduct trials for successful cell therapies with positive results to increase neurorestorative effects; (2) to avoid in repeating failed cell therapies with negative results in same diseases because it is nonsense for them to be done with similar treatment methods, such as cell dosage, transplanting way, time of window, etc. Furthermore, we strongly suggest not to do non-randomized clinical trials for cells that had shown negative results in randomized clinical trials.}, } @article {pmid37786905, year = {2021}, author = {Huang, ZQ and Ba, ZS and Huang, NQ and Li, YY and Luo, Y}, title = {Aberrant TDP-43 phosphorylation: a key wind gap from TDP-43 to TDP-43 proteinopathy.}, journal = {Ibrain}, volume = {7}, number = {2}, pages = {119-131}, pmid = {37786905}, issn = {2769-2795}, abstract = {TDP-43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA-binding protein of 43-kDa molecular weight (TDP-43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP-43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP-43 plays an important role in triggering or promoting the occurrence and progression of TDP-43 proteinopathy. The hyperphosphorylation of TDP-43 is undoubtedly an important factor in triggering or promoting the process of TDP-43 proteinopathy. Hyperphosphorylation of TDP-43 can inhibit the degradation of TDP-43, aggravate the aggregation of TDP-43 protein, increase the wrong localization of TDP-43 in cells, and enhance the cytotoxicity of TDP-43. More and more evidences show that the hyperphosphorylation of TDP-43 plays an important role in the pathogenesis of TDP-43 proteinopathy. Inhibition of TDP-43 hyperphosphorylation may be one of the important strategies for the treatment of TDP-43 proteinopathy. Therefore, this article reviews the role of TDP-43 phosphorylation in TDP-43 proteinopathy and the related mechanisms.}, } @article {pmid37787812, year = {2024}, author = {Beswick, E and Johnson, M and Newton, J and Dakin, R and Stenson, A and Abrahams, S and Carson, A and Chandran, S and Pal, S}, title = {Factors impacting trial participation in people with motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {543-552}, pmid = {37787812}, issn = {1432-1459}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; *Motor Neuron Disease/therapy ; Probability ; Prospective Studies ; Randomized Controlled Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder with limited treatment options. Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. The Motor Neuron Disease-Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) seeks to identify effective disease modifying drugs. This study investigates person-specific factors affecting recruitment and retention. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. Participants with MND completed questionnaires and this was supplemented with clinical data. 12 months after completing the questionnaires we used MND-SMART recruitment data to establish if members of our cohort engaged with the trial. 120 people with MND completed questionnaires for this study. Mean age at participation was 66 (SD = 9), 14% (n = 17) were categorised as long survivors, with 68% (n = 81) of participants male and 60% (n = 73) had the ALS sub-type. Of the 120 study participants, 50% (n = 60) were randomised into MND-SMART and 78% (n = 94) expressed interest an in participating. After the 1-year follow-up period 65% (n = 39) of the 60 randomised participants remained in MND-SMART. Older age was significantly associated with reduced likelihood of participation (OR = 0.92, 95% CI = 0.88-0.96, p = 0.000488). The findings show that people with MND are highly motivated to engage in research, but older individuals remain significantly less likely to participate. We recommend the inclusion of studies to explore characteristics of prospective and current participants alongside trials.}, } @article {pmid37787835, year = {2024}, author = {Li, S and Zhao, L and Xiao, J and Guo, Y and Fu, R and Zhang, Y and Xu, S}, title = {The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.}, journal = {Molecular and cellular biochemistry}, volume = {479}, number = {9}, pages = {2217-2243}, pmid = {37787835}, issn = {1573-4919}, support = {No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neurodegenerative Diseases/therapy/microbiology ; *Fecal Microbiota Transplantation ; *Probiotics/therapeutic use ; Animals ; Parkinson Disease/therapy/microbiology ; Alzheimer Disease/therapy/microbiology ; }, abstract = {There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.}, } @article {pmid37791873, year = {2023}, author = {Kour, S and Fortuna, T and Anderson, EN and Mawrie, D and Bilstein, J and Sivasubramanian, R and Ward, C and Roy, R and Rajasundaram, D and Sterneckert, J and Pandey, UB}, title = {Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.}, journal = {Nucleic acids research}, volume = {51}, number = {20}, pages = {11258-11276}, pmid = {37791873}, issn = {1362-4962}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; }, mesh = {Animals ; Amyotrophic Lateral Sclerosis/metabolism ; Drosophila/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Mutation ; Neurons/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Neurodegenerative Diseases/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism ; Humans ; *Ribonuclease III/metabolism ; *Drosophila Proteins/metabolism ; }, abstract = {Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.}, } @article {pmid37795580, year = {2024}, author = {Rodriguez, P and Blakely, RD}, title = {Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?.}, journal = {Journal of cellular physiology}, volume = {239}, number = {6}, pages = {e31125}, doi = {10.1002/jcp.31125}, pmid = {37795580}, issn = {1097-4652}, support = {22A01//Florida Department of Health Ed/ ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Phenotype ; Humans ; *Disease Models, Animal ; Caenorhabditis elegans Proteins/genetics/metabolism ; Paralysis/genetics ; Swimming ; Signal Transduction/genetics ; Dopamine/metabolism ; }, abstract = {Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.}, } @article {pmid37800457, year = {2023}, author = {Billings, JL and Hilton, JBW and Liddell, JR and Hare, DJ and Crouch, PJ}, title = {Fundamental Neurochemistry Review: Copper availability as a potential therapeutic target in progressive supranuclear palsy: Insight from other neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {167}, number = {3}, pages = {337-346}, doi = {10.1111/jnc.15978}, pmid = {37800457}, issn = {1471-4159}, mesh = {Humans ; *Supranuclear Palsy, Progressive/diagnosis/pathology ; Copper ; *Neurodegenerative Diseases/therapy ; Superoxide Dismutase-1 ; *Neurochemistry ; *Parkinson Disease/pathology ; }, abstract = {Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD-like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper-deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP.}, } @article {pmid37804412, year = {2024}, author = {Kusama-Eguchi, K and Tokui, Y and Minoura, A and Yanai, Y and Hirose, D and Furukawa, M and Kosuge, Y and Miura, M and Ohkoshi, E and Makino, M and Minagawa, K and Matsuzaki, K and Ogawa, Y and Watanabe, K and Ohsaki, A}, title = {2(3H)-Dihydrofranolactone metabolites from Pleosporales sp. NUH322 as anti-amyotrophic lateral sclerosis drugs.}, journal = {Journal of natural medicines}, volume = {78}, number = {1}, pages = {146-159}, pmid = {37804412}, issn = {1861-0293}, support = {12-021//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 13-023//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 22590088//Grant-in-Aid for Scientific Research/ ; }, mesh = {Mice ; Male ; Female ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Spinal Cord/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3-7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001-0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor.}, } @article {pmid37807406, year = {2023}, author = {Anderson, G}, title = {Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Cancer.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {28}, pages = {2699-2719}, doi = {10.2174/0115680266253465230920114223}, pmid = {37807406}, issn = {1873-4294}, mesh = {Humans ; *Melatonin/metabolism ; *Alzheimer Disease ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Neoplasms ; Tumor Microenvironment ; }, abstract = {Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including in the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.}, } @article {pmid37807839, year = {2023}, author = {Paganoni, S and Quintana, M and Sherman, AV and Vestrucci, M and Wu, Y and Timmons, J and Cudkowicz, M and , }, title = {Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {12}, pages = {2297-2304}, pmid = {37807839}, issn = {2328-9503}, support = {//ALS Association/ ; //ALS Finding a Cure®/ ; //Amylyx Pharmaceuticals, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/pharmacology/therapeutic use ; Survival Analysis ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

METHODS: Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS.

RESULTS: Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO-ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p = 0.00048).

INTERPRETATION: This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.}, } @article {pmid37814618, year = {2023}, author = {Li, B and Zhang, W and Zhong, S and Pan, J and Wang, X and Zou, H and Dou, X}, title = {Short-term outcome of plasma adsorption therapy in amyotrophic lateral sclerosis.}, journal = {Journal of medical biochemistry}, volume = {42}, number = {3}, pages = {401-406}, pmid = {37814618}, issn = {1452-8258}, abstract = {BACKGROUND: To observe the short-term outcome of plasma adsorption PA therapy in amyotrophic lateral sclerosis (ALS).

METHODS: 28 cases of als patients were recruited in this study, of which 20 were male and 8 were female with a mean age of 53.21±9.07 years and the average course of 33±23.35 months. The clinical manifestations were limb weakness (N=27), muscular atrophy (N=27), muscular tremor (N=5), dysphagia (N=12) and dysarthria (N=12). The clinical data of the patients recruited were graded by Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRSR) : <10 (N=1), 11-20 (N=4), 21-30 (N=6), 31-40 (N=12), >40 (N=5). All patients received PA therapy once a week for three successive times after examining the conditions of blood coagulation and virus infection. PA therapy was supplemented with neurotrophic therapy meanwhile. All patients' clinical manifestations and scores of ALSFRSR before treatment and one week after treatment were evaluated and compared. The levels of serum superoxide dismutase (SOD), interleukin-10 (IL-10), serum creatine kinase (CK) and lactate dehydrogenase (LDH) before and after treatment were compared.

RESULTS: After PA therapy, 14 patients have improved obviously in muscle strength, 4 patients in hypermyotonia partially, 3 patients in muscular tremor, 5 patients in dysarthria, 3 patients in salivation to some extent and 2 patients in swallowing function. The score of ALSFRSR after PA treatment (31.89±10.36) was remarkably higher than that before PA treatment (30.68±10.52) (P<0.01). The levels of SOD (155.10±21.87 IU/L) and IL-10 (138.06±185.88 pg/mL) after PA treatment were significantly higher than the levels before PA treatment (143.08.3±19.16 IU/L and 46.34±75.31 pg/mL, respectively) (P<0.05). The levels of CK (168.86±113.50 IU/L) and LDH (152.07±32.65 IU/L) after PA treatment were significantly lower than the levels before PA treatment (356.68±250.30 IU/L and 181.36±33.74 IU/L respectively) (P<0.01). At the end of follow-up period (November, 2019), five patients died of respiratory failure 16-21 months after PA treatment and two patents died of respiratory infection 15-20 months after PA treatment. 7 patients were still alive. The score of ALSFRS-R of these patients who survived at the end of follow-up (13.00±13.37) were significantly lower than before PA treatment (36.71±8.56) (P<0.05) and after PA treatment (38.14±8.82) (P<0.05).

CONCLUSIONS: Plasma adsorption (PA) therapy has shortterm therapeutic effects on als. The effects might be attributed to the anti-oxygen free radical effect by increasing SOD level and the anti-inflammation effect by increasing IL-10 level. As the efficacy of PA therapy was obtained in a small sample size and short follow-up period, the longterm observation of PA efficacy in treating als should be further investigated.}, } @article {pmid37815307, year = {2024}, author = {Liu, KF and Ramachandran, S and Chang, CW and Chen, RF and Huang, CH and Huang, HT and Lee, CC and Li, YT and Kuo, YR}, title = {The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival.}, journal = {Plastic and reconstructive surgery}, volume = {154}, number = {4}, pages = {775-783}, doi = {10.1097/PRS.0000000000011135}, pmid = {37815307}, issn = {1529-4242}, support = {SH11003//Kaohsiung Medical University Hospital, Taiwan./ ; }, mesh = {Animals ; *Immunosuppressive Agents/therapeutic use ; *Graft Survival/drug effects/immunology ; *Rats, Inbred Lew ; Rats ; *Vascularized Composite Allotransplantation/methods ; *Hindlimb/transplantation ; Male ; Combined Modality Therapy ; Cyclosporine ; Graft Rejection/prevention & control/immunology ; Phototherapy/methods ; Rats, Inbred BN ; Antilymphocyte Serum ; }, abstract = {BACKGROUND: The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model.

METHODS: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis.

RESULTS: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (P < 0.01). Group 4 also showed a significant increase in regulatory T cells (P = 0.04) and transforming growth factor-β1 levels (P = 0.02), and a trend toward a decrease in interleukin-1β levels (P = 0.03) at 16 weeks after transplantation as compared with control (group 1).

CONCLUSIONS: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

CLINICAL RELEVANCE STATEMENT: Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.}, } @article {pmid37816542, year = {2024}, author = {McHenry, KL}, title = {Airway Clearance Strategies and Secretion Management in Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {69}, number = {2}, pages = {227-237}, pmid = {37816542}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Respiratory Therapy/methods ; *Chest Wall Oscillation ; Bodily Secretions ; *Insufflation/methods ; Cough/etiology ; *Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative motor neuron disease that affects voluntary muscle movement. Often, difficulty in coughing, breathing, and swallowing are sequela associated with the condition, and the presence of bulbar muscle predominant weakness results in deleterious effects on airway clearance and secretion management. This narrative review will provide practical guidance for clinicians treating this population. Cough insufficiency in this population typically manifests as a prolonged, slow, weak cough effort that impedes the clearability of secretions and airway protection. Dystussia and dysphagia frequently occur simultaneously in bulbar dysfunction, subsequently impacting respiratory health. Measures of respiratory strength should be obtained and monitored every 3-6 months, preferably in a multidisciplinary clinic setting. Cough augmentation, whether manual or mechanical techniques, should be sought as early in the disease progression as possible to adequately control secretions in the proximal airways. This airway clearance strategy can aid in the prevention and treatment of respiratory tract infections (RTIs), which can pose a significant clinical hurdle to those with ALS. The use of mechanical insufflation-exsufflation may be complicated by severe bulbar dysfunction rendering this technique ineffective. Though peripheral airway clearance strategies, such as high-frequency chest-wall compression, have the advantage of being less impacted by bulbar dysfunction, it is only recommended this modality be used in conjunction with, versus in lieu of, proximal strategies. Salivary secretion management includes the use of anticholinergics, botulinum toxin, and radiation therapy depending on severity and desire for relief.}, } @article {pmid37827137, year = {2024}, author = {Heckmann, JG and Kiem, M and Immich, G}, title = {Forest Therapy as a Nature-Based Intervention: An Option for Neurological Rehabilitation?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {56-63}, doi = {10.1159/000534533}, pmid = {37827137}, issn = {2504-2106}, mesh = {Humans ; *Medicine ; *Neurological Rehabilitation ; *Sleep Wake Disorders ; *Stroke/therapy ; *Dementia ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Forest therapy demonstrates positive effects on mood, immune system, stress levels, and general well-being. Studies on depression, stress-related illnesses, sleep disorders, and arterial hypertension have provided evidence-based proof of this.

SUMMARY: The aim of this review was to examine the possible effects of forest therapy with regard to its evidence in the treatment of chronic neurological diseases such as stroke in the rehabilitation phase, Parkinson's disease, dementia, and multiple sclerosis. Therefore, the electronic databases Medline, Scopus, and Cochrane were searched for such clinical trials for the years 1970 to mid-2023 without language restriction. The literature search revealed only few studies with positive indications but too few cases to be able to make generalizable evidence-based statements. In terms of improvement in the Hamilton Depression Scale analysis of two studies in stroke patients showed slight benefits in the forest therapy group (standard mean difference -0.43; 95% CI: -0.76 to -0.10; p < 0.01). One observational study revealed a higher rate of stroke survival in patients living in marked greenness. Few nature-based interventions in dementia patients showed certain benefits in particular details.

KEY MESSAGES: There are no evidence-based results on the benefit of forest therapy for chronic neurological diseases. However, there are hints that forest therapy could have a positive benefit. Therefore, a proposal for forest therapy as a component of multimodal neurological rehabilitation is presented.

UNLABELLED: HintergrundDie Waldtherapie zeigt positive Auswirkungen auf die Stimmung, das Immunsystem, das Stressniveau und das allgemeine Wohlbefinden. Studien zu Depressionen, stressbedingten Erkrankungen, Schlafstörungen und arteriellem Bluthochdruck haben dies evidenzbasiert belegt.ZusammenfassungZiel dieser Übersichtsarbeit war es, die möglichen Wirkungen der Waldtherapie im Hinblick auf ihre Evidenz bei der Behandlung chronischer neurologischer Erkrankungen wie Schlaganfall in der Rehabilitationsphase, Morbus Parkinson, Demenz und Multiple Sklerose zu untersuchen. Dazu wurden die elektronischen Datenbanken Medline, Scopus und Cochrane für die Jahre 1970 bis Mitte 2023 ohne sprachliche Einschränkung nach solchen klinischen Studien durchsucht. Die Literaturrecherche ergab nur wenige Studien mit positiven Indikationen, aber zu wenigen Fällen, um verallgemeinerbare evidenzbasierte Aussagen machen zu können. Im Hinblick auf Verbesserung in der Hamilton Depressionsskala zeigte die Analyse von 2 Studien bei Schlaganfallpatienten leichte Vorteile der Waldtherapiegruppen (Standard Mean Difference −0.43; 95% CI: -0.76- -0,10; p < 0.01). Eine Beobachtungsstudie ergab eine höhere Schlaganfall-Überlebensrate bei Patienten, die in ausgeprägtem Grün leben. Einige naturbasierte Interventionen bei Demenzpatienten zeigten in einzelnen Parametern gewisse Vorteile.FazitEs gibt bis dato keine verallgemeinerbaren evidenzbasierten Ergebnisse zum Nutzen der Waldtherapie bei chronischen neurologischen Erkrankungen. Es gibt jedoch Hinweise, dass die Waldtherapie einen positiven Nutzen haben könnte. Es wird daher ein Vorschlag für eine Waldtherapie als Bestandteil einer multimodalen neurologischen Rehabilitation vorgestellt.}, } @article {pmid37827930, year = {2023}, author = {Cassereau, J and Bernard, E and Genestet, S and Chebbah, M and Le Clanche, S and Verschueren, A and Couratier, P}, title = {Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.}, journal = {Revue neurologique}, volume = {179}, number = {10}, pages = {1134-1144}, doi = {10.1016/j.neurol.2023.07.011}, pmid = {37827930}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Riluzole/therapeutic use ; Motor Neurons ; Diagnosis, Differential ; Phenylbutyrates ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).}, } @article {pmid37831200, year = {2023}, author = {Latorre-Rodríguez, AR and Huang, J and Schaheen, L and Smith, MA and Hashimi, S and Bremner, RM and Mittal, SK}, title = {Diagnosis and management of anastomotic leaks after Ivor Lewis esophagectomy: a single-center experience.}, journal = {Langenbeck's archives of surgery}, volume = {408}, number = {1}, pages = {397}, pmid = {37831200}, issn = {1435-2451}, mesh = {Humans ; *Anastomotic Leak/diagnosis/etiology/therapy ; Esophagectomy/adverse effects ; *Esophageal Neoplasms/surgery ; Endoscopy, Gastrointestinal/adverse effects ; Retrospective Studies ; Postoperative Complications/diagnosis/epidemiology/etiology ; Anastomosis, Surgical/adverse effects ; Treatment Outcome ; }, abstract = {PURPOSE: Esophageal anastomotic leaks (ALs) after esophagectomy are a common and serious complication. The incidence, diagnostic approach, and management have changed over time. We described the diagnosis and management of patients who developed an esophageal AL after an Ivor Lewis esophagectomy at our center.

METHODS: After IRB approval, we queried our prospectively maintained database for patients who developed an esophageal AL after esophagectomy from August 2016 through July 2022. Data pertaining to demographics, comorbidities, surgical and oncological characteristics, and clinical course were extracted and analyzed.

RESULTS: During the study period, 145 patients underwent an Ivor Lewis esophagectomy; 10 (6.9%) developed an AL, diagnosed a median of 7.5 days after surgery, and detected by enteric contents in wound drains (n = 3), endoscopy (n = 3), CT (n = 2), and contrast esophagogram (n = 2). Nine patients (90%) had an increasing white blood cell count and additional signs of sepsis. One asymptomatic patient was identified by contrast esophagography. All patients received enteral nutritional support, intravenous antibiotics, and antifungals. Primary treatment of ALs included endoscopic placement of a self-expanding metal stent (SEMS; n = 6), surgery (n = 2), and SEMS with endoluminal vacuum therapy (n = 2). One patient required surgery after SEMS placement. The median length of ICU and total hospital stays were 11.5 and 22.5 days, respectively. There was no 30-day mortality.

CONCLUSION: The incidence of esophageal ALs at our center is similar to that of other high-volume centers. Most ALs can be managed without surgery; however, ALs remain a significant source of postoperative morbidity despite clinical advancements that have improved mortality.}, } @article {pmid37833013, year = {2023}, author = {Bryukhovetskiy, AS and Grivtsova, LY and Bogachev, SS and Ustyugov, AA and Nebogatikov, VO and Shurdov, MA}, title = {Technology of genomic balancing of chromatin of autologous hematopoietic stem cells for gene therapy of fatal immune-mediated diseases of civilization, extended life expectancy and sudden human death prevention.}, journal = {International review of neurobiology}, volume = {172}, number = {}, pages = {237-284}, doi = {10.1016/bs.irn.2023.07.005}, pmid = {37833013}, issn = {2162-5514}, mesh = {Rats ; Humans ; Animals ; Mice ; *Chromatin/metabolism ; *Quality of Life ; Rats, Wistar ; Hematopoietic Stem Cells/metabolism ; Genetic Therapy ; Life Expectancy ; Genomics ; DNA/metabolism ; Technology ; Death, Sudden ; Civilization ; }, abstract = {A biotechnology for personalized ex vivo gene therapy based on molecular genomic balancing of hematopoietic stem cell (HSC) chromatin with nucleosome monomers of human genomic DNA (hDNA[nmr]) has been developed and implemented in the clinic to change (to "correct") mutant chromosome loci genomes of dominant HSC clones that form mono- and oligoclonal hematopoiesis during aging and major (oncological, cardiovascular, neurodegenerative and autoimmune) fatal immune-mediated diseases of civilization. A fundamentally new biotechnological approach has been applied to the delivery of genetic material into eukaryotic stem and progenitor cells by establishing an artificial "recombinogenic situation" in them to induce homologous recombination (equivalent replacement) of mutant DNA regions with healthy hDNA[nmr]. In experimental preclinical trials, the effectiveness of genomic balancing technology has been proven to reduce the risk of sudden death in old animals and to increase the lifespan of outbred mice by 30% and Wistar rats by 57%. The improvement in their quality of life, compared with the control, is explained by an increase in the telomeric regions of the HSCs and HPCs chromosomes by 1.5-2 times. The potential of the technology to slow down the hereditary neurodegenerative diseases on the model of amyotrophic lateral sclerosis is shown. The effectiveness of this technology in clinical practice is presented on the example of a terminal patient with stage 4 neuroendocrine cancer. This technology used in the treatment of a number of oncological, neurodegenerative, autoimmune and hereditary diseases with clonal hematopoiesis is able to arrest the progression of the disease, prevent its recurrence, prolong the active life of a person, increase the average life expectancy and prevent sudden death.}, } @article {pmid37836771, year = {2023}, author = {Colombo, E and Olla, S and Minnelli, C and Formato, A and Veroni, C and Corbisiero, S and Pericolo, M and Siguri, C and Mobbili, G and Agresti, C and Seneci, P}, title = {Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836771}, issn = {1420-3049}, support = {2017/R/2//Fondazione Italiana Sclerosi Multipla/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oxidative Stress ; Esters/pharmacology ; }, abstract = {Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N[1]-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.}, } @article {pmid37838979, year = {2024}, author = {Jagadish, A and Shankaranarayana, AM and Natarajan, M and Solomon, JM}, title = {Transcranial direct current stimulation for fatigue in neurological conditions: A systematic scoping review.}, journal = {Physiotherapy research international : the journal for researchers and clinicians in physical therapy}, volume = {29}, number = {1}, pages = {e2054}, doi = {10.1002/pri.2054}, pmid = {37838979}, issn = {1471-2865}, mesh = {Humans ; *Brain Injuries, Traumatic ; Fatigue/therapy/etiology ; *Multiple Sclerosis/complications/therapy ; *Parkinson Disease ; Quality of Life ; *Stroke ; *Transcranial Direct Current Stimulation/adverse effects ; }, abstract = {BACKGROUND AND PURPOSE: Fatigue following neurological conditions negatively impacts daily activities, reducing overall quality of life. Transcranial direct current stimulation (tDCS) for fatigue management is still underexplored. This scoping review explores its use in managing fatigue among various neurological conditions.

METHODS: A thorough literature search was carried out using PubMed, Scopus, CINAHL, Web of Science, Embase, ProQuest, and the Cochrane Library. Google Scholar and clinicaltrials.gov were manually searched for gray literature and ongoing trials, respectively. Regardless of the study design, all studies utilizing tDCS for the management of fatigue in various neurological conditions were considered. Two reviewers independently screened all the studies, following which the data were retrieved.

RESULTS: Studies employing tDCS for fatigue management across neurological conditions is as follows: Multiple sclerosis (MS) (n = 28, 66%), stroke (n = 5, 12%), Parkinson's disease (PD) (n = 4, 10%), post-polio syndrome (PPS) (n = 2, 5%), traumatic brain injury (TBI) (n = 2, 5%), and amyotrophic lateral sclerosis (n = 1, 2%). All the studies used anodal stimulation, with the common stimulation site being the left dorsolateral prefrontal cortex for MS, stroke, and PD. A stimulation intensity of 1.0-4.0 mA with a duration ranging from 15 to 30 min in 1 to 24 sessions were commonly reported. The Fatigue Severity Scale (n = 21) and Modified Fatigue Impact Scale (n = 17) were frequently implemented outcome measures. Regardless of the study design, 36/42 (85.7%) studies reported an improvement in fatigue scores in the tDCS group. The common adverse events noted were tingling (n = 8, 35%), headache (n = 6, 26%), and itching (n = 6, 26%).

DISCUSSION: Application of tDCS for fatigue was explored in individuals with stroke, PD, PPS, and TBI after MS. Even though a wide range of treatment parameters and outcome measures were adopted to assess and target fatigue, tDCS proves to have a promising role in alleviating this symptom.}, } @article {pmid37842553, year = {2023}, author = {Zucchi, E and Musazzi, UM and Fedele, G and Martinelli, I and Gianferrari, G and Simonini, C and Fini, N and Ghezzi, A and Caputo, M and Sette, E and Vacchiano, V and Zinno, L and Anceschi, P and Canali, E and Vinceti, M and Ferro, S and Mandrioli, J and , }, title = {Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102256}, pmid = {37842553}, issn = {2589-5370}, abstract = {BACKGROUND: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only.

METHODS: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients.

FINDINGS: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae.

INTERPRETATION: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug.

FUNDING: Emilia-Romagna Region.}, } @article {pmid37845449, year = {2023}, author = {Shin, J and Kang, H and Kim, S}, title = {Primo Vessels Inside Lymphatic Vessels Are Absent in an ALS Mouse Model.}, journal = {Advances in experimental medicine and biology}, volume = {1438}, number = {}, pages = {113-117}, pmid = {37845449}, issn = {0065-2598}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; *Lymphatic Vessels ; Lymph Nodes ; Oxygen/analysis ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the central nervous system. It is also a representative rare disease among degenerative diseases of the nervous system. Although many drugs for the treatment of degenerative brain diseases are being developed, they are not delivered correctly to the target due to the blood-brain barrier. The present study aimed to analyze changes in the primo vascular system (PVS) in ALS mice with symptoms and the partial oxygen pressure (pO2) in normal mice. In normal mice, we consistently observed primo vessels in lymphatic vessels (L-PVS). However, in ALS mice with symptoms, L-PVS were mostly lost, rendering them difficult to observe. The pO2 of the L-PVS in normal mice was significantly higher than that of normal dermis and lymph nodes.In conclusion, the relatively higher oxygen levels measured in the L-PVS than in normal dermis and lymph nodes suggest a role for the PVS in oxygen transport and enable a hypothesis that the L-PVS can function as a drug delivery pathway.}, } @article {pmid37847372, year = {2023}, author = {Sattler, R and Traynor, BJ and Robertson, J and Van Den Bosch, L and Barmada, SJ and Svendsen, CN and Disney, MD and Gendron, TF and Wong, PC and Turner, MR and Boxer, A and Babu, S and Benatar, M and Kurnellas, M and Rohrer, JD and Donnelly, CJ and Bustos, LM and Van Keuren-Jensen, K and Dacks, PA and Sabbagh, MN and , }, title = {Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.}, journal = {Neurology and therapy}, volume = {12}, number = {6}, pages = {1821-1843}, pmid = {37847372}, issn = {2193-8253}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; ZIAAG000933-15/AG/NIA NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; R35 NS116846/NS/NINDS NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, abstract = {A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.}, } @article {pmid37849894, year = {2023}, author = {Fang, M and Deibler, SK and Nana, AL and Vatsavayai, SC and Banday, S and Zhou, Y and Almeida, S and Weiss, A and Brown, RH and Seeley, WW and Gao, FB and Green, MR}, title = {Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1251228}, pmid = {37849894}, issn = {1662-4548}, support = {R01 NS104437/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 GM035490/GM/NIGMS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.}, } @article {pmid37851042, year = {2023}, author = {Izenberg, A}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1538-1563}, pmid = {37851042}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Biomarkers ; }, abstract = {OBJECTIVE: This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases.

LATEST DEVELOPMENTS: A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023.

ESSENTIAL POINTS: There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.}, } @article {pmid37855859, year = {2024}, author = {Vieira, TCRG and Barros, CA and Domingues, R and Outeiro, TF}, title = {PrP meets alpha-synuclein: Molecular mechanisms and implications for disease.}, journal = {Journal of neurochemistry}, volume = {168}, number = {8}, pages = {1625-1639}, doi = {10.1111/jnc.15992}, pmid = {37855859}, issn = {1471-4159}, support = {SFB1286 (B8)//Deutsche Forschungsgemeinschaft/ ; EXC 2067/1-390729940//Deutsche Forschungsgemeinschaft/ ; //Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; }, mesh = {Humans ; *alpha-Synuclein/metabolism ; Animals ; Synucleinopathies/metabolism/pathology ; Prion Proteins/metabolism ; }, abstract = {The discovery of prions has challenged dogmas and has revolutionized our understanding of protein-misfolding diseases. The concept of self-propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha-synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor-mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrP[C]) may play a crucial role in this process. PrP[C] has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrP[C] and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrP[C]'s role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrP[C] may offer potential treatment options for synucleinopathies.}, } @article {pmid37862202, year = {2024}, author = {Tarot, P and Lasbleiz, C and Liévens, JC}, title = {NRF2 signaling cascade in amyotrophic lateral sclerosis: bridging the gap between promise and reality.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1006-1012}, pmid = {37862202}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.}, } @article {pmid37862205, year = {2024}, author = {Romano, R and Bucci, C}, title = {Antisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1027-1035}, pmid = {37862205}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Currently, there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide. Therefore, it is necessary to find new therapeutic approaches, and antisense therapies offer this possibility, having the great advantage of not modifying cellular genome and potentially being safer. Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases. The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases, with a focus on those antisense therapies that have already received the approval of the U.S. Food and Drug Administration.}, } @article {pmid37862206, year = {2024}, author = {Hu, Y and Chen, W and Wei, C and Jiang, S and Li, S and Wang, X and Xu, R}, title = {Pathological mechanisms of amyotrophic lateral Sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1036-1044}, pmid = {37862206}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.}, } @article {pmid37862967, year = {2023}, author = {Rabeh, N and Hajjar, B and Maraka, JO and Sammanasunathan, AF and Khan, M and Alkhaaldi, SMI and Mansour, S and Almheiri, RT and Hamdan, H and Abd-Elrahman, KS}, title = {Targeting mGluR group III for the treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115733}, doi = {10.1016/j.biopha.2023.115733}, pmid = {37862967}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Signal Transduction/physiology ; Glutamic Acid ; Neurotransmitter Agents ; Neurons ; *Receptors, Metabotropic Glutamate/physiology ; }, abstract = {Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.}, } @article {pmid37864389, year = {2024}, author = {Xiao, F and He, Z and Wang, S and Li, J and Fan, X and Yan, T and Yang, M and Yang, D}, title = {Regulatory mechanism of circular RNAs in neurodegenerative diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14499}, pmid = {37864389}, issn = {1755-5949}, support = {//China Scholarship Council/ ; //National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics ; RNA, Circular/metabolism ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease ; Biomarkers ; }, abstract = {BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins.

AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases.

METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases.

RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD.

CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.}, } @article {pmid37868386, year = {2023}, author = {Hoxhaj, P and Hastings, N and Kachhadia, MP and Gupta, R and Sindhu, U and Durve, SA and Azam, A and Auz Vinueza, MJ and Bhuvan, and Win, SH and Rathod, DC and Afsar, AP}, title = {Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects.}, journal = {Cureus}, volume = {15}, number = {9}, pages = {e45489}, pmid = {37868386}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease requiring a multidisciplinary treatment approach and a collaborative therapeutic effort. A combination of both upper and lower motor neuron degeneration ultimately leads to respiratory failure, similar to other dementia-type neurodegenerative diseases. The aim of this paper is to pioneer current ALS research by carrying out a narrative literature review of the current treatment modalities of the disease. Through these efforts, we hope to condense the most pertinent information regarding current treatments and enhance the management of ALS patients as a whole, giving these patients a better quality of life as the search for a cure continues. We used a Pubmed search strategy and specific MeSH terms for the selection of the literature articles using the keywords "ALS," "new treatment," "treatment," and "symptomatic treatment." A combination of pharmaceutical interventions, psychological support, and physical rehabilitation has been most effective in enhancing the quality of life of patients with ALS (PALS). Among potential pharmacological therapies, only a few have been approved by the US Food and Drug Administration(FDA) to be used to treat ALS and its symptoms. Other treatment modalities being considered include gene therapy, cellular therapy, psychological therapy, physical therapy, and speech therapy, alongside robotics, alternative feeding methods, and communication devices.}, } @article {pmid37872794, year = {2023}, author = {You, FL and Xia, GF and Cai, J}, title = {Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report.}, journal = {Current Alzheimer research}, volume = {20}, number = {5}, pages = {371-378}, doi = {10.2174/1567205020666230811092906}, pmid = {37872794}, issn = {1875-5828}, mesh = {Male ; Humans ; Aged ; *Frontotemporal Dementia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases ; Memantine/therapeutic use ; Mutation/genetics ; Neuropsychological Tests ; Sodium ; Cyclins/genetics ; }, abstract = {BACKGROUND: Frontal, temporal lobe dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases. Studies have found that CCNF mutations have been found in patients with familial and sporadic ALS and FTD. Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive deterioration of personality, social behaviour, and cognitive function, which is most closely related to genetic factors. As the early symptoms of bvFTD are highly heterogeneous, the condition is often misdiagnosed as Alzheimer's disease or psychiatric disorders. In this study, a bvFTD patient had a CCNF gene mutation, which led to ubiquitinated protein accumulation and ultimately caused neurodegenerative disease. Genetic detection should be improved urgently for bvFTD patients and family members to provide a clinical reference for early diagnosis of frontotemporal dementia.

CASE PRESENTATION: In this case, the patient was 65 years old with an insidious onset, early-onset memory loss, a significant decline in the episodic memory, an early AD diagnosis, and oral treatment with donepezil hydrochloride for 3 years with poor efficacy, followed by a change to oral memantine hydrochloride tablets, which controlled the condition for several months. His medication was switched to sodium oligomannate capsules, and his condition was gradually controlled, but no significant improvement was observed. After spontaneous drug withdrawal, the patient's condition progressed rapidly; therefore, he visited our hospital and underwent neuropsychological tests for moderate to severe cognitive impairment. AD cerebrospinal fluid markers showed no significant abnormalities, and cranial MRI revealed frontotemporal lobe atrophy and decreased hippocampal volume. Genetic testing for the presence of the CCNF gene revealed a c.1532C > A (p. T511N) heterozygous variant, which might be a diagnostic criterion for bvFTD. Therefore, the patient's symptoms recurred after transient improvement with the combination of donepezil, oral memantine hydrochloride tablets, and sodium oligomannate, but his overall condition was improved compared to that before, and this treatment regimen was continued to observe changes during the follow-up.

CONCLUSION: The early clinical manifestations of bvFTD are complex and variable, and the condition is easily misdiagnosed, thus delaying treatment. Therefore, for patients with a high clinical suspicion of FTD, in addition to a detailed understanding of their medical history and family history and improvement of relevant examinations, genetic testing should be performed as early as possible to help confirm the diagnosis. For diseases closely related to genes, genetic testing of other family members should be optimised as much as possible to allow early diagnosis and intervention and guide fertility in the next generation.}, } @article {pmid37873269, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37873269}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10[-39]; OR=4.73, p = 2 × 10[-10]; OR=2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid37874905, year = {2023}, author = {Harrison, D and Billinton, A and Bock, MG and Doedens, JR and Gabel, CA and Holloway, MK and Porter, RA and Reader, V and Scanlon, J and Schooley, K and Watt, AP}, title = {Discovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders.}, journal = {Journal of medicinal chemistry}, volume = {66}, number = {21}, pages = {14897-14911}, doi = {10.1021/acs.jmedchem.3c01398}, pmid = {37874905}, issn = {1520-4804}, mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology ; Neuroinflammatory Diseases ; Brain/metabolism ; Esters ; }, abstract = {The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, have been shown to have a component driven by NLRP3 inflammasome activation. Diseases such as these with large unmet medical needs have resulted in an interest in inhibiting the NLRP3 inflammasome as a potential pharmacological treatment, but to date, no marketed drugs specifically targeting NLRP3 have been approved. Furthermore, the requirement for CNS-penetrant molecules adds additional complexity to the search for NLRP3 inflammasome inhibitors suitable for clinical investigation of neuroinflammatory disorders. We designed a series of ester-substituted carbamate compounds as selective NLRP3 inflammasome inhibitors, leading to NT-0796, an isopropyl ester that undergoes intracellular conversion to NDT-19795, the carboxylic acid active species. NT-0796 was shown to be a potent and selective NLRP3 inflammasome inhibitor with demonstrated in vivo brain penetration.}, } @article {pmid37875101, year = {2024}, author = {Karacaoglu, C and Ersoy, S and Pala, E and Engin, VS}, title = {Evaluation of the Effectiveness of Wet Cupping Therapy in Fibromyalgia Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {10-19}, doi = {10.1159/000534637}, pmid = {37875101}, issn = {2504-2106}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Cupping Therapy ; *Fibromyalgia/therapy ; Quality of Life ; Treatment Outcome ; Adolescent ; Young Adult ; Aged ; }, abstract = {INTRODUCTION: The aim of this study was to investigate the efficacy of wet cupping therapy (WCT) in patients diagnosed with fibromyalgia syndrome (FMS) as a complementary method in fibromyalgia treatment.

MATERIALS AND METHODS: A total of 120 participants between 18 and 65 years who were diagnosed with FMS were included in the study. They were randomized into two groups: 60 patients as the intervention and 60 patients as the control group. Each participant in the intervention group received 3 sessions of WCT once a month in addition to their ongoing treatment whereas the control group received only routine medical treatment. The evaluation was conducted in both groups based on the fibromyalgia impact questionnaire (FIQ), visual analog scale (VAS), and quality of life scale (QoL) parameters initially (at 0th week) and 1 week after the WCT sessions (at the 10th week). For the comparison of quantitative variables showing a normal distribution between the two groups, the Student's t test was used, while the Mann-Whitney U test was employed for variables not showing a normal distribution. The χ2 test and Continuity (Yates) Correction were used for the comparison of qualitative data. The significance level was set at p < 0.05.

RESULTS: The study included 107 female and 13 male participants, with a mean age of 45.79 ± 8.49 years. When comparing the pretreatment FIQ, VAS, and QoL scores with the scores obtained after three sessions of WCT, it was observed that in the WCT group, the FIQ and VAS values significantly decreased compared to the control group while the QoL significantly increased compared to the control group (p < 0.001 in all).

CONCLUSION: The findings obtained from this study indicate that WCT can be an effective treatment option for patients with FMS.

UNLABELLED: EinleitungMit dieser Studie soll die Wirksamkeit der blutigen Schröpftherapie (wet cupping therapy, WCT) bei Patienten mit diagnostiziertem Fibromyalgie-Syndrom (FMS) als komplementäre Methode in der Fibromyalgie-Behandlung untersucht werden.Material und MethodenInsgesamt wurden 120 Teilnehmer mit diagnostiziertem FMS zwischen 18 und 65 Jahren in die Studie aufgenommen. Diese wurden randomisiert zwei Gruppen zugeordnet: 60 Patienten wurden der Interventionsgruppe zugewiesen und 60 Patienten der Kontrollgruppe. Alle Teilnehmer der Interventionsgruppe erhielten einmal im Monat drei Sitzungen WCT zusätzlich zu ihrer laufenden Therapie, während die Kontrollgruppe lediglich die Standardbehandlung erhielt. Die Bewertung erfolgte in beiden Gruppen anhand des Fibromyalgia Impact Questionnaire (FIQ), der Visuellen Analogskala (VAS) und der Parameter der Quality of Life (QoL) Scale zu Beginn (in Woche 0) und eine Woche nach den WCT-Sitzungen (in Woche 10). Für den Vergleich von quantitativen Variablen, die eine Normalverteilung zwischen den beiden Gruppen aufwiesen, wurde der Student’s t-Test verwendet, während bei Variablen ohne Normalverteilung der Mann-Whitney-U-Test zur Anwendung kam. Qualitative Daten wurden mit dem Chi-Quadrat-Test und der Kontinuitätskorrektur (Yates) verglichen. Das Signifikanzniveau wurde auf p < 0,05 festgelegt.ErgebnisseIn die Studie wurden 107 Frauen und 13 Männer mit einem Durchschnittsalter von 45,79 ± 8,49 Jahren aufgenommen. Beim Vergleich der FIQ-, VAS- und QoL-Werte vor der Behandlung mit den nach drei WCT-Sitzungen erhobenen Werten zeigte sich in der WCT-Gruppe ein signifikanter Rückgang der FIQ- und VAS-Werte im Vergleich zur Kontrollgruppe, wohingegen bei der QoL ein signifikanter Anstieg gegenüber der Kontrollgruppe zu beobachten war (p < 0,001 in allen Fällen).SchlussfolgerungDie Ergebnisse dieser Studie deuten darauf hin, dass die WCT eine wirksame therapeutische Option für Patienten mit FMS sein kann.}, } @article {pmid37875807, year = {2023}, author = {Loubet, I and Meyer, L and Michel, S and Pernin, F and Carrère, S and Barrès, B and Le Corre, V and Délye, C}, title = {A high diversity of non-target site resistance mechanisms to acetolactate-synthase (ALS) inhibiting herbicides has evolved within and among field populations of common ragweed (Ambrosia artemisiifolia L.).}, journal = {BMC plant biology}, volume = {23}, number = {1}, pages = {510}, pmid = {37875807}, issn = {1471-2229}, support = {DRAGON 29001099-1944//Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement/ ; DRAGON 29001099-1944//ACTA - Les instituts techniques agricoles/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; }, mesh = {Humans ; Ambrosia/genetics ; *Herbicides/pharmacology ; *Acetolactate Synthase ; Transcriptome ; Herbicide Resistance/genetics ; Lactates ; }, abstract = {BACKGROUND: Non-target site resistance (NTSR) to herbicides is a polygenic trait that threatens the chemical control of agricultural weeds. NTSR involves differential regulation of plant secondary metabolism pathways, but its precise genetic determinisms remain fairly unclear. Full-transcriptome sequencing had previously been implemented to identify NTSR genes. However, this approach had generally been applied to a single weed population, limiting our insight into the diversity of NTSR mechanisms. Here, we sought to explore the diversity of NTSR mechanisms in common ragweed (Ambrosia artemisiifolia L.) by investigating six field populations from different French regions where NTSR to acetolactate-synthase-inhibiting herbicides had evolved.

RESULTS: A de novo transcriptome assembly (51,242 contigs, 80.2% completeness) was generated as a reference to seek genes differentially expressed between sensitive and resistant plants from the six populations. Overall, 4,609 constitutively differentially expressed genes were identified, of which none were common to all populations, and only 197 were shared by several populations. Similarly, population-specific transcriptomic response was observed when investigating early herbicide response. Gene ontology enrichment analysis highlighted the involvement of stress response and regulatory pathways, before and after treatment. The expression of 121 candidate constitutive NTSR genes including CYP71, CYP72, CYP94, oxidoreductase, ABC transporters, gluco and glycosyltransferases was measured in 220 phenotyped plants. Differential expression was validated in at least one ragweed population for 28 candidate genes. We investigated whether expression patterns at some combinations of candidate genes could predict phenotype. Within populations, prediction accuracy decreased when applied to an additional, independent plant sampling. Overall, a wide variety of genes linked to NTSR was identified within and among ragweed populations, of which only a subset was captured in our experiments.

CONCLUSION: Our results highlight the complexity and the diversity of NTSR mechanisms that can evolve in a weed species in response to herbicide selective pressure. They strongly point to a non-redundant, population-specific evolution of NTSR to ALS inhibitors in ragweed. It also alerts on the potential of common ragweed for rapid adaptation to drastic environmental or human-driven selective pressures.}, } @article {pmid37877583, year = {2024}, author = {Haldar, S and Khan, AH and De, A and Reichmayr, F and Morag, A and Yu, M and Schneemann, A and Kaskel, S}, title = {Fluorinated Benzimidazole-Linked Highly Conjugated Polymer Enabling Covalent Polysulfide Anchoring for Stable Sulfur Batteries.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {2}, pages = {e202302779}, doi = {10.1002/chem.202302779}, pmid = {37877583}, issn = {1521-3765}, support = {SPP2248//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Sulfur is one of the most abundant and economical elements in the p-block family and highly redox active, potentially utilizable as a charge-storing electrode with high theoretical capacities. However, its inherent good solubility in many electrolytes inhibits its accessibility as an electrode material in typical metal-sulfur batteries. In this work, the synthetically designed fluorinated porous polymer, when treated with elemental sulfur through a well-known nucleophilic aromatic substitution mechanism (SN Ar), allows for the covalent integration of polysulfides into a highly conjugated benzimidazole polymer by replacing the fluorine atoms. Chemically robust benzimidazole linkages allow such harsh post-synthetic treatment and facilitate the electronic activation of the anchored polysulfides for redox reactions under applied potential. The electrode amalgamated with sulfurized polymer mitigates the so-called polysulfide shuttle effect in the lithium-sulfur (Li-S) battery and also enables a reversible, more environmentally friendly, and more economical aluminum-sulfur (Al-S) battery that is configured with mostly p-block elements as cathode, anode, and electrolytes. The improved cycling stabilities and reduction of the overpotential in both cases pave the way for future sustainable energy storage solutions.}, } @article {pmid37879951, year = {2023}, author = {Liu, JY and Lu, YR and Guo, J and Li, H and Wang, Y and Zhao, YQ and Li, J and Wang, Q}, title = {Effect of electroacupuncture intervention on the spinal cord PPIA/NF-κB signaling pathway in mice with amyotrophic lateral sclerosis.}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {48}, number = {10}, pages = {1009-1016}, doi = {10.13702/j.1000-0607.20230251}, pmid = {37879951}, issn = {1000-0607}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; DNA-Binding Proteins/metabolism ; *Electroacupuncture ; Motor Neurons/metabolism ; NF-kappa B/genetics/metabolism ; Riluzole ; Signal Transduction ; Spinal Cord ; Superoxide Dismutase-1/genetics/metabolism ; Peptidylprolyl Isomerase/metabolism ; }, abstract = {OBJECTIVES: To observe the effects of electroacupuncture (EA) on motor function, expression of extracellular cyclophile A(PPIA) and PPIA/nuclear factor-κB (NF-κB) signaling pathway in spinal cord of amyotrophic la-teral sclerosis (ALS) mice, so as to explore the mechanism of EA intervention in regulating extracellular PPIA on neuroinflammation in ALS mice.

METHODS: Thirty ALS-SOD1[G93A] mice with hSOD1-G93A gene were randomly divided into model, EA and Riluzole groups , with 10 mice in each group, and other 10 ALS-SOD1[G93A] negative mice were used as the blank group. EA was applied to bilateral "Yanglingquan"(GB34) and "Zusanli"(ST36) for 20 min once daily, 5 days a week for 2 weeks. In the Riluzole group, riluzole solution (30 mg·kg[-1]·d[-1]) was administrated intragastrically, and the treatment time was the same as that in the EA group.Rotating rod experiment and open field experiment were used to evaluate the changes in motor function of mice .The morphology of motor neurons in the anterior horn of spinal cord was observed by HE staining.The relative protein expression levels of PPIA, TDP-43 and NF-κB in the spinal cord were detected by Western blot.The positive expression level of TDP-43 in the spinal cord was detected by immunohistochemistry. The positive expression level of PPIA in spinal cord was marked by immunofluorescence. Serum PPIA content was determined by ELISA.

RESULTS: Compared with the blank group, the time of rod dropping and the total distance of open field movement in the model group were shortened (P<0.01), the number of motor neurons in the anterior horn of the spinal cord was reduced, the cell morphology was incomplete, the cell body was atrophied, the protein expression and positive expression of TDP-43 were increased (P<0.01), the protein expressions of PPIA and NF-κB in the spinal cord were increased(P<0.01), the serum content of PPIA and immunofluorescence expression of PPIA in spinal cord were increased (P<0.01). Compared with the model group, the time of rod dropping and the total distance of open field movement of mice in the EA group and the Riluzole group were prolonged (P<0.05, P<0.01), and the injury of motor neuron in the anterior horn of the spinal cord was decreased, the protein expression and positive expression of TDP-43 in the spinal cord were decreased (P<0.05, P<0.01)；the relative expression levels of PPIA and NF-κB proteins were decreased (P<0.05, P<0.01), and the content of PPIA in serum and the immunofluorescence expression of PPIA in the spinal cord were decreased (P<0.05, P<0.01) in the EA group；the relative protein expression of NF-κB and fluorescence expression of PPIA in spinal cord of mice in the Riluzole group were decreased (P<0.05).

CONCLUSIONS: EA intervention can improve motor function in ALS mice, and its mechanism may be related to the inhibition of PPIA/NF-κB signaling pathway by EA to alleviating neuroinflammatory response.}, } @article {pmid37882288, year = {2023}, author = {Barco-Antoñanzas, M and Font-Farre, M and Eceiza, MV and Gil-Monreal, M and van der Hoorn, RAL and Royuela, M and Zabalza, A}, title = {Cysteine proteases are activated in sensitive Amaranthus palmeri populations upon treatment with herbicides inhibiting amino acid biosynthesis.}, journal = {Physiologia plantarum}, volume = {175}, number = {5}, pages = {e13993}, doi = {10.1111/ppl.13993}, pmid = {37882288}, issn = {1399-3054}, support = {//Eusko Jaurlaritza/ ; 2020 117723-RB-100//Ministerio de Ciencia e Innovación/ ; AGL2016-77531-R//Ministerio de Economía y Competitividad/ ; }, mesh = {Herbicide Resistance ; *Amaranthus/metabolism ; *Herbicides/pharmacology/metabolism ; *Cysteine Proteases/metabolism/pharmacology ; }, abstract = {The herbicides glyphosate and pyrithiobac inhibit the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the aromatic amino acid biosynthetic pathway and acetolactate synthase (ALS) in the branched-chain amino acid biosynthetic pathway, respectively. Here we characterise the protease activity profiles of a sensitive (S), a glyphosate-resistant (GR) and a multiple-resistant (MR) population of Amaranthus palmeri in response to glyphosate and pyrithiobac. Amino acid accumulation and cysteine protease activities were induced with both herbicides in the S population and with pyrithiobac in the GR population, suggesting that the increase in cysteine proteases is responsible for the increased degradation of the available proteins and the observed increase in free amino acids. Herbicides did not induce any changes in the proteolytic activities in the populations with target-site resistance, indicating that this effect was only induced in sensitive plants.}, } @article {pmid37882882, year = {2023}, author = {Wang, Y and Sun, S and Zhai, J and Liu, Y and Song, C and Sun, C and Li, Q and Liu, J and Jiang, H and Liu, Y}, title = {scAAV9-VEGF alleviates symptoms of amyotrophic lateral sclerosis (ALS) mice through regulating aromatase.}, journal = {Experimental brain research}, volume = {241}, number = {11-12}, pages = {2817-2827}, pmid = {37882882}, issn = {1432-1106}, support = {ZR2020QH126//Natural Science Foundation of Shandong Province Youth Fund/ ; ZR2020QH124//Natural Science Foundation of Shandong Province Youth Fund/ ; 2019ZC010137//Zibo city key research and development plan/ ; 2021Q048//TCM science and technology Project of Shandong Province/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Motor Neurons/physiology ; Vascular Endothelial Growth Factor A/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Aromatase/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Estrogens/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, chronic, progressive, and fatal neurodegenerative disease that leads to progressive atrophy and weakness of the muscles throughout the body. Herein, we found that the intrathecal injection of adeno-associated virus (AAV)-delivered VEGF in SOD1-G93A transgenic mice, as well as ALS mice, could significantly delay disease onset and preserve motor functions and neurological functions, thus prolonging the survival of mice models. Moreover, we found that VEGF treatment could induce the elevated expression of aromatase, which is a key enzyme in estrogen synthesis, in neurons but not in astrocytes. On the other hand, the changes in the expression of oxidative stress-related factors HO-1 and GCLM and autophagy-related proteins p62 and LC3II upon the administration of VEGF revealed the involvement of oxidative stress and autophagy underlying the downstream of the VEGF-induced mitigation of ALS. In conclusion, this study proved the protective effects of VEGF in the onset and development of ALS and revealed the involvement of estrogen, oxidative stress and autophagy in the VEGF-induced alleviation of ALS. Our results highlighted the potential of VEGF as a promising therapeutic agent in the treatment of ALS.}, } @article {pmid37885757, year = {2023}, author = {Krannich, T and Sarrias, MH and Ben Aribi, H and Shokrof, M and Iacoangeli, A and Al-Chalabi, A and Sedlazeck, FJ and Busby, B and Al Khleifat, A}, title = {VariantSurvival: a tool to identify genotype-treatment response.}, journal = {Frontiers in bioinformatics}, volume = {3}, number = {}, pages = {1277923}, pmid = {37885757}, issn = {2673-7647}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Motivation: For a number of neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribute to the lifecycle of drug development. Results: To this end, we introduce VariantSurvival, a tool that identifies changes in survival relative to structural variants within target genes. VariantSurvival matches annotated structural variants with genes that are clinically relevant to neurological diseases. A Cox regression model determines the change in survival between the placebo and clinical trial groups with respect to the number of structural variants in the drug target genes. We demonstrate the functionality of our approach with the exemplary case of the SETX gene. VariantSurvival has a user-friendly and lightweight graphical user interface built on the shiny web application package.}, } @article {pmid37887305, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, ML}, title = {lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887305}, issn = {2073-4409}, support = {RF1NS112719/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03AG064266/NH/NIH HHS/United States ; R01NS094535/NH/NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; R01NS088645/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Motor Neurons/metabolism ; Mutation/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, } @article {pmid37887320, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887320}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Arginine/metabolism ; C9orf72 Protein/genetics/metabolism ; Dipeptides/metabolism ; Motor Neurons/pathology ; Neuro-Oncological Ventral Antigen ; Proline/metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Betulinic Acid ; Nerve Tissue Proteins ; }, abstract = {C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes the production of proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to the molecular pathology characteristic of ALS. UNC13A is critical for maintaining the synaptic function of MNs. Most ALS patients have nuclear deletion of the splicing repressor TDP-43 in MNs, which causes inclusion of the cryptic exon (CE) of UNC13A mRNA, resulting in nonsense-mediated mRNA decay and reduced protein expression. Therefore, in this study, we explored the role of PR-DPR in CE inclusion of UNC13A mRNA. Our results showed that PR-DPR (PR50) induced CE inclusion and decreased the protein expression of UNC13A in human neuronal cell lines. We also identified an interaction between the RNA-binding protein NOVA1 and PR50 by yeast two-hybrid screening. NOVA1 expression is known to be reduced in patients with ALS. We found that knockdown of NOVA1 enhanced CE inclusion of UNC13A mRNA. Furthermore, the naturally occurring triterpene betulin can inhibit the interaction between NOVA1 and PR50, thus preventing CE inclusion of UNC13A mRNA and protein reduction in human neuronal cell lines. This study linked PR-DPR with CE inclusion of UNC13A mRNA and developed candidate therapeutic strategies for C9-ALS using betulin.}, } @article {pmid37890889, year = {2023}, author = {Ilieva, H and Vullaganti, M and Kwan, J}, title = {Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.}, journal = {BMJ (Clinical research ed.)}, volume = {383}, number = {}, pages = {e075037}, pmid = {37890889}, issn = {1756-1833}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Pathology, Molecular ; Disease Progression ; }, abstract = {Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.}, } @article {pmid37891966, year = {2023}, author = {Grossini, E and De Marchi, F and Venkatesan, S and Mele, A and Ferrante, D and Mazzini, L}, title = {Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891966}, issn = {2076-3921}, abstract = {Oxidative stress, the alteration of mitochondrial function, and the neurovascular unit (NVU), play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. We aimed to demonstrate the changes in the plasma redox system and nitric oxide (NO) in 32 new ALS-diagnosed patients in treatment with Acetyl-L-Carnitine (ALCAR) compared to healthy controls. We also evaluated the effects of plasma on human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. The analyses were performed at the baseline (T0), after three months (T1), and after six months (T2). In ALS patients at T0/T1, the plasma markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS) and 4-hydroxy nonenal (4-HNE) were higher, whereas the antioxidants, glutathione (GSH) and the glutathione peroxidase (GPx) activity were lower than in healthy controls. At T2, plasma TBARS and 4-HNE decreased, whereas plasma GSH and the GPx activity increased in ALS patients. As regards NO, the plasma levels were firmly lower at T0-T2 than those of healthy controls. Cell viability, and mitochondrial membrane potential in HUVEC/astrocytes treated with the plasma of ALS patients at T0-T2 were reduced, while the oxidant release increased. Those results, which confirmed the fundamental role of oxidative stress, mitochondrial function, and of the NVU in ALS pathogenesis, can have a double meaning, acting as disease markers at baseline and potential markers of drug effects in clinical practice and during clinical trials.}, } @article {pmid37891975, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891975}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//the Ministry of Science and Technology (Taiwan)/ ; DMR-111-140//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA50) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA50 interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA50, thus inhibiting NLRP3 inflammasome activity in GA50-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.}, } @article {pmid37893003, year = {2023}, author = {Wu, YS and Taniar, D and Adhinugraha, K and Tsai, LK and Pai, TW}, title = {Detection of Amyotrophic Lateral Sclerosis (ALS) Comorbidity Trajectories Based on Principal Tree Model Analytics.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893003}, issn = {2227-9059}, support = {MOST 111-2221-E-027 -113 -MY2//National Science and Technology Council/ ; }, abstract = {The multifaceted nature and swift progression of Amyotrophic Lateral Sclerosis (ALS) pose considerable challenges to our understanding of its evolution and interplay with comorbid conditions. This study seeks to elucidate the temporal dynamics of ALS progression and its interaction with associated diseases. We employed a principal tree-based model to decipher patterns within clinical data derived from a population-based database in Taiwan. The disease progression was portrayed as branched trajectories, each path representing a series of distinct stages. Each stage embodied the cumulative occurrence of co-existing diseases, depicted as nodes on the tree, with edges symbolizing potential transitions between these linked nodes. Our model identified eight distinct ALS patient trajectories, unveiling unique patterns of disease associations at various stages of progression. These patterns may suggest underlying disease mechanisms or risk factors. This research re-conceptualizes ALS progression as a migration through diverse stages, instead of the perspective of a sequence of isolated events. This new approach illuminates patterns of disease association across different progression phases. The insights obtained from this study hold the potential to inform doctors regarding the development of personalized treatment strategies, ultimately enhancing patient prognosis and quality of life.}, } @article {pmid37893165, year = {2023}, author = {De Marchi, F and Munitic, I and Vidatic, L and Papić, E and Rački, V and Nimac, J and Jurak, I and Novotni, G and Rogelj, B and Vuletic, V and Liscic, RM and Cannon, JR and Buratti, E and Mazzini, L and Hecimovic, S}, title = {Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893165}, issn = {2227-9059}, abstract = {Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.}, } @article {pmid37894774, year = {2023}, author = {Moțățăianu, A and Șerban, G and Andone, S}, title = {The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894774}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; Aged ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Fatty Acids, Volatile/metabolism ; Fatty Acids/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.}, } @article {pmid37901127, year = {2023}, author = {Aslam, A and Sarmad, E and Nawaz, A and Numan, A and Ahmad, A and Hassan, MA}, title = {Brait-Fahn-Schwartz Disease: A Unique Co-Occurrence of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Case reports in neurology}, volume = {15}, number = {1}, pages = {207-214}, pmid = {37901127}, issn = {1662-680X}, abstract = {The Parkinson's disease-amyotrophic lateral sclerosis (ALS) complex typically manifests as levodopa-responsive parkinsonism, followed by ALS. It is extremely rare for Parkinson's disease and ALS to coexist without other neurological disorders. Named after the scientists who first described this overlap of two neurodegenerative conditions, it is referred to as Brait-Fahn-Schwartz disease. Given its variable presentation, increasing rarity, and lack of any diagnostic test, it poses a diagnostic challenge for physicians. We present a case of a 55-year-old Pakistani male experiencing progressive quadriparesis with spastic lower limbs and flaccid upper limbs, in addition to the cardinal features of idiopathic Parkinson's disease. Since there is currently no cure available for either Parkinson's disease or ALS, all available treatment focuses on improving quality of life, which we achieved in our patient. This case is unique in being the first incidence of Parkinson's disease-ALS complex in a novel geographic region such as Pakistan, where genetic testing and cost constraints limit the diagnosis of rare disorders. The coexistence of extrapyramidal symptoms and pyramidal symptoms is uncommon. In such situations, physicians may overlook one group of symptoms, potentially leading to a misdiagnosis. This case highlights the value of a thorough physical examination and electrodiagnostic studies and suggests the association between Parkinson's disease and ALS. This case demonstrates the significance of understanding when Parkinson's disease symptoms start to appear in patients with ALS and the need to start dopaminergic therapy in those who had Parkinson's disease features before ALS to alleviate the suffering of an individual and enhance quality of life.}, } @article {pmid37904013, year = {2024}, author = {Chen, X and Luo, J and Zheng, W and Huang, Q and Du, C and Yuan, H and Xiao, F}, title = {Hyperhidrosis as the initial symptom in FUS mutation-associated amyotrophic lateral sclerosis: a case report and comprehensive literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1523-1527}, pmid = {37904013}, issn = {1590-3478}, mesh = {Female ; Humans ; Young Adult ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Hyperhidrosis/genetics ; Mutation ; *Neurodegenerative Diseases ; Quality of Life ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis.

METHOD: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted.

RESULT: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene.

CONCLUSION: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis.}, } @article {pmid37906785, year = {2022}, author = {Matamala, JM and Moreno-Roco, J and Acosta, I and Hughes, R and Lillo, P and Casar, JC and Earle, N}, title = {[Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis].}, journal = {Revista medica de Chile}, volume = {150}, number = {12}, pages = {1633-1646}, doi = {10.4067/s0034-98872022001201633}, pmid = {37906785}, issn = {0717-6163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/psychology ; *Neurodegenerative Diseases ; Quality of Life ; Palliative Care ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system, resulting in progressive weakness and muscle wasting. Despite the tremendous advances in physiopathological and clinical characterization, we do not have a curative treatment yet. The progressive and fatal course of ALS makes its management particularly complex and challenging given the diversity of symptoms presenting during the disease progression. The main goal in the treatment of ALS patients is to minimize morbidity and maximize the quality of life. Currently, a series of therapeutic interventions improve the quality of life and prolong survival, including multidisciplinary care, respiratory management, and disease-modifying therapy. Within the supportive interventions, weight maintenance through nutritional and metabolic support is critical. In addition, the management of neuropsychiatric manifestations and preservation of communicative capacity before speech loss are also crucial. Lastly, early palliative care intervention is essential to optimize symptomatic management. Anticipatory guidelines to face the inevitable patient deterioration should be devised. This article updates the main therapeutic strategies used in these patients, including evolving clinical trials with promising novel therapies.}, } @article {pmid37906991, year = {2023}, author = {Prohaska, S and Matthias, K}, title = {Effectiveness of Mindfulness-Based Stress Reduction as a Nondrug Preventive Intervention in Patients with Migraine: A Systematic Review with Meta-Analyses.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {525-534}, doi = {10.1159/000534653}, pmid = {37906991}, issn = {2504-2106}, mesh = {Adult ; Humans ; *Mindfulness ; Treatment Outcome ; *Migraine Disorders/prevention & control ; Headache ; Stress, Psychological ; }, abstract = {INTRODUCTION: Migraine is a neurological disorder characterized by recurrent, severe headaches that are often accompanied by other symptoms. There are various factors that can trigger a migraine in sufferers. Stress can be such a trigger. Drug and nondrug treatments are available for the preventive treatment of migraine. According to a German guideline, mindfulness can be recommended for the prophylaxis of migraine. Therefore, the aim was to investigate the effectiveness of mindfulness-based stress reduction (MBSR) in relation to patient-relevant outcomes in adult patients with migraine. Patient-relevant outcomes in this context are migraine frequency, headache intensity during a migraine attack, depressive symptoms, and quality of life.

MATERIAL AND METHODS: The conduct of this study was guided by the PRISMA 2020 statement. A systematic literature search for randomized controlled trials (RCTs) of the effectiveness of MBSR in adult migraine patients was conducted in December 2021 in three databases: MEDLINE via PubMed, the Cochrane Library, and Web of Science. In addition, a review of reference lists and a search of study registries were performed. The last search was conducted on October 7, 2022. In a two-step process, studies were selected based on predefined inclusion and exclusion criteria. The potential for bias was assessed using the Cochrane Risk of Bias Tool 2. The results were summarized descriptively and by means of quantitative synthesis.

RESULTS: Four RCTs with a total of 275 patients and the follow-up publication of one of these studies were included. The risk of bias in one study each was judged to be low or of some concern and high in two studies. Four studies were included in the quantitative analysis. For the endpoint migraine frequency, the meta-analytic summary of three studies failed to show a statistically significant benefit for MBSR (SMD: -0.23; 95% CI: -0.79 to 0.32). For the endpoint depressive symptoms, a meta-analytic summary of three studies showed a statistically significant benefit for MBSR (SMD: -0.59; 95% CI: -0.93 to -0.25). No study had examined the severity of headaches during a migraine episode.

CONCLUSION: Some results suggest that migraine patients may benefit from MBSR. However, the evidence base is currently insufficient for recommendations on the use of MBSR as a nondrug treatment option. Further adequately powered, high-quality RCTs are needed.

UNLABELLED: EinleitungMigräne ist eine neurologische Erkrankung, die durch wiederkehrende, starke Kopfschmerzen gekennzeichnet ist, die häufig von anderen Symptomen einhergehen. Es gibt verschiedene Faktoren, die bei den Betroffenen eine Migräne auslösen können. Ein solcher Auslöser kann Stress sein. Für die präventive Behandlung der Migräne stehen medikamentöse und nichtmedikamentöse Verfahren zur Verfügung. Laut einer deutschen Leitlinie kann Achtsamkeit zur Prophylaxe von Migräne empfohlen werden. Ziel der Studie war es daher, die Wirksamkeit von achtsamkeitsbasierter Stressreduktion (MBSR) in Bezug auf patientenrelevante Outcomes bei erwachsenen Migränepatienten zu untersuchen. Patientenrelevante Outcomes in diesem Zusammenhang sind Migränehäufigkeit, Kopfschmerzintensität während einer Migräneattacke, depressive Symptome und Lebensqualität.MethodenDie Durchführung dieser Studie orientierte sich am PRISMA-Statement. Eine systematische Literatursuche nach randomisierten kontrollierten Studien zur Wirksamkeit von MBSR bei erwachsenen Migränepatienten wurde im Dezember 2021 in drei Datenbanken durchgeführt: MEDLINE über PubMed, die Cochrane Library und Web of Science. Darüber hinaus wurden Referenzlisten und Studienregister durchsucht. Die letzte Suche erfolgte am 7. Oktober 2022. In einem zweistufigen Verfahren wurden die Studien anhand von vordefinierten Ein- und Ausschlusskriterien ausgewählt. Das Verzerrungspotential der Studien wurde mit dem Cochrane Risk of Bias Tool 2 bewertet. Die Ergebnisse wurden deskriptiv und mit Hilfe einer quantitativen Synthese zusammengefasst.ErgebnisseEs wurden vier randomisiert-kontrollierte Studien mit insgesamt 275 Patienten und die Nachfolgepublikation einer dieser Studien eingeschlossen. Das Verzerrungspotential wurde bei je einer Studie als gering oder bedenklich und bei zwei Studien als hoch eingestuft. Vier Studien wurden in die quantitative Analyse einbezogen. Für den Endpunkt Migränehäufigkeit ergab die metaanalytische Zusammenfassung von drei Studien keinen statistisch signifikanten Vorteil für MBSR (SMD −0.23; 95% CI −0.79 bis 0.32). Für den Endpunkt depressive Symptome zeigte eine metaanalytische Zusammenfassung von drei Studien einen statistisch signifikanten Vorteil für MBSR (SMD −0.59; 95% CI −0.93 bis −0.25). Keine Studie hatte die Schwere der Kopfschmerzen während einer Migräneepisode untersucht.SchlussfolgerungEinige Ergebnisse deuten darauf hin, dass Migränepatienten von MBSR profitieren können. Allerdings ist die Evidenzbasis derzeit nicht ausreichend, um Empfehlungen für den Einsatz von MBSR als nichtmedikamentöse Behandlungsoption abzuleiten. Es werden daher weitere qualitativ hochwertige randomisiert-kontrollierte Studien mit ausreichender statistischer Power benötigt.}, } @article {pmid37907134, year = {2023}, author = {Birajdar, SV and Mazahir, F and Alam, MI and Kumar, A and Yadav, AK}, title = {Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {961}, number = {}, pages = {176117}, doi = {10.1016/j.ejphar.2023.176117}, pmid = {37907134}, issn = {1879-0712}, mesh = {Humans ; Mice ; Animals ; Hypoglycemic Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/drug therapy ; Drug Repositioning ; Neuroinflammatory Diseases ; *Alzheimer Disease/drug therapy ; Insulin/metabolism ; *Metformin/pharmacology ; }, abstract = {The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid β metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aβ deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aβ monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders.}, } @article {pmid37907717, year = {2024}, author = {Yamamoto, K and Itoi, T and Matsunami, Y and Sofuni, A and Tsuchiya, T and Mukai, S and Kojima, H and Minami, H and Nakatsubo, R and Tonozuka, R}, title = {Early and late effects of endoscopic interventions in patients with malignant afferent loop syndrome: A single-center experience and literature review.}, journal = {Journal of hepato-biliary-pancreatic sciences}, volume = {31}, number = {2}, pages = {120-132}, doi = {10.1002/jhbp.1380}, pmid = {37907717}, issn = {1868-6982}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; *Cholestasis/etiology ; Drainage ; Endoscopy ; Endosonography ; Liver/pathology ; Retrospective Studies ; Stents/adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND/PURPOSE: Afferent loop syndrome (ALS) is a rare adverse event after gastrointestinal surgery requiring appropriate early decompression treatment. Several endoscopic interventions have been attempted for treatment, including endoscopic enteral metal stent placement (EMSP), endoscopic ultrasound (EUS)-guided entero-enterostomy (EUS-EE), and EUS-guided hepaticogastrostomy (EUS-HGS). However, there are limited data on outcomes, including duration of stent patency. In this study, we evaluated the usefulness of each endoscopic intervention for malignant ALS.

METHODS: We retrospectively investigated nine patients with malignant ALS who underwent EMSP, EUS-EE, or EUS-HGS. Information on technical success, clinical efficacy, adverse events, stent dysfunction, and overall survival was collected and analyzed.

RESULTS: The most common symptoms were abdominal pain and cholangitis. ALS was treated by EMSP in three patients, EUS-EE in three patients, and EUS-HGS in three patients. Stent placement was successful and clinically effective in all patients with no adverse events. During follow-up, stent dysfunction occurred in two patients treated by EUS-HGS. Eight patients died of primary disease during a median follow-up of 157 days.

CONCLUSIONS: Each of the available endoscopic interventions for malignant ALS can be expected to produce similar outcomes, including duration of stent patency. The choice of endoscopic intervention should be made based on the characteristics of each treatment.}, } @article {pmid37910649, year = {2025}, author = {Franklin, JE}, title = {Palliative hypnosis approaches in the symptomatic treatment of amyotrophic lateral sclerosis (ALS).}, journal = {The American journal of clinical hypnosis}, volume = {67}, number = {1}, pages = {54-68}, doi = {10.1080/00029157.2023.2252875}, pmid = {37910649}, issn = {2160-0562}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Palliative Care/methods ; *Hypnosis/methods ; Male ; Middle Aged ; Aged ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and ultimately fatal, devastating, progressive degenerative neurologic disease. It causes upheaval in the lives of patients and family caregivers alike. Palliative care can play an important supportive role in the care of patients and families dealing with the devastation of this illness. Clinical hypnosis has demonstrated benefits in treating the symptoms associated with severe chronic illness. There are, however, few studies looking at the benefits of clinical hypnosis in treating the symptom burden of ALS. This article describes palliative care and how it can provide an additional layer of support to seriously ill patients. A brief review of previous studies of hypnosis in the supportive, symptomatic treatment of ALS is provided, followed by a description of a case series of 30 Veterans who received clinical hypnosis and self-hypnosis training as a complementary treatment for the symptoms of ALS. Details of three case histories are included to highlight and discuss specific strategies and emblematic clinical responses. There is evidence that clinical hypnosis can benefit ALS patients and family caregivers struggling with this devastating illness.}, } @article {pmid37913752, year = {2023}, author = {Chou, PY and Chen, CM and Wang, CC and Tai, CJ and Lin, YK and Tang, YJ}, title = {Characteristics and Effects of Chinese Herbal Medicine in the Management of Female Infertility: A Hospital-Based Study.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {481-491}, doi = {10.1159/000534590}, pmid = {37913752}, issn = {2504-2106}, mesh = {Humans ; Female ; Retrospective Studies ; *Drugs, Chinese Herbal/therapeutic use ; *Infertility, Female/therapy ; Treatment Outcome ; Hospitals ; }, abstract = {BACKGROUND: In Taiwan, Chinese herbal medicine (CHM) is used to treat female infertility. Evidence indicates that the absence of monotherapy efficacy assessment and comparison with mainstream interventions may lead to the improper use of CHM for female infertility.

METHODS: A retrospective cohort study enrolled female patients at a hospital undergoing CHM intervention to treat infertility from 2012 to 2020 in order to determine the outcomes of CHM monotherapy for female infertility. Kaplan-Meier analysis under strict assumptions was used to estimate the cumulative probability of pregnancy and live births after CHM. Cox hazard regression analysis was used to estimate the hazard ratios of prognostic variables, namely, the woman's age and diagnostic category.

RESULTS: 694 women met the inclusion criteria and accounted for 2,145 cycles. A total of 190 pregnancies resulted in 125 live births, all of which were singleton births of babies with 16 perinatal complications requiring hospitalization. The real cumulative pregnancy rate and cumulative live birth rate (CLBR) for the total population after 10 cycles were between 27.4% and 35.2% and between 18% and 22.1%, respectively. Compared with the live birth rate corresponding to patients aged under 35 years, that of older patients, particularly those aged 38-39 years, was significantly lower (hazard ratio: 0.19, 95% confidence interval: 0.11-0.33). Women with other diagnoses, namely, uterine problems or endometriosis, had a greater probability of a live birth than did women with tubal pathology (hazard ratio: 6.31, 95% confidence interval: 1.99-20.07).

CONCLUSION: To the best of our knowledge, this is the first retrospective study to employ life table analysis to determine the CHM treatment outcomes in terms of female infertility. The study established a basis to compare in vitro fertilization (IVF) with CHM and identified the advantages and disadvantages of CHM for treating female infertility. Although the CLBR of present study is lower than those reported in IVF studies, CHM in treating female infertility can still be beneficial to women aged younger than 38 years or with diagnoses other than tubal pathology and worth recommendation by reproductive specialists according to the promising results gained from the strict criteria. However, in order to determine the optimal timing, possible mechanism, corresponding side effects, and the efficacy of CHM combined with IVF for treating female infertility, rigorous research is required.

UNLABELLED: HintergrundIn Taiwan wird die chinesische Heilpflanzenmedizin (CHM) zur Behandlung weiblicher Infertilität angewendet. Es liegen Hinweise vor, nach denen fehlende Wirksamkeitsbeurteilungen der Monotherapien und Vergleiche mit herkömmlichen Interventionen zu einer unsachgemäßen Anwendung von CHM bei weiblicher Infertilität führen können.MethodenEine retrospektive Kohortenstudie schloss Patientinnen eines Krankenhauses ein, die von 2012 bis 2020 wegen Infertilität mit CHM behandelt wurden, um die Behandlungsergebnisse der CHM-Monotherapie bei weiblicher Infertilität zu ermitteln. Zur Schätzung der kumulativen Wahrscheinlichkeit von Schwangerschaften und Lebendgeburten nach einer CHM-Behandlung wurde die Kaplan-Meier-Analyse unter strengen Annahmen verwendet. Mit Hilfe der Cox-Hazard-Regressionsanalyse wurden die Risikoverhältnisse der prognostischen Variablen Alter der Frau und Diagnosekategorie geschätzt.Ergebnisse694 Frauen erfüllten die Einschlusskriterien und die Zahl der Zyklen betrug 2,145. Insgesamt 190 Schwangerschaften führten zu 125 Lebendgeburten, allesamt Einlingsgeburten, mit 16 perinatalen Komplikationen, die eine Hospitalisierung erforderten. Die reale kumulative Schwangerschaftsrate und die kumulative Lebendgeburtenrate (cumulative live birth rate, CLBR) für die Gesamtpopulation nach 10 Zyklen lagen zwischen 27.4% und 35.2% bzw. zwischen 18% und 22.1%. Die Lebendgeburtenrate bei älteren Patientinnen, insbesondere im Alter von 38 bis 39 Jahren, war deutlich niedriger als bei Patientinnen unter 35 Jahren (Hazard Ratio: 0.19, 95%-Konfidenzintervall: 0.11–0.33). Bei Frauen mit anderen Diagnosen wie Gebärmutterproblemen oder Endometriose war die Wahrscheinlichkeit einer Lebendgeburt höher als bei Frauen mit Eileitererkrankungen (Hazard Ratio: 6.31, 95%-Konfidenzintervall: 1.99–20.07).SchlussfolgerungUnseres Wissens ist dies die erste retrospektive Studie, in der die Ergebnisse der CHM-Behandlung bei weiblicher Infertilität mittels Sterbetafelanalyse ermittelt wurden. Die Studie bildet eine Grundlage für den Vergleich von In-vitro-Fertilisation (IVF) mit CHM und zeigt die Vor- und Nachteile der CHM zur Behandlung weiblicher Infertilität auf. Zwar fällt die kumulative Lebendgeburtenrate in der vorliegenden Studie niedriger aus als in IVF-Studien, doch kann die CHM bei der Behandlung weiblicher Infertilität für Frauen unter 38 Jahren oder Frauen, die eine andere Diagnose als eine Eileitererkrankung haben, von Nutzen sein und angesichts der vielversprechenden Ergebnisse, die aus den strengen Kriterien gewonnen wurden, ist sie eine Empfehlung durch Reproduktionsspezialisten wert. Allerdings sind rigorose Forschungsarbeiten erforderlich, um die optimale Zeitplanung, den möglichen Mechanismus, die entsprechenden Nebenwirkungen und die Wirksamkeit der CHM in Kombination mit IVF zur Behandlung der weiblichen Infertilität zu ermitteln.}, } @article {pmid37915644, year = {2023}, author = {Kassahun Bekele, B and Kwizera, L and Abdul Razzak, R and Alfadul, ESA and Anand, A and Wojtara, M and Nazir, A and Uwishema, O}, title = {ALS in Africa: current knowledge and exciting opportunities for future study - short communication.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {11}, pages = {5827-5830}, pmid = {37915644}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can present with motor and extra-motor manifestations. Its global prevalence is 4.42 per 1 000 000, and it has a high mortality rate. In sub-Saharan Africa alone, 15 per 100 000 develop ALS mainly between their 40s and 60s and only one-fourth of them have access to treatment. ALS was found to be not only affected by genetic variation but also by the patient's mood and lifestyle. In Africa, males and younger people tend to be affected with ALS and rarely present with bulbar onset. ALS diagnosis is very challenging due to the lack of ALS-specific biomarkers and the sharing of some clinical features with other syndromes. ALS treatment is mainly riluzole and supportive treatment via nasogastric tube and ventilatory support. The access to treatment in Africa is very limited, thus a very bad prognosis with a median survival time of 14 months post-diagnosis. Further research is needed to assess the real situation in Africa and to try to closely monitor patients suffering from ALS.}, } @article {pmid37920145, year = {2024}, author = {Stamatelatou, A and Bertinetto, CG and Jansen, JJ and Postma, G and Selnaes, KM and Bathen, TF and Heerschap, A and Scheenen, TWJ and , }, title = {A multivariate curve resolution analysis of multicenter proton spectroscopic imaging of the prostate for cancer localization and assessment of aggressiveness.}, journal = {NMR in biomedicine}, volume = {37}, number = {3}, pages = {e5062}, doi = {10.1002/nbm.5062}, pmid = {37920145}, issn = {1099-1492}, support = {813120//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Male ; Humans ; *Prostate/diagnostic imaging/pathology ; Protons ; *Prostatic Neoplasms/diagnostic imaging ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; }, abstract = {In this study, we investigated the potential of the multivariate curve resolution alternating least squares (MCR-ALS) algorithm for analyzing three-dimensional (3D) [1] H-MRSI data of the prostate in prostate cancer (PCa) patients. MCR-ALS generates relative intensities of components representing spectral profiles derived from a large training set of patients, providing an interpretable model. Our objectives were to classify magnetic resonance (MR) spectra, differentiating tumor lesions from benign tissue, and to assess PCa aggressiveness. We included multicenter 3D [1] H-MRSI data from 106 PCa patients across eight centers. The patient cohort was divided into a training set (N = 63) and an independent test set (N = 43). Singular value decomposition determined that MR spectra were optimally represented by five components. The profiles of these components were extracted from the training set by MCR-ALS and assigned to specific tissue types. Using these components, MCR-ALS was applied to the test set for a quantitative analysis to discriminate tumor lesions from benign tissue and to assess tumor aggressiveness. Relative intensity maps of the components were reconstructed and compared with histopathology reports. The quantitative analysis demonstrated a significant separation between tumor and benign voxels (t-test, p < 0.001). This result was achieved including voxels with low-quality MR spectra. A receiver operating characteristic analysis of the relative intensity of the tumor component revealed that low- and high-risk tumor lesions could be distinguished with an area under the curve of 0.88. Maps of this component properly identified the extent of tumor lesions. Our study demonstrated that MCR-ALS analysis of [1] H-MRSI of the prostate can reliably identify tumor lesions and assess their aggressiveness. It handled multicenter data with minimal preprocessing and without using prior knowledge or quality control. These findings indicate that MCR-ALS can serve as an automated tool to assess the presence, extent, and aggressiveness of tumor lesions in the prostate, enhancing diagnostic capabilities and treatment planning of PCa patients.}, } @article {pmid37922093, year = {2024}, author = {Jellinger, KA}, title = {Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {2}, pages = {107-115}, pmid = {37922093}, issn = {1435-1463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; Depression/complications ; Quality of Life ; Affect ; *Neurodegenerative Diseases/complications ; }, abstract = {Depression with an average prevalence of 25-40% is a serious condition in amyotrophic lateral sclerosis (ALS) that can impact quality of life and survival of patients and caregiver burden, yet the underlying neurobiology is poorly understood. Preexisting depression has been associated with a higher risk of developing ALS, while people with ALS have a significantly higher risk of developing depression that can cause multiple complications. Depression may be a prodromal or subclinical symptom prior to motor involvement, although its relations with disease progression and impairment of quality of life are under discussion. Unfortunately, there are no studies existing that explore the pathogenic mechanisms of depression associated with the basic neurodegenerative process, and no specific neuroimaging data or postmortem findings for the combination of ALS and depression are currently available. Experience from other neurodegenerative processes suggests that depressive symptoms in ALS may be the consequence of cortical thinning in prefrontal regions and other cortex areas, disruption of mood-related brain networks, dysfunction of neurotransmitter systems, changing cortisol levels and other, hitherto unknown mechanisms. Treatment of both ALS and depression is a multidisciplinary task, depression generally being treated with a combination of antidepressant medication, physiotherapy, psychological and other interventions, while electroconvulsive therapy and deep brain stimulation might not be indicated in the majority of patients in view of their poor prognosis. Since compared to depression in other neurodegenerative diseases, our knowledge of its molecular basis in ALS is missing, multidisciplinary clinicopathological studies to elucidate the pathomechanism of depression in motor system disorders including ALS are urgently warranted.}, } @article {pmid37924056, year = {2023}, author = {Sun, J and Chen, J and Xie, Q and Sun, M and Zhang, W and Wang, H and Liu, N and Wang, Q and Wang, M}, title = {Sodium butyrate alleviates R97-116 peptide-induced myasthenia gravis in mice by improving the gut microbiota and modulating immune response.}, journal = {Journal of inflammation (London, England)}, volume = {20}, number = {1}, pages = {37}, pmid = {37924056}, issn = {1476-9255}, abstract = {Fermented butyrate exhibits an anti-inflammatory response to maintain immune homeostasis within the gut. However, the effect and underlying mechanism of butyrate on myasthenia gravis (MG) remain unclear. The changes in the gut microbiota and fecal contents of SCFAs in MG patients were examined. R97-116 peptide was used to induce the experimental autoimmune myasthenia gravis (EAMG) mice and sodium butyrate (NaB) was gavaged to the EAMG mice. Gut microbiota, the frequency of Th1, Th17, Treg, Tfh, and B cells, the levels of IFN-γ, IL-17 A, IL-10, IL-21, and anti-R97-116 IgG, RNA-seq of total B cells in the spleen were explored by metagenomics, flow cytometry, ELISA, and transcriptomics. A significant reduction in SCFA-producing bacteria including Butyricimonas synergistica and functional modules including butyrate synthesis/production II was observed in MG patients and fecal SCFAs detection confirmed the increase. The EAMG mice were successfully constructed and NaB supplementation has changed the composition and function of the gut microbiota. The numbers of Th1, Th17, Tfh, and B cells were significantly increased while that of Treg cells was obviously decreased in EAMG mice compared with controls. Interestingly, NaB treatment has reduced the amounts of Th17, Tfh, and B cells but increased that of Treg cells. Accordingly, the levels of IL-17 A, IL-21, and IgG were increased while IL-10 was decreased in EAMG mice. However, NaB treatment reduced IL-17 A and IL-21 but increased that of IL-10. RNA-seq of B cells has revealed 4577 deferentially expressed genes (DEGs), in which 1218 DEGs were up-regulated while 3359 DEGs were down-regulated in NaB-treated EAMG mice. GO enrichment and KEGG pathway analysis unveiled that the function of these DEGs was mainly focused on immunoglobulin production, mitochondrial respiratory chain complex, ribosome, oxidative phosphorylation, and CNS diseases including amyotrophic lateral sclerosis. We have found that butyrate was significantly reduced in MG patients and NaB gavage could evidently improve MG symptoms in EAMG mice by changing the gut microbiota, regulating the immune response, and altering the gene expression and function of B cells, suggesting NaB might be a potential immunomodulatory supplement for MG drugs.}, } @article {pmid37928442, year = {2023}, author = {Chen, SK and Hawley, ZCE and Zavodszky, MI and Hana, S and Ferretti, D and Grubor, B and Hawes, M and Xu, S and Hamann, S and Marsh, G and Cullen, P and Challa, R and Carlile, TM and Zhang, H and Lee, WH and Peralta, A and Clarner, P and Wei, C and Koszka, K and Gao, F and Lo, SC}, title = {Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection.}, journal = {Molecular therapy. Nucleic acids}, volume = {34}, number = {}, pages = {102057}, pmid = {37928442}, issn = {2162-2531}, abstract = {Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%-3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNS-related toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy.}, } @article {pmid37930481, year = {2024}, author = {Domi, T and Schito, P and Sferruzza, G and Russo, T and Pozzi, L and Agosta, F and Carrera, P and Riva, N and Filippi, M and Quattrini, A and Falzone, YM}, title = {Unveiling the SOD1-mediated ALS phenotype: insights from a comprehensive meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1342-1354}, pmid = {37930481}, issn = {1432-1459}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Phenotype ; Genetic Testing ; Mutation ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis associated with mutations in SOD1 (SOD1-ALS) might be susceptible to specific treatment. The aim of the study is to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining SOD1-ALS phenotype may assist clinicians in identifying patients who should be prioritized for genetic testing.

METHODS: We performed an extensive literature research including original studies which reported the clinical features of SOD1-ALS and at least one of the following patient groups: C9ORF72 hexanucleotide repeat expansion (C9-ALS), TARDBP (TARDBP-ALS), FUS (FUS-ALS) or patients without a positive test for a major-ALS gene (N-ALS). A random effects meta-analytic model was applied to clinical data extracted encompassing sex, site and age of onset. To reconstruct individual patient survival data, the published Kaplan-Meier curves were digitized. Data were measured as odds ratio (OR) or standardized mean difference (SMD) as appropriate. Median survival was compared between groups.

RESULTS: Twenty studies met the inclusion criteria. We identified 721 SOD1-ALS, 470 C9-ALS, 183 TARDBP-ALS, 113 FUS-ALS and 2824 N-ALS. SOD1-ALS showed a higher rate of spinal onset compared with N-ALS and C9-ALS (OR = 4.85, 95% CI = 3.04-7.76; OR = 10.47, 95% CI = 4.32-27.87) and an earlier onset compared with N-ALS (SMD = - 0.45, 95% CI = - 0.72 to - 0.18). SOD1-ALS had a similar survival compared with N-ALS (p = 0.14), a longer survival compared with C9-ALS (p < 0.01) and FUS-ALS (p = 0.019) and a shorter survival compared with TARDBP-ALS (p < 0.01).

DISCUSSION: This study indicates the presence of a specific SOD1-ALS phenotype. Insights in SOD1-ALS clinical features are important in genetic counseling, disease prognosis and support patients' stratification in clinical trials.}, } @article {pmid37934576, year = {2023}, author = {Gao, H and Yu, J and Chen, J and Wang, H and Liang, S and Feng, Z and Gu, Y and Dong, L}, title = {Target-Site and Metabolic Resistance Mechanisms to Penoxsulam in Late Watergrass (Echinochloa phyllopogon) in China.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {46}, pages = {17742-17751}, doi = {10.1021/acs.jafc.3c05921}, pmid = {37934576}, issn = {1520-5118}, mesh = {*Echinochloa/genetics/metabolism ; Herbicide Resistance/genetics ; Tandem Mass Spectrometry ; *Herbicides/pharmacology/metabolism ; *Acetolactate Synthase/genetics/metabolism ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa phyllopogon, a malignant weed in Northeast China's paddy fields, is currently presenting escalating resistance concerns. Our study centered on the HJHL-715 E. phyllopogon population, which showed heightened resistance to penoxsulam, through a whole-plant bioassay. Pretreatment with a P450 inhibitor malathion significantly increased penoxsulam sensitivity in resistant plants. In order to determine the resistance mechanism of the resistant population, we purified the resistant population from individual plants and isolated target-site resistance (TSR) and nontarget-site resistance (NTSR) materials. Pro-197-Thr and Trp-574-Leu mutations in acetolactate synthase (ALS) 1 and ALS2 of the resistant population drove reduced sensitivity of penoxsulam to the target-site ALS, the primary resistance mechanisms. To fully understand the NTSR mechanism, NTSR materials were investigated by using RNA-sequencing (RNA-seq) combined with a reference genome. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis further supported the enhanced penoxsulam metabolism in NTSR materials. Gene expression data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation confirmed 29 overexpressed genes under penoxsulam treatment, with 16 genes concurrently upregulated with quinclorac and metamifop treatment. Overall, our study confirmed coexisting TSR and NTSR mechanisms in E. phyllopogon's resistance to ALS inhibitors.}, } @article {pmid37938192, year = {2023}, author = {Maharaj, D and Kaur, K and Saltese, A and Gouvea, J}, title = {Personalized Precision Immunotherapy for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {2}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023048372}, pmid = {37938192}, issn = {2162-6472}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Immunotherapy ; Brain ; Cytokines ; Inflammation ; }, abstract = {Neurological syndrome amyotrophic lateral sclerosis (ALS) affects motor neurons and is characterized by progressive motor neuron loss in the brain and spinal cord. ALS starts with mainly focal onset but when the disease progresses, it spreads to different parts of the body, with survival limits of 2-5 years after disease initiation. To date, only supportive care is provided for ALS patients, and no effective treatment or cure has been discovered. This review is focused on clinical and immunological aspects of ALS patients, based on our case studies, and we discuss the treatment we have provided to those patients based on a detailed evaluation of their peripheral blood immune cells and blood-derived serum secreted factors, cytokines, chemokines and growth factors. We show that using a personalized approach of low dose immunotherapy there is an improvement in the effects on inflammation and immunological dysfunction.}, } @article {pmid37942135, year = {2023}, author = {Shi, Y and Zhu, R}, title = {Analysis of damage-associated molecular patterns in amyotrophic lateral sclerosis based on ScRNA-seq and bulk RNA-seq data.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1259742}, pmid = {37942135}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the exact etiology of ALS remains elusive. Emerging evidence highlights the critical role of the immune system in ALS pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by stressed or damaged cells, acting as danger signals and activating immune responses. However, their specific involvement in ALS remains unclear.

METHODS: We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the primary motor cortex in the Gene Expression Omnibus (GEO) database. To better understand genes associated with DAMPs, we performed analyses on cell-cell communication and trajectory. The abundance of immune-infiltrating cells was assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. We performed univariate Cox analysis to construct the risk model and utilized the least absolute shrinkage and selection operator (LASSO) analysis. Finally, we identified potential small molecule drugs targeting ALS by screening the Connectivity Map database (CMap) and confirmed their potential through molecular docking analysis.

RESULTS: Our study annotated 10 cell types, with the expression of genes related to DAMPs predominantly observed in microglia. Analysis of intercellular communication revealed 12 ligand-receptor pairs in the pathways associated with DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 pair demonstrated the greatest contribution. Furthermore, trajectory analysis demonstrated distinct differentiation fates of different microglial states. Additionally, we constructed a risk model incorporating four genes (TRPM2, ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by multivariate analysis. Moreover, external validation from dataset GSE112681 confirmed the predictive power of the model, which yielded consistent results with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis suggested that five compounds, namely mead-acid, nifedipine, nifekalant, androstenol, and hydrastine, hold promise as potential candidates for the treatment of ALS.

CONCLUSION: Taken together, our study demonstrated that DAMP entities were predominantly observed in microglial cells within the context of ALS. The utilization of a prognostic risk model can accurately predict ALS patient survival. Additionally, genes related to DAMPs may present viable drug targets for ALS therapy.}, } @article {pmid37944503, year = {2023}, author = {Sun, HJ and Zhang, J and Lu, JP and Wu, MT}, title = {The Improvement in Function of Poststroke Spasticity by Vibrational and Heated Stone-Needle Therapy and Meridian Dredging Exercise: A Randomized, Controlled, Preliminary Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {492-501}, doi = {10.1159/000534993}, pmid = {37944503}, issn = {2504-2106}, mesh = {Humans ; Animals ; Mice ; *Quality of Life ; *Meridians ; Physical Therapy Modalities ; }, abstract = {BACKGROUND: Poststroke spasticity (PSS) is a common complication of stroke. Current PSS treatments have been linked to high costs, lack of long-term effectiveness, and undesirable side effects. Vibrational and heated stone-needle therapy (VHS) has not been utilized to treat PSS, and its safety and effectiveness have yet to be proven by high-quality clinical research.

OBJECTIVE: The aim of this study was to determine the effectiveness of VHS combined with meridian dredging exercise (MDE) in patients with PSS.

METHODS: One hundred participants with stroke were included and randomly assigned to a treatment group (VHS plus MDEs) and a control group (MDEs alone). Patients in both groups were treated for 4 weeks. The primary outcome measures were the Modified Ashworth Scale (MAS) and Fugl-Meyer Assessment (FMA), while the secondary outcome measures were the Activity of Daily Living (ADL) Scale and Stroke-Specific Quality of Life Scale (SS-QOL). The evaluations were at baseline (T0) at 4 weeks of treatment (T1) and at 12 weeks of follow-up without treatment (T2).

RESULTS: At T1 and T2, there were significant differences in MAS between the two groups (p = 0.001). From the perspective of distribution, the VHS plus MDE group had significant changes, and the group-time interactions of upper and lower extremities in FMA, ADL, and SS-QOL were statistically significant (p < 0.001), indicating that patients' symptoms improved after treatment. But the overall effect size is small, especially the effect size of improvement in SS-QOL at T1.

CONCLUSION: VHS in combination with MDE can consistently alleviate PSS, enhance limb function, and improve the quality of life of patients with PSS. But we need to optimize the device further and observe the improvement of patients for a more extended period.

UNLABELLED: HintergrundSpastik nach Schlaganfall (PSS; post-stroke spasticity) ist eine häufige Komplikation des Schlaganfalls. Gegenwärtige PSS-Behandlungen sind mit hohen Kosten, mangelnder langfristiger Wirksamkeit und unerwünschten Nebenwirkungen in Verbindung gebracht worden. Vibrierende und erhitzte Steinnadeln (VHS) sind bisher nicht zur Behandlung des PSS eingesetzt worden, und der Nachweis ihrer Sicherheit und Wirksamkeit durch hochwertige klinische Forschung steht noch aus.ZielBeurteilung der Wirksamkeit von vibrierenden und erhitzten Steinnadeln (VHS) in Kombination mit Meridian-Ausbagger-Übungen (MDE) bei Patienten mit PSS.Methoden100 Patienten mit Schlaganfall wurden eingeschlossen und per Randomisierung auf eine Behandlungsgruppe (VHS plus MDEs) und eine Kontrollgruppe (nur MDE) aufgeteilt. In beiden Gruppen wurden die Patienten 4 Wochen lang behandelt. Die primären Messinstrumente waren die Modified Ashworth Scale (MAS) und das Fugl-Meyer Assessment (FMA), als sekundäre Messinstrumente wurden die Activity of Daily Living Scale (ADL) und die Stroke-Specific Quality of Life Scale (SS-QOL) erhoben. Die Beurteilungszeitpunkte waren bei Baseline (T0) nach 4 Wochen Behandlung (T1) und nach 12 Wochen Nachbeobachtung ohne Behandlung (T2).ErgebnisseBei T1 und T2 bestanden signifikante Unterschiede bei der MAS zwischen den Gruppen (p = 0.001). Aus der Perspektive der Distribution zeigte die “VHS plus MDE”-Gruppe signifikante Veränderungen, und die Gruppe*Zeit-Interaktionen der oberen and unteren Extremitäten bei FMA, ADL und SS-QOL waren statistisch signifikant (p < 0.001), was darauf hindeutet, dass die Beschwerden der Patienten sich nach der Behandlung besserten. Die Effektstärke ist allerdings gering, insbesondere die der SS-QOL-Verbesserung bei T1.SchlussfolgerungDie Anwendung von vibrierenden und erhitzten Steinnadeln in Kombination mit Meridian-Ausbagger-Übungen kann PSS durchgängig lindern, die Funktion der Extremitäten verbessern und die Lebensqualität der Patienten mit PSS erhöhen. Jedoch muss das Produkt weiter optimiert werden, und die Verbesserungen bei den Patienten müssen über einen längeren Zeitraum beobachtet werden.}, } @article {pmid37945695, year = {2023}, author = {Faria Assoni, A and Giove Mitsugi, T and Wardenaar, R and Oliveira Ferreira, R and Farias Jandrey, EH and Machado Novaes, G and Fonseca de Oliveira Granha, I and Bakker, P and Kaid, C and Zatz, M and Foijer, F and Keith Okamoto, O}, title = {Neurodegeneration-associated protein VAPB regulates proliferation in medulloblastoma.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19481}, pmid = {37945695}, issn = {2045-2322}, mesh = {Child ; Humans ; *Medulloblastoma/genetics ; *Cerebellar Neoplasms/genetics ; Cell Proliferation/genetics ; Vesicular Transport Proteins ; }, abstract = {VAMP (Vesicle-associated membrane protein)-associated protein B and C (VAPB) has been widely studied in neurodegenerative diseases such as ALS, but little is known about its role in cancer. Medulloblastoma is a common brain malignancy in children and arises from undifferentiated cells during neuronal development. Therefore, medulloblastoma is an interesting model to investigate the possible relationship between VAPB and tumorigenesis. Here we demonstrate that high VAPB expression in medulloblastoma correlates with decreased overall patient survival. Consistent with this clinical correlation, we find that VAPB is required for normal proliferation rates of medulloblastoma cells in vitro and in vivo. Knockout of VAPB (VAPB[KO]) delayed cell cycle progression. Furthermore, transcript levels of WNT-related proteins were decreased in the VAPB[KO]. We conclude that VAPB is required for proliferation of medulloblastoma cells, thus revealing VAPB as a potential therapeutic target for medulloblastoma treatment.}, } @article {pmid37946793, year = {2023}, author = {Rogers, ML and Schultz, DW and Karnaros, V and Shepheard, SR}, title = {Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad287}, pmid = {37946793}, issn = {2632-1297}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.}, } @article {pmid37950760, year = {2024}, author = {Beloribi-Djefaflia, S and Morales, RJ and Fatehi, F and Isapof, A and Servais, L and Leonard-Louis, S and Michaud, M and Verdure, P and Gidaro, T and Pouget, J and Poinsignon, V and Bonello-Palot, N and Attarian, S}, title = {Clinical and genetic features of patients suffering from CMT4J.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1355-1365}, pmid = {37950760}, issn = {1432-1459}, mesh = {Adolescent ; Humans ; *Amyotrophic Lateral Sclerosis ; *Charcot-Marie-Tooth Disease/diagnosis/genetics ; *Flavoproteins/genetics ; Heterozygote ; Mutation/genetics ; Phenotype ; *Phosphoric Monoester Hydrolases/genetics ; }, abstract = {Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot-Marie-Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.}, } @article {pmid37951279, year = {2024}, author = {Vu Trung, K and Heise, C and Abou-Ali, E and Auriemma, F and Karam, E and van der Wiel, SE and Bruno, MJ and Caillol, F and Giovannini, M and Masaryk, V and Will, U and Anderloni, A and Pérez-Cuadrado-Robles, E and Dugic, A and Meier, B and Paik, WH and Petrone, MC and Wichmann, D and Dinis-Ribeiro, M and Gonçalves, TC and Wedi, E and Schmidt, A and Gulla, A and Hoffmeister, A and Rosendahl, J and Ratone, JP and Saadeh, R and Repici, A and Deprez, P and Sauvanet, A and Souche, FR and Fabre, JM and Muehldorfer, S and Caca, K and Löhr, M and Michl, P and Krug, S and Regner, S and Gaujoux, S and Hollenbach, M}, title = {Endoscopic papillectomy for ampullary lesions of minor papilla.}, journal = {Gastrointestinal endoscopy}, volume = {99}, number = {4}, pages = {587-595.e1}, doi = {10.1016/j.gie.2023.10.040}, pmid = {37951279}, issn = {1097-6779}, mesh = {Humans ; Treatment Outcome ; *Ampulla of Vater/surgery/pathology ; Endoscopy, Gastrointestinal ; Pancreatic Ducts/pathology ; *Pancreatic Neoplasms/pathology ; *Duodenal Neoplasms/pathology ; *Common Bile Duct Neoplasms/surgery/pathology ; Retrospective Studies ; }, abstract = {BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied.

METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test.

RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months).

CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.}, } @article {pmid37952517, year = {2024}, author = {Zürcher, BF}, title = {The Tibetan Formula Cong zhi 6 in the ORL (ENT) Practice: Experiences with Laryngopharyngeal Reflux.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {84-88}, doi = {10.1159/000534212}, pmid = {37952517}, issn = {2504-2106}, mesh = {Humans ; *Laryngopharyngeal Reflux/drug therapy ; Retrospective Studies ; Pepsin A ; Tibet ; Europe ; }, abstract = {BACKGROUND: Laryngopharyngeal reflux (LPR) is a frequent condition; in European countries, the prevalence can be estimated as 10-30% of the general population. Treatment includes lifestyle measures and highly dosed proton pump inhibitors (PPIs) over at least 4 weeks. However, PPIs are not unproblematic due to their potential side effects and the known phenomenon of rebound acid hypersecretion. Cong zhi 6 is a multi-herbal Tibetan formula additionally containing calcium carbonate and is available in several European countries as a food supplement Padma Aciben/Padma AciTib.

CASE REPORT: Ten patients with LPR took Cong zhi 6. The course of the complaints was documented, and the data were retrospectively analysed. Clinical symptoms as assessed with the Reflux Symptom Index (RSI) questionnaire and the findings in laryngoscopy with the Reflux Finding Score (RFS) both showed marked improvement of several symptoms. The number of patients with pathological LPR sum score was significantly reduced from 8 to 2 patients and from 10 to 1 patient in RSI and RFS, respectively. The mean sum scores were reduced from 18.1 to 8.4 (RSI) and from 12.9 to 4.4 (RFS), respectively. Also, other gastrointestinal symptoms, such as abdominal pain, bloating, feeling of fullness, and nausea, which are usually associated with functional dyspepsia and irritable bowel syndrome, were markedly improved (reduction of mean score of the 3 most frequent symptoms by 77-87%).

CONCLUSION: Standard medical treatment for LPR consists in high dosed PPI for at least 4 weeks, which is known for several side effects and does not treat reliable the nonacid component of LPR of pepsin or other gastric enzymes. Therefore, other medical treatment options are urgently needed. The promising data of this case series suggest that the Tibetan herbal formula Cong zhi 6 may be a treatment option in LPR and related gastrointestinal symptoms and warrant further research.

UNLABELLED: HintergrundDer laryngopharyngeale Reflux (LPR) ist eine häufige Erkrankung. In europäischen Ländern wird die Prävalenz in der Gesamtbevölkerung auf 10–30% geschätzt. Die Behandlung beinhaltet Ernährungs- und Verhaltensänderung sowie die Gabe hochdosierter Protonen-Pumpen-Hemmer (PPI) über mindestens 4 Wochen. PPI sind jedoch aufgrund ihrer hohen potenziellen Nebenwirkungen und des bekannten Rebound-Phänomens der sauren Magensafthypersekretion nicht unproblematisch. Cong zhi 6 ist eine tibetische Rezeptur aus einem Vielpflanzengemisch sowie zusätzlich Calciumcarbonat und ist in einigen europäischen Ländern als Nahrungsergänzungsmittel Padma Aciben/Padma AciTib erhältlich.Case ReportZehn Patienten mit laryngo-pharyngealem Reflux (LPR) nahmen Cong zhi 6 ein. Der Beschwerdeverlauf wurde dokumentiert und die Daten retrospektiv analysiert. Die klinischen Symptome, die mithilfe des Reflux Symptom Index (RSI) Fragebogens erfasst wurden und die mittels des Reflux Finding Score (RFS) beurteilten laryngoskopischen Befunde zeigten beide eine deutliche Verbesserung verschiedener Symptome. Die Zahl der Patienten mit pathologischen LPR-Summenscore reduzierte sich signifikant, im RSI von 8 auf 2 und im RFS von 10 auf 1 Patienten. Der mittlere Summenwert sank von 18.1 auf 8.4 (RSI) und von 12.9 auf 4.4 (RFS). Des Weiteren zeigte sich auch bei anderen gastrointestinalen Beschwerden, wie Bauchschmerzen, Blähungen, Völlegefühl und Übelkeit, die normalerweise mit funktioneller Dyspepsie oder Reizdarm zusammenhängen, eine deutliche Verbesserung (durchschnittliche Verringerung des Scores der drei häufigsten Symptome um 77–87%).ZusammenfassungDie medikamentöse Standardbehandlung bei LPR besteht aus der hochdosierten PPI-Gabe über mindestens 4 Wochen, die jedoch für verschiedene Nebenwirkungen bekannt ist und die nicht-saure Komponente von LPR, wie Pepsin oder andere digestive Enzyme, nicht mitbehandelt. Daher sind andere medikamentöse Behandlungsmöglichkeiten dringend erforderlich. Die vielversprechenden Daten dieser Fallserie deuten darauf hin, dass die tibetische Pflanzenrezeptur Cong zhi 6 eine Behandlungsoption bei LPR sowie deren gastrointestinalen Symptome darstellt und rechtfertigen weitere Studien.}, } @article {pmid37952981, year = {2023}, author = {Okano, H and Morimoto, S and Kato, C and Nakahara, J and Takahashi, S}, title = {Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {167}, number = {5}, pages = {603-614}, doi = {10.1111/jnc.16005}, pmid = {37952981}, issn = {1471-4159}, support = {JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Drug Evaluation, Preclinical ; *Neurodegenerative Diseases/metabolism ; Translational Research, Biomedical ; Randomized Controlled Trials as Topic ; Carbamates ; Phenylenediamines ; }, abstract = {It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.}, } @article {pmid37953075, year = {2023}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Akimoto, M and Yashiro, M and Ueda, M and Hirai, M and Yoshino, H and Mizutani, T and Kanai, K and Kano, O and Kimura, H and Sekino, H and Ito, K}, title = {Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Clinical therapeutics}, volume = {45}, number = {12}, pages = {1251-1258}, doi = {10.1016/j.clinthera.2023.09.025}, pmid = {37953075}, issn = {1879-114X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics ; Glucuronides/therapeutic use ; *Neuroprotective Agents/pharmacokinetics ; Sulfates/therapeutic use ; }, abstract = {PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.

METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.

FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.

IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.

CLINICALTRIALS: gov.}, } @article {pmid37954904, year = {2023}, author = {Zhao, K and Chen, P and Alexander-Bloch, A and Wei, Y and Dyrba, M and Yang, F and Kang, X and Wang, D and Fan, D and Ye, S and Tang, Y and Yao, H and Zhou, B and Lu, J and Yu, C and Wang, P and Liao, Z and Chen, Y and Huang, L and Zhang, X and Han, Y and Li, S and Liu, Y}, title = {A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102276}, pmid = {37954904}, issn = {2589-5370}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems.

METHODS: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD.

FINDINGS: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10[-16]), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aβ (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10[-14]) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10[-15]) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10[-16]) in capturing longitudinal changes in individuals with conversion to AD than CSF Aβ (beta = -0.26, p = 4.40 × 10[-9]) and CSF Tau (beta = 0.12, p = 1.02 × 10[-5]).

INTERPRETATION: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials.

FUNDING: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.}, } @article {pmid37955056, year = {2024}, author = {Spörndly-Nees, S and Jakobsson Larsson, B and Zetterberg, L and Åkerblom, Y and Nyholm, D and Åsenlöf, P}, title = {Pain in patients with motor neuron disease: Variation of pain and association with disease severity, health-related quality of life and depression - A longitudinal study.}, journal = {Palliative & supportive care}, volume = {22}, number = {5}, pages = {1150-1157}, doi = {10.1017/S1478951523001347}, pmid = {37955056}, issn = {1478-9523}, mesh = {Humans ; Female ; Male ; *Quality of Life/psychology ; Middle Aged ; Longitudinal Studies ; *Depression/psychology/etiology/complications ; Aged ; *Motor Neuron Disease/complications/psychology ; Prospective Studies ; *Pain/psychology/etiology/complications ; Severity of Illness Index ; Surveys and Questionnaires ; Pain Measurement/methods ; Adult ; Cohort Studies ; Disease Progression ; Psychometrics/methods/instrumentation ; }, abstract = {OBJECTIVES: To describe levels of pain over time during disease progression in individual patients and for a total sample of patients with motor neuron disease (MND), respectively, and to examine associations between pain, disease severity, health-related quality of life (HRQOL), and depression.

METHODS: A prospective cohort study was conducted on 68 patients with MND, including data collected on five occasions over a period of 2 years. Pain was assessed using the Brief Pain Inventory - Short Form. Depression was assessed using the Amyotrophic Lateral Sclerosis (ALS)-Depression-Inventory (ADI-12). Disability progression was measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version (ALSFRS-R). HRQOL was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5).

RESULTS: Participants reported great individual variation over time. The median level of pain was 4 (min 0 and max 10). Higher levels of pain during the last 24 h were associated with higher depression scores (ADI-12), poorer quality of life (ALSAQ-5), and lower reporting of fine and gross motor skills (ALSFRS-R). Baseline pain levels did not predict future values of depression and function. Individuals reporting average pain >3 experienced more hopelessness toward the future and reported higher depression scores compared with participants reporting average pain <3.

SIGNIFICANCE OF RESULTS: Great within-individual variation of pain intensity was reported. Pain intensity was associated with depression, function and HRQOL cross-sectionally, but it did not have a strong prognostic value for future depression, function, or HRQOL. Patients with MND should be offered frequent assessment of pain and depressive symptoms in person-centered care, allowing for individualization of treatment.}, } @article {pmid37958767, year = {2023}, author = {Gonzalo-Gobernado, R and Moreno-Martínez, L and González, P and Dopazo, XM and Calvo, AC and Pidal-Ladrón de Guevara, I and Seisdedos, E and Díaz-Muñoz, R and Mellström, B and Osta, R and Naranjo, JR}, title = {Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958767}, issn = {1422-0067}, support = {PI21/00372//Instituto de Salud Carlos III/ ; 307//Biomedical Research Networking Center on Neurodegenerative Diseases/ ; }, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Activating Transcription Factor 6/genetics/metabolism ; Neuroprotection ; Motor Neurons/metabolism ; Kv Channel-Interacting Proteins/metabolism ; Superoxide Dismutase/genetics/metabolism ; Disease Models, Animal ; Carbamates ; Piperidines ; }, abstract = {The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.}, } @article {pmid37958929, year = {2023}, author = {Boylan, MA and Pincetic, A and Romano, G and Tatton, N and Kenkare-Mitra, S and Rosenthal, A}, title = {Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958929}, issn = {1422-0067}, mesh = {Humans ; Progranulins/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; *Frontotemporal Dementia/genetics ; Neurons/pathology ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer's disease (AD), Parkinson's disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain's immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state.}, } @article {pmid37966683, year = {2024}, author = {Ansari, MA and Tripathi, T and Venkidasamy, B and Monziani, A and Rajakumar, G and Alomary, MN and Alyahya, SA and Onimus, O and D'souza, N and Barkat, MA and Al-Suhaimi, EA and Samynathan, R and Thiruvengadam, M}, title = {Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.}, journal = {Molecular neurobiology}, volume = {61}, number = {5}, pages = {3042-3089}, pmid = {37966683}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Animals ; *Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Multifunctional Nanoparticles/chemistry ; }, abstract = {Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.}, } @article {pmid37968433, year = {2024}, author = {Quattrocchi, S and Bonan, L and Cirillo, L and Avoni, P and Di Stasi, V and Rizzo, G and Liguori, R and Vacchiano, V}, title = {Bibrachial amyotrophy as a rare manifestation of intraspinal fluid collection: a case report and systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2279-2288}, pmid = {37968433}, issn = {1590-3478}, mesh = {Humans ; Male ; Middle Aged ; *Magnetic Resonance Imaging ; Electromyography ; Motor Neuron Disease/diagnosis/complications ; }, abstract = {INTRODUCTION: Intraspinal cerebrospinal fluid (CSF) collection has been reported as a rare cause of lower motor neuron (LMN) disorder. We report a case of bibrachial diplegia associated with intraspinal CSF collection and perform a systematic literature review.

PATIENT AND METHODS: A 52-year-old man developed a bibrachial amyotrophy over 6 years, confirmed by the presence of cervical subacute neurogenic changes at electromyography (EMG). Brain magnetic resonance imaging (MRI) revealed cerebral siderosis, while spine MRI showed a ventral longitudinal intraspinal fluid collection (VLISFC) from C2 to L2. No CSF leakage was localized at myelography; a conservative treatment was chosen. We searched for all published cases until 30th April 2023 and extrapolated data of 44 patients reported in 27 publications.

RESULTS: We observed a male predominance, a younger disease onset compared to amyotrophic lateral sclerosis, and a quite long disease duration, highlighting a slow disease progression. LMN signs were more frequently bilateral, mostly involving C5-C6 myotomes. Around 61% of patients presented additional symptoms, but only three referred to a history of headache. Accordingly, CSF opening pressure was mostly normal. Spinal MRI revealed the presence of VLISFC and in some cases myelomalacia. EMG patterns displayed both chronic and subacute neurogenic change in the cervical region. The disease course mainly depended on the treatment choice, which was mostly represented by a surgical approach when a specific dural defect was detected by imaging.

CONCLUSION: Bibrachial diplegia due to VLISFC can be a treatable cause of focal amyotrophy and presents some clinical and radiological "red flags" which cannot be missed by a clinical neurologist.}, } @article {pmid37972860, year = {2023}, author = {Rizzuti, M and Sali, L and Melzi, V and Scarcella, S and Costamagna, G and Ottoboni, L and Quetti, L and Brambilla, L and Papadimitriou, D and Verde, F and Ratti, A and Ticozzi, N and Comi, GP and Corti, S and Gagliardi, D}, title = {Genomic and transcriptomic advances in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102126}, doi = {10.1016/j.arr.2023.102126}, pmid = {37972860}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Transcriptome/genetics ; Gene Expression Profiling/methods ; *MicroRNAs/genetics/metabolism ; Biomarkers ; Epigenomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.}, } @article {pmid37973064, year = {2024}, author = {Lisi, E and Abellan, JJ}, title = {Statistical analysis of actigraphy data with generalised additive models.}, journal = {Pharmaceutical statistics}, volume = {23}, number = {3}, pages = {308-324}, doi = {10.1002/pst.2350}, pmid = {37973064}, issn = {1539-1612}, support = {//GlaxoSmithKline/ ; }, mesh = {Humans ; *Actigraphy/statistics & numerical data/methods ; *Models, Statistical ; Exercise/physiology ; Data Interpretation, Statistical ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Pulmonary Disease, Chronic Obstructive/physiopathology/diagnosis ; Time Factors ; }, abstract = {There is a growing interest in the use of physical activity data in clinical studies, particularly in diseases that limit mobility in patients. High-frequency data collected with digital sensors are typically summarised into actigraphy features aggregated at epoch level (e.g., by minute). The statistical analysis of such volume of data is not straightforward. The general trend is to derive metrics, capturing specific aspects of physical activity, that condense (say) a week worth of data into a single numerical value. Here we propose to analyse the entire time-series data using Generalised Additive Models (GAMs). GAMs are semi-parametric models that allow inclusion of both parametric and non-parametric terms in the linear predictor. The latter are smooth terms (e.g., splines) and, in the context of actigraphy minute-by-minute data analysis, they can be used to assess daily patterns of physical activity. This in turn can be used to better understand changes over time in longitudinal studies as well as to compare treatment groups. We illustrate the application of GAMs in two clinical studies where actigraphy data was collected: a non-drug, single-arm study in patients with amyotrophic lateral sclerosis, and a physical-activity sub-study included in a phase 2b clinical trial in patients with chronic obstructive pulmonary disease.}, } @article {pmid37974227, year = {2023}, author = {Awuah, WA and Ahluwalia, A and Ghosh, S and Roy, S and Tan, JK and Adebusoye, FT and Ferreira, T and Bharadwaj, HR and Shet, V and Kundu, M and Yee, ALW and Abdul-Rahman, T and Atallah, O}, title = {The molecular landscape of neurological disorders: insights from single-cell RNA sequencing in neurology and neurosurgery.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {529}, pmid = {37974227}, issn = {2047-783X}, mesh = {Humans ; *Neurosurgery ; Neurosurgical Procedures ; *Neurology ; *Brain Neoplasms/genetics ; Sequence Analysis, RNA ; Tumor Microenvironment ; }, abstract = {Single-cell ribonucleic acid sequencing (scRNA-seq) has emerged as a transformative technology in neurological and neurosurgical research, revolutionising our comprehension of complex neurological disorders. In brain tumours, scRNA-seq has provided valuable insights into cancer heterogeneity, the tumour microenvironment, treatment resistance, and invasion patterns. It has also elucidated the brain tri-lineage cancer hierarchy and addressed limitations of current models. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have been molecularly subtyped, dysregulated pathways have been identified, and potential therapeutic targets have been revealed using scRNA-seq. In epilepsy, scRNA-seq has explored the cellular and molecular heterogeneity underlying the condition, uncovering unique glial subpopulations and dysregulation of the immune system. ScRNA-seq has characterised distinct cellular constituents and responses to spinal cord injury in spinal cord diseases, as well as provided molecular signatures of various cell types and identified interactions involved in vascular remodelling. Furthermore, scRNA-seq has shed light on the molecular complexities of cerebrovascular diseases, such as stroke, providing insights into specific genes, cell-specific expression patterns, and potential therapeutic interventions. This review highlights the potential of scRNA-seq in guiding precision medicine approaches, identifying clinical biomarkers, and facilitating therapeutic discovery. However, challenges related to data analysis, standardisation, sample acquisition, scalability, and cost-effectiveness need to be addressed. Despite these challenges, scRNA-seq has the potential to transform clinical practice in neurological and neurosurgical research by providing personalised insights and improving patient outcomes.}, } @article {pmid37974279, year = {2023}, author = {Pelaez, MC and Desmeules, A and Gelon, PA and Glasson, B and Marcadet, L and Rodgers, A and Phaneuf, D and Pozzi, S and Dutchak, PA and Julien, JP and Sephton, CF}, title = {Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {182}, pmid = {37974279}, issn = {2051-5960}, support = {RGPIN-2020-06376//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2020-00060//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2018-06227//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2018-00093//Natural Sciences and Engineering Research Council of Canada/ ; Junior 1//Fonds de Recherche du Québec - Santé/ ; }, mesh = {Aged ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Disease Progression ; *Frontotemporal Dementia/pathology ; Mice, Transgenic ; Motor Neurons/metabolism ; Mutation ; NF-kappa B/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD. Expression of ALS-linked FUS mutants in mice causes cognitive and motor defects, which correlate with loss of motor neuron dendritic branching and synapses, in addition to other pathological features of ALS/FTD. The role of ALS-linked FUS mutants in causing ALS/FTD-associated disease phenotypes is well established, but there are significant gaps in our understanding of the cell-autonomous role of FUS in promoting structural changes to motor neurons, and how these changes relate to disease progression. Here we generated a neuron-specific FUS-transgenic mouse model expressing the ALS-linked human FUSR521G variant, hFUS[R521G/Syn1], to investigate the cell-autonomous role of FUSR521G in causing loss of dendritic branching and synapses of motor neurons, and to understand how these changes relate to ALS-associated phenotypes. Longitudinal analysis of mice revealed that cognitive impairments in juvenile hFUS[R521G/Syn1] mice coincide with reduced dendritic branching of cortical motor neurons in the absence of motor impairments or changes in the neuromorphology of spinal motor neurons. Motor impairments and dendritic attrition of spinal motor neurons developed later in aged hFUS[R521G/Syn1] mice, along with FUS cytoplasmic mislocalisation, mitochondrial abnormalities and glial activation. Neuroinflammation promotes neuronal dysfunction and drives disease progression in ALS/FTD. The therapeutic effects of inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) pathway with an analog of Withaferin A, IMS-088, were assessed in symptomatic hFUS[R521G/Syn1] mice and were found to improve cognitive and motor function, increase dendritic branches and synapses of motor neurons, and attenuate other ALS/FTD-associated pathological features. Treatment of primary cortical neurons expressing FUSR521G with IMS-088 promoted the restoration of dendritic mitochondrial numbers and mitochondrial activity to wild-type levels, suggesting that inhibition of NF-κB permits the restoration of mitochondrial stasis in our models. Collectively, this work demonstrates that FUSR521G has a cell-autonomous role in causing early pathological changes to dendritic and synaptic structures of motor neurons, and that these changes precede motor defects and other well-known pathological features of ALS/FTD. Finally, these findings provide further support that modulation of the NF-κB pathway in ALS/FTD is an important therapeutic approach to attenuate disease.}, } @article {pmid37975632, year = {2024}, author = {Fornage, LB and O'Neil, C and Dowker, SR and Wanta, ER and Lewis, RS and Brown, LH}, title = {Prehospital Intervention Improves Outcomes for Patients Presenting in Atrial Fibrillation with Rapid Ventricular Response.}, journal = {Prehospital emergency care}, volume = {28}, number = {7}, pages = {910-919}, doi = {10.1080/10903127.2023.2283885}, pmid = {37975632}, issn = {1545-0066}, support = {R01-HL137964/NH/NIH HHS/United States ; }, mesh = {Humans ; Retrospective Studies ; Male ; Female ; *Atrial Fibrillation/therapy/drug therapy ; Aged ; *Emergency Medical Services/methods ; Middle Aged ; Adult ; Aged, 80 and over ; Adolescent ; Cohort Studies ; Advanced Cardiac Life Support/methods ; Propensity Score ; Out-of-Hospital Cardiac Arrest/therapy/mortality ; Young Adult ; }, abstract = {OBJECTIVE: To compare outcomes of patients presenting to emergency medical services (EMS) with atrial fibrillation with rapid ventricular response (AF-RVR) who did and did not receive prehospital advanced life support (ALS) rate or rhythm control intervention(s).

METHODS: This retrospective cohort study used the 2021 ESO Data Collaborative (Austin, TX) dataset. We identified 9-1-1 scene responses for patients aged 16 to 100 years old presenting with AF and an initial heart rate ≥ 110 beats per minute (bpm). Prehospital ALS interventions for AF-RVR included medications (e.g., calcium channel blockers, beta blockers, etc.) or electrical cardioversion. Outcome measures included prehospital rate control (i.e., final prehospital heart rate < 110 bpm), emergency department (ED) discharge to home, ED and hospital length of stay, and mortality. We also evaluated prehospital adverse events-specifically bradycardia, hypotension, and cardiac arrest. We used propensity score matching to compare outcomes among treated and untreated patients with similar demographic and clinical characteristics. We determined the average treatment effect on the treated (ATET) with 95% confidence intervals (CI) and the number needed to treat (NNT).

RESULTS: After propensity score matching, prehospital outcomes were available for 4,859 treated patients matched with 4,859 similar untreated patients. Prehospital rate control was more frequent for treated than for untreated patients (41.0% vs. 18.2%, ATET +22.8%, CI: +21.1%; +24.6%, NNT = 5). Hospital outcomes were available for 1,347 treated patients matched with 1,347 similar untreated patients. Treated patients were more likely to be discharged from the ED (37.9% vs. 34.0%, ATET +3.9%, CI: +0.2%; +7.5%, NNT = 26) and less likely to die (4.3% vs. 6.7%, ATET -2.5%, CI: -4.2%; -0.8%, NNT = 40) compared to untreated patients. Hypotension occurred more often in treated patients (ATET +2.6%, CI: +1.5%; +3.7%), but resolved before ED arrival in 73% of affected patients. Otherwise, adverse event rates did not significantly differ for the two groups.

CONCLUSIONS: In this propensity score matched study of patients presenting to EMS with AF-RVR, prehospital ALS interventions were associated with more frequent prehospital rate control, more frequent discharge to home from the ED, and lower mortality.}, } @article {pmid37975796, year = {2024}, author = {Witzel, S and Statland, JM and Steinacker, P and Otto, M and Dorst, J and Schuster, J and Barohn, RJ and Ludolph, AC}, title = {Longitudinal course of neurofilament light chain levels in amyotrophic lateral sclerosis-insights from a completed randomized controlled trial with rasagiline.}, journal = {European journal of neurology}, volume = {31}, number = {3}, pages = {e16154}, pmid = {37975796}, issn = {1468-1331}, support = {R01 FD003739/FD/FDA HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Intermediate Filaments ; Biomarkers ; Neurofilament Proteins ; Disease Progression ; *Indans ; }, abstract = {BACKGROUND AND PURPOSE: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS.

METHODS: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2 mg/day (n = 48) or placebo (n = 17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters.

RESULTS: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre-baseline (r = 0.64, p < 0.001) and during the study (r = 0.61, p < 0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4 pg/mL (interquartile range [IQR] -5.6, 14.2) across all follow-up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n = 13], -6.9 pg/mL, IQR -20.4, 6.0; low [n = 18], +5.9 pg/mL, IQR -1.4, 19.7; p = 0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course.

CONCLUSION: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis-generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors.}, } @article {pmid37975798, year = {2024}, author = {Saini, A and Chawla, PA}, title = {Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16140}, pmid = {37975798}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Oligonucleotides/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease.

METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary.

RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS.

CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.}, } @article {pmid37977335, year = {2023}, author = {Benussi, A and Cantoni, V and Grassi, M and Libri, I and Cotelli, MS and Tarantino, B and Datta, A and Thomas, C and Huber, N and Kärkkäinen, S and Herukka, SK and Haapasalo, A and Filosto, M and Padovani, A and Borroni, B}, title = {Cortico-spinal tDCS in amyotrophic lateral sclerosis: A randomized, double-blind, sham-controlled trial followed by an open-label phase.}, journal = {Brain stimulation}, volume = {16}, number = {6}, pages = {1666-1676}, doi = {10.1016/j.brs.2023.11.008}, pmid = {37977335}, issn = {1876-4754}, mesh = {Humans ; *Transcranial Direct Current Stimulation ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Transcranial Magnetic Stimulation ; Double-Blind Method ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available.

OBJECTIVE: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase.

METHODS: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates.

RESULTS: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival.

CONCLUSIONS: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival.

CLINICAL TRIAL REGISTRATION: NCT04293484.}, } @article {pmid37981210, year = {2024}, author = {Kim, Y and Lee, Y and Choo, M and Yun, N and Cho, JW and Oh, YJ}, title = {A surge of cytosolic calcium dysregulates lysosomal function and impairs autophagy flux during cupric chloride-induced neuronal death.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {1}, pages = {105479}, pmid = {37981210}, issn = {1083-351X}, mesh = {*Autophagy/drug effects/genetics ; *Calcium/metabolism ; *Copper/pharmacology ; *Dopaminergic Neurons/cytology/drug effects/metabolism/ultrastructure ; *Lysosomes/metabolism ; Animals ; Mice ; Cell Line ; Cell Survival/drug effects ; Cytosol/metabolism ; }, abstract = {Autophagy is a degradative pathway that plays an important role in maintaining cellular homeostasis. Dysfunction of autophagy is associated with the progression of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although one of the typical features of brain aging is an accumulation of redox-active metals that eventually lead to neurodegeneration, a plausible link between trace metal-induced neurodegeneration and dysregulated autophagy has not been clearly determined. Here, we used a cupric chloride-induced neurodegeneration model in MN9D dopaminergic neuronal cells along with ultrastructural and biochemical analyses to demonstrate impaired autophagic flux with accompanying lysosomal dysfunction. We found that a surge of cytosolic calcium was involved in cupric chloride-induced dysregulated autophagy. Consequently, buffering of cytosolic calcium by calbindin-D28K overexpression or co-treatment with the calcium chelator BAPTA attenuated the cupric chloride-induced impairment in autophagic flux by ameliorating dysregulation of lysosomal function. Thus, these events allowed the rescue of cells from cupric chloride-induced neuronal death. These phenomena were largely confirmed in cupric chloride-treated primary cultures of cortical neurons. Taken together, these results suggest that abnormal accumulation of trace metal elements and a resultant surge of cytosolic calcium leads to neuronal death by impairing autophagic flux at the lysosomal level.}, } @article {pmid37982993, year = {2023}, author = {Tsui, A and Kouznetsova, VL and Kesari, S and Fiala, M and Tsigelny, IF}, title = {Role of Senataxin in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {11-12}, pages = {996-1009}, pmid = {37982993}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Gene Expression Regulation ; Mutation ; DNA Helicases/genetics ; RNA Helicases/genetics/metabolism ; Multifunctional Enzymes/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.}, } @article {pmid37983563, year = {2024}, author = {Wen, D and Ji, Y and Li, Y and Duan, W and Wang, Y and Li, Z and Tao, M and Liu, Y}, title = {OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.}, journal = {The FEBS journal}, volume = {291}, number = {4}, pages = {795-813}, doi = {10.1111/febs.17009}, pmid = {37983563}, issn = {1742-4658}, support = {H2021206048//Hebei Natural Science Foundation/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Autophagy/genetics ; Mitochondria/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage-dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS.}, } @article {pmid37984338, year = {2023}, author = {Topaloğlu Ören, ED and Dorukoğlu, S and Ertem, G}, title = {The Use of Complementary and Alternative Medicine and Coping with Stress by Patients with Gynecological Cancer: A Cross-Sectional Study in Türkiye.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {502-516}, doi = {10.1159/000534707}, pmid = {37984338}, issn = {2504-2106}, mesh = {Humans ; Female ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Turkey ; *Neoplasms ; *Complementary Therapies ; Adaptation, Psychological ; }, abstract = {INTRODUCTION: Gynecological cancers are long-term, challenging, and stressful diseases. In Türkiye, the majority of patients with gynecological cancer use complementary and alternative medicine (CAM). Considering the stress that gynecological cancer patients are exposed to, patients need to know how to cope with stress.

OBJECTIVE: This study aimed to determine the use of CAM and coping with stress by patients with gynecological cancer and the relationships between them and the factors that predict the approaches to coping with stress in women with gynecological cancer in Türkiye.

METHODS: This is a descriptive and cross-sectional study. The study was conducted with 204 patients between April and August 2022. The data of the study were collected by face-to-face interview and filled out by the patients using the Descriptive Information Form and the Stress Coping Styles Scale (SCSS). Number, percentage, mean, χ2, one-way ANOVA, t test, and the Spearman correlation analysis were used in the data analysis. To analyze the multivariate independent associations between variables, a multivariate ordinal logistic regression model was used, with the SCSS domains as dependent variables. A 95% confidence interval was calculated, and all statistical tests had an alpha level of 0.05.

RESULTS: The mean age of the patients was 58.38 ± 12.64 years (32-80). The prevalence of CAM use by patients was 39.2%, and the most common types of CAM were herbal products (43.8%) and supplication (42.5%). The reasons for using CAM were relaxation (symptomatic)-feeling healthy (63.8%) and treating cancer (36.2%). No statistically significant difference was found between the use of CAM and their approaches to coping with stress (p > 0.05). As a result of multivariate ordinal logistic regression analysis, education level under high school, having ovary, cervix, and endometrium cancer, being in the first stage of cancer, receiving chemotherapy, receiving surgical treatment, having another cancer patient in the social environment and increased interest in a partner after the diagnosis of cancer was associated with an effective coping with stress (p < 0.05, adjusted R2 = 0.27, 0.79, and 0.32, respectively). Not working, experiencing an abortion, having another cancer patient in their social environment, being in the third stage of cancer, having an extended family, and living in a rural area of residence were associated with ineffective coping with stress (p < 0.05, adjusted R2 = 0.20 and 0.24, respectively).

CONCLUSIONS: The prevalence of CAM use by patients was low. While determining the approaches of the patients to cope with stress, their education level, place of residence, family type, diagnosis of cancer, stage of cancer, treatment, partner support, and stressful life events should be considered. As nurses, we need to be more knowledgeable about the use of CAM to provide correct guidance to our patients for access to accurate and effective information. We need to determine our patients' stressors and how our patients cope with stress.

UNLABELLED: EinleitungGynäkologische Krebserkrankungen sind langfristige, herausfordernde und belastende Krankheiten. In der Türkei nehmen die meisten Patientinnen mit gynäkologischen Krebserkrankungen Komplementär- und Alternativmedizin in Anspruch. Angesichts der großen Belastungen, denen Patientinnen mit gynäkologischen Krebserkrankungen ausgesetzt sind, müssen sie wissen, wie sie mit Stress umgehen können.ZielMit dieser Studie sollen die Inanspruchnahme von Komplementär- und Alternativmedizin und die Stressbewältigung von Patientinnen mit gynäkologischer Krebserkrankung ermittelt werden und es sollen die Zusammenhänge zwischen diesen beiden Aspekten und den prädiktiven Faktoren für die Ansätze zur Stressbewältigung bei Frauen mit gynäkologischer Krebserkrankung untersucht werden.MethodenEs handelt sich um eine deskriptive Querschnittsstudie. Die Studie wurde mit 204 Patientinnen zwischen April und August 2022 durchgeführt. Die Erhebung der Studiendaten erfolgte durch persönliche Befragung und mithilfe des deskriptiven Informationsformulars sowie der Stress Coping Styles-Skala, die die Patientinnen ausfüllten. Für die Datenanalyse wurden Anzahl, Prozentanteil, Mittelwert, Chi-Quadrat-Test, einfaktorielle ANOVA, t Test und die Spearman-Korrelationsanalyse verwendet. Zur Analyse der multivariaten unabhängigen Zusammenhänge zwischen den Variablen wurde ein multivariates ordinales logistisches Regressionsmodell verwendet mit den SCSS (Stress Coping Styles-Skala)-Domänen als abhängigen Variablen. Es wurde ein 95%-Konfidenzintervall berechnet, und das Signifikanzniveau betrug für alle statistischen Tests α = 0.05.ErgebnisseDas Durchschnittsalter der Patientinnen betrug 58.38 ± 12.64 Jahre (32–80 Jahre). Die Prävalenz der Inanspruchnahme von Komplementär- und Alternativmedizin (CAM) durch die Patientinnen lag bei 39.2%, und die häufigsten CAM-Arten waren pflanzliche Produkte (43.8%) und Bittgebete (42.5%). Die Gründe für die Inanspruchnahme von Komplementär- und Alternativmedizin waren Entspannung (symptomatisch), das Gefühl von Gesundheit (63.8%) und die Behandlung der Krebserkrankung (36.2%). Es fand sich kein statistisch signifikanter Unterschied zwischen der Inanspruchnahme von Komplementär- und Alternativmedizin und ihren Ansätzen zur Stressbewältigung (p > 0.05). Die multivariate ordinale logistische Regressionsanalyse zeigte, dass ein Bildungsniveau unterhalb der Oberstufe sowie Ovarial-, Zervix- und Endometriumkarzinom, Krebs im Anfangsstadium, Chemotherapie, operative Behandlung, eine andere Krebspatientin im sozialen Umfeld und ein gesteigertes Interesse an einem Partner nach der Krebsdiagnose mit effektiver Stressbewältigung assoziiert waren (p < 0.05, adjustiertes R2 = 0.27, 0.79 bzw. 0.32). Fehlende Berufstätigkeit, Fehlgeburt/Schwangerschaftsabbruch, eine andere Krebspatientin im sozialen Umfeld, eine Krebserkrankung im dritten Stadium, eine Großfamilie zu haben und in einer ländlichen Gegend zu leben waren mit ineffektiver Stressbewältigung verbunden (p < 0.05, adjustiertes R2 = 0.20 bzw. 0.24).SchlussfolgerungenDie Prävalenz der Inanspruchnahme von Komplementär- und Alternativmedizin durch die Patientinnen war gering. Bei der Ermittlung der Ansätze der Patientinnen zur Stressbewältigung sollten ihr Bildungsniveau, ihr Wohnort, ihr Familientyp, die Krebsdiagnose, das Krebsstadium, die Behandlung, die Unterstützung durch den Partner und belastende Lebensereignisse berücksichtigt werden. Als Pflegekräfte müssen wir mehr über die Inanspruchnahme von Komplementär- und Alternativmedizin wissen, um unsere Patientinnen in Hinblick auf den Zugang zu genauen und wirksamen Informationen die richtige Orientierungshilfe zu geben. Wir müssen die Stressfaktoren unserer Patientinnen ermitteln und herausfinden, wie unsere Patientinnen mit Stress umgehen.}, } @article {pmid37986827, year = {2023}, author = {Simmonds, E and Levine, KS and Han, J and Iwaki, H and Koretsky, MJ and Kuznetsov, N and Faghri, F and Solsberg, CW and Schuh, A and Jones, L and Bandres-Ciga, S and Blauwendraat, C and Singleton, A and Escott-Price, V and Leonard, HL and Nalls, MA}, title = {Sleep disturbances as risk factors for neurodegeneration later in life.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37986827}, abstract = {The relationship between sleep disorders and neurodegeneration is complex and multi-faceted. Using over one million electronic health records (EHRs) from Wales, UK, and Finland, we mined biobank data to identify the relationships between sleep disorders and the subsequent manifestation of neurodegenerative diseases (NDDs) later in life. We then examined how these sleep disorders' severity impacts neurodegeneration risk. Additionally, we investigated how sleep attributed risk may compensate for the lack of genetic risk factors (i.e. a lower polygenic risk score) in NDD manifestation. We found that sleep disorders such as sleep apnea were associated with the risk of Alzheimer's disease (AD), amyotrophic lateral sclerosis, dementia, Parkinson's disease (PD), and vascular dementia in three national scale biobanks, with hazard ratios (HRs) ranging from 1.31 for PD to 5.11 for dementia. These sleep disorders imparted significant risk up to 15 years before the onset of an NDD. Cumulative number of sleep disorders in the EHRs were associated with a higher risk of neurodegeneration for dementia and vascular dementia. Sleep related risk factors were independent of genetic risk for Alzheimer's and Parkinson's, potentially compensating for low genetic risk in overall disease etiology. There is a significant multiplicative interaction regarding the combined risk of sleep disorders and Parkinson's disease. Poor sleep hygiene and sleep apnea are relatively modifiable risk factors with several treatment options, including CPAP and surgery, that could potentially reduce the risk of neurodegeneration. This is particularly interesting in how sleep related risk factors are significantly and independently enriched in manifesting NDD patients with low levels of genetic risk factors for these diseases.}, } @article {pmid37992159, year = {2023}, author = {Shimizu, M and Shiraishi, N and Tada, S and Sasaki, T and Beck, G and Nagano, S and Kinoshita, M and Sumi, H and Sugimoto, T and Ishida, Y and Koda, T and Ishikura, T and Sugiyama, Y and Kihara, K and Kanakura, M and Nakajima, T and Takeda, S and Takahashi, MP and Yamashita, T and Okuno, T and Mochizuki, H}, title = {RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.}, journal = {Science advances}, volume = {9}, number = {47}, pages = {eadg3193}, pmid = {37992159}, issn = {2375-2548}, mesh = {Animals ; Humans ; Mice ; Actins ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Antibodies ; Mice, Transgenic ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Nerve Tissue Proteins ; GPI-Linked Proteins ; }, abstract = {Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.}, } @article {pmid37992921, year = {2024}, author = {Li, L and Lei, T and Xing, C and Du, H}, title = {Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128308}, doi = {10.1016/j.ijbiomac.2023.128308}, pmid = {37992921}, issn = {1879-0003}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Microfluidics ; *Alzheimer Disease ; Amyloid beta-Peptides ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.}, } @article {pmid38001260, year = {2023}, author = {Kuan, LH and Parnianpour, P and Kushol, R and Kumar, N and Anand, T and Kalra, S and Greiner, R}, title = {Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {20713}, pmid = {38001260}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Probability ; Brain ; Learning ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Accurately predicting the survival time for ALS patients can help patients and clinicians to plan for future treatment and care. We describe the application of a machine-learned tool that incorporates clinical features and cortical thickness from brain magnetic resonance (MR) images to estimate the time until a composite respiratory failure event for ALS patients, and presents the prediction as individual survival distributions (ISDs). These ISDs provide the probability of survival (none of the respiratory failures) at multiple future time points, for each individual patient. Our learner considers several survival prediction models, and selects the best model to provide predictions. We evaluate our learned model using the mean absolute error margin (MAE-margin), a modified version of mean absolute error that handles data with censored outcomes. We show that our tool can provide helpful information for patients and clinicians in planning future treatment.}, } @article {pmid38001557, year = {2024}, author = {Genge, A and Wainwright, S and Vande Velde, C}, title = {Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {225-236}, doi = {10.1080/21678421.2023.2278503}, pmid = {38001557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.}, } @article {pmid38001861, year = {2023}, author = {Fu, RH}, title = {Pectolinarigenin Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-Associated Proline-Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001861}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//The Ministry of Science and Technology (Taiwan)/ ; DMR112-122//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is considered a fatal progressive degeneration of motor neurons (MN) caused by oxidative stress and mitochondrial dysfunction. There are currently no treatments available. The most common inherited form of ALS is the C9orf72 mutation (C9-ALS). The proline-arginine dipeptide repeat protein (PR-DPR) produced by C9-ALS has been confirmed to be a functionally acquired pathogenic factor that can cause increased ROS, mitochondrial defects, and apoptosis in motor neurons. Pectolinarigenin (PLG) from the traditional medicinal herb Linaria vulgaris has antioxidant and anti-apoptotic properties. I established a mouse NSC-34 motor neuron cell line model expressing PR-DPR and confirmed the neuroprotective effect of PLG. The results showed that ROS production and apoptosis caused by PR-DPR could be improved by PLG treatment. In terms of mechanism research, PR-DPR inhibited the activity of the mitochondrial fusion proteins OPA1 and mitofusin 2. Conversely, the expression of fission protein fission 1 and dynamin-related protein 1 (DRP1) increased. However, PLG treatment reversed these effects. Furthermore, I found that PLG increased the expression and deacetylation of OPA1. Deacetylation of OPA1 enhances mitochondrial fusion and resistance to apoptosis. Finally, transfection with Sirt3 small interfering RNA abolished the neuroprotective effects of PLG. In summary, the mechanism by which PLG alleviates PR-DPR toxicity is mainly achieved by activating the SIRT3/OPA1 axis to regulate the balance of mitochondrial dynamics. Taken together, the potential of PLG in preclinical studies for C9-ALS drug development deserves further evaluation.}, } @article {pmid38001967, year = {2023}, author = {Seki, S and Kitaoka, Y and Kawata, S and Nishiura, A and Uchihashi, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S}, title = {Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001967}, issn = {2227-9059}, support = {21K17088//JSPS KAKENHI/ ; 20H03887//JSPS KAKENHI/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.}, } @article {pmid38002490, year = {2023}, author = {Yang, J and Xin, C and Huo, J and Li, X and Dong, H and Liu, Q and Li, R and Liu, Y}, title = {Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {13}, number = {11}, pages = {}, pmid = {38002490}, issn = {2076-3425}, support = {H2021206310//Natural Science Foundation of Hebei Province/ ; }, abstract = {BACKGROUND: Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells.

METHODS: Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression.

RESULTS: Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (ΔFS).

CONCLUSIONS: The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.}, } @article {pmid38003309, year = {2023}, author = {Toader, C and Dobrin, N and Brehar, FM and Popa, C and Covache-Busuioc, RA and Glavan, LA and Costin, HP and Bratu, BG and Corlatescu, AD and Popa, AA and Ciurea, AV}, title = {From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003309}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/diagnosis ; Biomarkers/metabolism ; }, abstract = {With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.}, } @article {pmid38005288, year = {2023}, author = {Lapshina, MA and Shevtsova, EF and Grigoriev, VV and Aksinenko, AY and Ustyugov, AA and Steinberg, DA and Maleev, GV and Dubrovskaya, ES and Goreva, TV and Epishina, TA and Zamoyski, VL and Makhaeva, GF and Fisenko, VP and Veselov, IM and Vinogradova, DV and Bachurin, SO}, title = {New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {22}, pages = {}, pmid = {38005288}, issn = {1420-3049}, support = {19-13-00378-P//Russian Science Foundation/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Adamantane ; Riluzole ; Amantadine/therapeutic use ; }, abstract = {Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.}, } @article {pmid38007795, year = {2023}, author = {Feng, T}, title = {Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.}, journal = {Studies in health technology and informatics}, volume = {308}, number = {}, pages = {648-655}, doi = {10.3233/SHTI230896}, pmid = {38007795}, issn = {1879-8365}, mesh = {Humans ; Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; Machine Learning ; Natural Language Processing ; }, abstract = {Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.}, } @article {pmid38008065, year = {2024}, author = {Maier, GS and Rosar, G and Dietz, G and Hemken, N and Kafchitsas, K and Seeger, JB and Horas, K}, title = {Effectiveness of Mud-Pack Therapy and Mud-Bath Therapy in Osteoarthritis: A Systematic Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {30-39}, doi = {10.1159/000535437}, pmid = {38008065}, issn = {2504-2106}, mesh = {Humans ; *Mud Therapy ; *Osteoarthritis, Knee ; *Osteoarthritis, Hip ; Quality of Life ; *Low Back Pain ; }, abstract = {OBJECTIVES: Osteoarthritis has a tremendous socioeconomic impact in terms of drug spending, hospital admissions, work productivity, and temporary or permanent incapacity. Mud therapy has been discussed as potential conservative treatment options for osteoarthritis. However, findings from several trials still remain controversial. For this reason, we aimed to systematically review the highest evidence provided by published trials to estimate the clinical effect of mud-pack and mud-bath therapy for the treatment of osteoarthritis.

METHODS: We searched PubMed, PEDro, and the Cochrane CENTRAL Register for Controlled Trials for articles published between 2000 and 2020 using the terms "orthopedics," "orthopaedics," "musculoskeletal," "osteoarthritis," and "mud bath," "mud pack."

RESULTS: Of the 19 studies included, 15 examined the effects of mud-bath therapy in knee osteoarthritis treatment. One study focused on the treatment effect of mud bath on hand osteoarthritis, another study examined treatment effects in hip and knee osteoarthritis, and two studies enrolled patients with chronic low back pain caused by lumbar spine osteoarthritis. We systematically reviewed the data obtained from the literature and summarized the results on the basis of the main outcomes. The results show significant improvements in function, quality of life, and perceived pain for patients with osteoarthritis.

CONCLUSION: Results of randomized controlled trials suggest that mud therapy is part of a promising integrated and synergistic multidisciplinary approach in combination with other treatment forms like pharmacotherapy or physiotherapy.

UNLABELLED: ZieleDie sozio-ökonomischen Auswirkungen der Arthrose sind immens. Heiltorfbehandlungen sind seit einiger Zeit als mögliche Ergänzung der konservativen Therapieoptionen dieser Erkrankung Gegenstand wissenschaftlicher Untersuchungen. Ziel dieser Studie war es, die aktuellen Erkenntnisse zur Heiltorftherapie bei Arthrose zusammenzufassen.MethodenWir führten eine systematische Literaturrecherche der Datenbanken Pubmed, PEDro und Cochrane CENTRAL Register of Controlled Trials durch. Hierbei wurden Artikel, die zwischen 2000 und 2020 publiziert wurden und mit den Schlagwörtern “orthopedics”, “orthopaedics”, “musculoskeletal”, “osteoarthritis” und “mud-bath”, “mud-pack” assoziiert waren, erfasst.ErgebnisseVon den 19 näher untersuchten Studien beschäftigten sich 15 mit den Effekten der Heiltorftherapie bei Patienten mit Kniearthrose, eine Studie untersuchte Patienten mit Arthrose der Hand, eine weitere Studie untersuchte die Auswirkung der Therapie bei Arthrose der Hüfte. 2 Studien untersuchten den Effekt der Moorbäder bei Patienten mit chronischen Rückenschmerzen. Insgesamt zeigten sich signifikante Verbesserungen der Funktion, Lebensqualität und Schmerzlinderung bei den Patienten unter Heiltorftherapie.ZusammenfassungDie Ergebnisse der randomisierten, kontrollierten Studien zeigen, dass die Heiltorftherapie eine vielversprechende Ergänzung in einem multidisziplinären Ansatz der Arthrosetherapie ist.}, } @article {pmid38008074, year = {2024}, author = {Saha, S and Singh, R and Mani, I and Chakraborty, K and Sarkar, P and Saha, S and Rana, A and Chattopadhyay, R}, title = {Individualized Homeopathic Medicines in the Treatment of Post-COVID-19 Fatigue in Adults: Single-Blind, Randomized, Placebo-Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {1-9}, doi = {10.1159/000535279}, pmid = {38008074}, issn = {2504-2106}, mesh = {Adult ; Humans ; *COVID-19/therapy ; India ; *Materia Medica ; Quality of Life ; Single-Blind Method ; Sulfur ; }, abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) is leading to unknown and unusual health conditions that are challenging to manage. Post-COVID-19 fatigue is one of those challenges, becoming increasingly common as the pandemic evolves, as it impairs the quality of life of an individual. This trial attempts to identify the preliminary evidence of the efficacy of individualized homeopathic medicines (IHMs) against placebos in the treatment of post-COVID-19 fatigue in adults.

METHODS: A 3-month, single-blind, randomized, placebo-controlled, parallel-arm trial was conducted at the outpatient department of The Calcutta Homoeopathic Medical College and Hospital, India. Sixty participants were randomized in a 1:1 ratio to receive either IHMs (n = 30) or identical-looking placebos (n = 30). The primary and secondary outcome measures were the Fatigue Assessment Scale (FAS) and Outcome in Relation to Impact on Daily Living (ORIDL), respectively, measured every month, for up to 3 months. Comparative analysis was carried out on the intention-to-treat sample to detect group differences.

RESULTS: Group differences in both the primary (FAS total: F1, 58 = 14.356, p < 0.001) and secondary outcomes (ORIDL: F1, 58 = 210.986, p < 0.001) after 3 months favored IHMs against placebos. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%), and Thuja occidentalis (10%) were the most frequently indicated medicines. No harm, unintended effects, homeopathic aggravations, or any serious adverse events were reported from either of the groups.

CONCLUSION: IHMs produced significantly better effects than placebos in the treatment of post-COVID-19 fatigue in adults. Definitive robust trials may be undertaken to confirm the findings.

UNLABELLED: EinleitungDie Coronainfektion (COVID-19) zieht unbekannte und ungewöhnliche gesundheitliche Probleme nach sich, deren Management oft eine Herausforderung darstellt. Das gilt unter anderem für Ermüdung nach einer COVID-19-Erkrankung, die mit zunehmender Dauer der Pandemie immer häufiger auftritt und die Lebensqualität der Betroffenen beeinträchtigt. In dieser Studie wird versucht, vorläufige Belege für die Wirksamkeit individualisierter homöopathischer Mittel (IHM) im Vergleich zu Placebo zur Behandlung von Ermüdung nach COVID-19 bei Erwachsenen zu identifizieren.MethodenEine einfach verblindete, randomisierte, placebokontrollierte Parallelgruppenstudie von 3 Monaten Dauer wurde im ambulanten Bereich des Calcutta Homoeopathic Medical College and Hospital in Indien durchgeführt. 60 Teilnehmer erhielten nach Randomisierung im Verhältnis 1:1 entweder IHM (n = 30) oder identisch aussehendes Placebo (n = 30). Die primäre und die sekundäre Zielgröße waren die Fatigue Assessment Scale (FAS) und das Outcome in Relation to Impact on Daily Living (ORIDL) für bis zu 3 Monate, jeweils monatlich gemessen. Vergleichende Analysen wurden an der Intent-to-treat-Population durchgeführt, um Unterschiede zwischen den Gruppen zu erkennen.ErgebnisseGruppenunterschiede bei der primären (FAS gesamt: F1, 58 = 14,356; p < 0.001) sowie der sekundären Zielgröße (ORIDL: F1, 58 = 210,986; p < 0.001) nach 3 Monaten sprachen für die IHM gegenüber Placebo. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%) und Thuja occidentalis (10%) waren die am häufigsten indizierten Mittel. In beiden Gruppen wurden keine Schädigungen, unbeabsichtigten Wirkungen, homöopathischen Verschlechterungen oder jegliche schwerwiegenden unerwünschten Ereignisse beobachtet.SchlussfolgerungDie IHM erzielten signifikant bessere Effekte als Placebo in der Behandlung von Post-COVID-Ermüdung bei Erwachsenen. Definitive, belastbare Studien können eingeleitet werden, um diese Befunde zu bestätigen.}, } @article {pmid38008627, year = {2024}, author = {Zhang, J and Wang, C and Zhou, M and Wang, Z}, title = {Comprehensive treatment of amyotrophic lateral sclerosis combined with colon cancer: A case report.}, journal = {Asian journal of surgery}, volume = {47}, number = {2}, pages = {1274-1275}, doi = {10.1016/j.asjsur.2023.11.063}, pmid = {38008627}, issn = {0219-3108}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Colonic Neoplasms ; }, } @article {pmid38010108, year = {2024}, author = {Hincelin-Mery, A and Nicolas, X and Cantalloube, C and Pomponio, R and Lewanczyk, P and Benamor, M and Ofengeim, D and Krupka, E and Hsiao-Nakamoto, J and Eastenson, A and Atassi, N}, title = {Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants.}, journal = {Clinical and translational science}, volume = {17}, number = {1}, pages = {e13690}, pmid = {38010108}, issn = {1752-8062}, mesh = {Adult ; Humans ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Area Under Curve ; Half-Life ; Double-Blind Method ; *Brain ; *Receptor-Interacting Protein Serine-Threonine Kinases ; }, abstract = {SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).}, } @article {pmid38010626, year = {2024}, author = {Zhong, R and Rua, MT and Wei-LaPierre, L}, title = {Targeting mitochondrial Ca[2+] uptake for the treatment of amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {8}, pages = {1519-1549}, pmid = {38010626}, issn = {1469-7793}, support = {R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; R56 NS117429/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.}, } @article {pmid38011420, year = {2021}, author = {Eishi-Oskouei, A and Basiri, K}, title = {Safety and efficacy of edaravone in well-defined Iranian patients with amyotrophic lateral sclerosis: A parallel-group single-blind trial.}, journal = {Current journal of neurology}, volume = {20}, number = {1}, pages = {1-7}, pmid = {38011420}, issn = {2717-011X}, abstract = {Background: This parallel-group single-blind trial evaluates the safety and efficacy of Edaravone, as a free radical scavenger, in a highly selective subgroup of Iranian patients with amyotrophic lateral sclerosis (ALS). Methods: The study was registered in ClinicalTrials.gov (registration number: NCT03272802) and Iranian Registry of Clinical Trials (registration number: IRCT20190324043105N). Patients were included into the study, who were diagnosed as probable or definite ALS (according to revised El Escorial criteria), mildly to moderately affected by the disease [according to Amyotrophic Lateral Sclerosis Health State Scale (ALS/HSS)], scored ≥ 2 points on all items of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and had forced vital capacity (FVC) of at least 80%. 20 patients (10 cases, 10 controls) were observed for 12 cycles (each cycle lasted four weeks). Cases received Edaravone for the first 14 days in the first cycle and for the first 10 days in the next cycles. In addition, all patients received Riluzole. The 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), ALSFRS-R, and Manual Muscle Testing (MMT) scores were measured every 3 cycles to evaluate the physical and functional status of the patients. Besides, injection reactions, adverse events (AEs), and serious adverse events (SAEs) were measured during the study. Results: ALSAQ-40, ALSFRS-R, and MMT scores were not significantly different between cases and controls in 5 different time points. During the study, no injection reactions were observed. AEs and SAEs were not significantly different between cases and controls. Conclusion: Our data did not demonstrate efficacy of Edaravone in ALS treatment, but showed its safety for use in patients with ALS. Further studies are necessary to investigate Edaravone efficacy in patients with ALS before prescribing this new drug outside Japan.}, } @article {pmid38011426, year = {2022}, author = {Fateh, HR and Askary-Kachoosangy, R and Shirzad, N and Akbarzadeh-Baghban, A and Fatehi, F}, title = {The effect of energy conservation strategies on fatigue, function, and quality of life in adults with motor neuron disease: Randomized controlled trial.}, journal = {Current journal of neurology}, volume = {21}, number = {2}, pages = {83-90}, pmid = {38011426}, issn = {2717-011X}, abstract = {Background: Fatigue is one of the most frequent complaints in patients with motor neuron diseases (MNDs), with a significant impact on the quality of life (QOL). There is lack of enough evidence for current pharmacological or non-pharmacological treatments of fatigue in this population to be applied in clinical setting. Energy conservation strategies are one of the key interventions for fatigue management in chronic diseases. We aimed to investigate the effect of applying these techniques in the fatigue management of patients with MND. Methods: This randomized controlled trial (RCT) study was carried out on 28 patients with MND. Participants were randomly assigned to either the intervention or control group. In addition to routine treatment, patients in the intervention group participated in 3 weekly 1-hour energy conservation programs provided by an experienced occupational therapist. The Fatigue Severity Scale (FSS) score, 36-Item Short Form Survey (SF-36), and Canadian Occupational Performance Measure (COPM) were measured at baseline, immediately after the last intervention session, and one month later. Results: FSS and COPM significantly changed after the course in the intervention group (P < 0.001 and P = 0.001, respectively). Both FSS and COPM improved significantly toward the final assessment only in the intervention group. The SF-36 changes were not significant in each of the groups. Conclusion: According to the findings of the present study, using energy conservation strategies could lead to better mid-term fatigue management and occupational performance improvement, but it did not improve QOL in patients with MND.}, } @article {pmid38011840, year = {2024}, author = {Asawadethmetakul, P and Xie, F and Xie, C and Ma, J and You, Y and Yao, F}, title = {Effect of Tuina Combined with Chinese Herbal Compress on Primary Dysmenorrhea with Cold Coagulation and Blood Stasis Syndrome: A Study Protocol for a Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {20-29}, doi = {10.1159/000534335}, pmid = {38011840}, issn = {2504-2106}, mesh = {Female ; Humans ; *Dysmenorrhea/drug therapy ; China ; *Pain Threshold ; Randomized Controlled Trials as Topic ; Observational Studies as Topic ; }, abstract = {INDRODUCTION: Primary dysmenorrhea (PD) is a very common issue in young women that reduces the quality of women's lives. Both Western medicine and traditional Chinese medicine (TCM) provide several ways to treat PD; however, TCM treatment exhibits fewer side effects for the patient. Tuina massage and Chinese herbal compresses are considered forms of external TCM therapy that have been widely used to treat PD, especially in China. Therefore, to provide the most effective and safe treatment for PD, we combined Tuina and Chinese herbal compresses together in this observational study.

METHODS: A randomized controlled trial (RCT) consisting of 114 participants from the Shanghai University of Traditional Chinese Medicine who meet inclusion criteria will be divided into two groups in a 1:1 allocation ratio. The intervention group will receive Tuina combined with Chinese herbal compress therapy, while the control group will only receive Chinese herbal compress therapy. The treatment will be given 3 days before menstruation (once per day, 3 times per menstrual cycle). The primary outcome will be measured with the Visual Analog Scale (VAS). The secondary outcomes will be measured by the Dysmenorrhea Symptom Score, the Chinese Medical Dysmenorrhea Symptom Score, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the pain threshold at Guanyuan (CV4).

CONCLUSION: This study will be the first RCT that will entail the combination of Tuina and Chinese herbal compresses to treat PD in the category of cold coagulation and blood stasis syndrome. If the results demonstrate that Tuina combined with a Chinese herbal compress is effective, we posit that this study will provide evidence-based references for a potential alternative treatment to treat PD in the future.

UNLABELLED: EinleitungDie primäre Dysmenorrhoe (PD) ist ein Problem, das bei jungen Frauen sehr häufig auftritt und ihre Lebensqualität beeinträchtigt. Sowohl die westliche Medizin als auch die traditionelle chinesische Medizin (TCM) bieten verschiedene Therapiemöglichkeiten zur Behandlung der PD, allerdings ist die TCM mit weniger Nebenwirkungen für die Patientin verbunden. Tuina-Massage und chinesische Kräuterkompressen gelten als Formen der äußerlichen TCM-Therapie, die besonders in China zur Behandlung der PD weit verbreitet sind. Daher haben wir in dieser Beobachtungsstudie Tuina und chinesische Kräuterkompressen kombiniert, um eine möglichst wirksame und sichere Behandlung der PD bereitzustellen.MethodenEs handelt sich um eine randomisierte kontrollierte Studie (randomized controlled trial, RCT), bei der 114 Teilnehmerinnen der Shanghai University of Traditional Chinese Medicine, die die Einschlusskriterien erfüllen, im Verhältnis 1:1 in zwei Gruppen aufgeteilt werden. Die Interventionsgruppe erhält Tuina in Kombination mit chinesischen Kräuterkompressen, während die Kontrollgruppe nur eine Behandlung mit chinesischen Kräuterkompressen erhält. Die Behandlung erfolgt drei Tage vor der Menstruation (einmal täglich, dreimal pro Menstruationszyklus). Das primäre Zielkriterium wird anhand der visuellen Analogskala (VAS) gemessen. Die sekundären Zielkriterien werden mithilfe des Dysmenorrhoe-Symptom-Scores, des chinesischen medizinischen Dysmenorrhoe-Symptom-Scores, der Self-rating Anxiety Scale (SAS), der Self-rating Depression Scale (SDS) und der Schmerzschwelle am Guanyuan-Akupunkturpunkt (CV4) ermittelt.SchlussfolgerungDiese Studie ist die erste randomisierte kontrollierte Studie, die die Kombination von Tuina und chinesischen Kräuterkompressen zur Behandlung von PD in der Kategorie Kältekoagulation und Blutstauungssyndrom untersucht. Sollten die Ergebnisse zeigen, dass Tuina in Kombination mit chinesischen Kräuterkompressen wirksam ist, erwarten wir, dass diese Studie evidenzbasierte Belege für eine mögliche alternative Behandlung von PD in der Zukunft liefern wird.}, } @article {pmid38013317, year = {2023}, author = {Wang, Z and Yang, H and Han, Y and Teng, J and Kong, X and Qi, X}, title = {Screening and identification of key biomarkers associated with amyotrophic lateral sclerosis and depression using bioinformatics.}, journal = {Medicine}, volume = {102}, number = {47}, pages = {e36265}, pmid = {38013317}, issn = {1536-5964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Depression/diagnosis/genetics ; Gene Expression Profiling ; *MicroRNAs/genetics ; Biomarkers ; Gene Regulatory Networks ; Computational Biology/methods ; }, abstract = {This study aims to identify common molecular biomarkers between amyotrophic lateral sclerosis (ALS) and depression using bioinformatics methods, in order to provide potential targets and new ideas and methods for the diagnosis and treatment of these diseases. Microarray datasets GSE139384, GSE35978 and GSE87610 were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between ALS and depression were identified. After screening for overlapping DEGs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified. Finally, a network between miRNAs and hub genes was constructed using the NetworkAnalyst tool, and possible key miRNAs were predicted. A total of 357 genes have been identified as common DEGs between ALS and depression. GO and KEGG enrichment analyses of the 357 DEGs showed that they were mainly involved in cytoplasmic translation. Further analysis of the PPI network using Cytoscape and MCODE plugins identified 6 hub genes, including mitochondrial ribosomal protein S12 (MRPS12), poly(rC) binding protein 1 (PARP1), SNRNP200, PCBP1, small G protein signaling modulator 1 (SGSM1), and DNA methyltransferase 1 (DNMT1). Five possible target miRNAs, including miR-221-5p, miR-21-5p, miR-100-5p, miR-30b-5p, and miR-615-3p, were predicted by constructing a miRNA-gene network. This study used bioinformatics techniques to explore the potential association between ALS and depression, and identified potential biomarkers. These biomarkers may provide new ideas and methods for the early diagnosis, treatment, and monitoring of ALS and depression.}, } @article {pmid38014203, year = {2023}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Pisliakova, M and Thompson, D and Digby, H and Simkin, RL and Diaz, JA and Mehta, PR and Keuss, MJ and Zanovello, M and Brown, AL and Harley, P and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS/FTD precision medicine.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38014203}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; }, abstract = {A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence. By placing part of a coding sequence within a novel cryptic exon, we tightly couple protein expression to TDP-LOF. Protein expression is activated by TDP-LOF in vitro and in vivo, including TDP-LOF induced by cytoplasmic TDP-43 aggregation. In addition to generating a variety of fluorescent and luminescent reporters, we use this system to perform TDP-LOF-dependent genomic prime editing to ablate the UNC13A cryptic donor splice site. Furthermore, we design a panel of tightly gated, autoregulating vectors encoding a TDP-43/Raver1 fusion protein, which rescue key pathological cryptic splicing events. In summary, we combine deep-learning and rational design to create sophisticated splicing sensors, resulting in a platform that provides far safer therapeutics for neurodegeneration, potentially even enabling preemptive treatment of at-risk individuals.}, } @article {pmid38014622, year = {2023}, author = {Yamashita, T and Nakano, Y and Sasaki, R and Tadokoro, K and Omote, Y and Yunoki, T and Kawahara, Y and Matsumoto, N and Taira, Y and Matsuoka, C and Morihara, R and Abe, K}, title = {Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial.}, journal = {Cell transplantation}, volume = {32}, number = {}, pages = {9636897231214370}, pmid = {38014622}, issn = {1555-3892}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Alprostadil/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.}, } @article {pmid38018119, year = {2024}, author = {Brown, A and Armon, C and Barkhaus, P and Beauchamp, M and Bertorini, T and Bromberg, M and Cadavid, JM and Carter, GT and Crayle, J and Feldman, EL and Heiman-Patterson, T and Jhooty, S and Linares, A and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Nathaniel, G and Pattee, G and Pierce, K and Ratner, D and Slactova, L and Wicks, P and Bedlack, R}, title = {ALSUntangled #72: Insulin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {416-419}, doi = {10.1080/21678421.2023.2288110}, pmid = {38018119}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Insulin/adverse effects ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.}, } @article {pmid38022117, year = {2023}, author = {Jain, A and Madkan, S and Patil, P}, title = {The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47861}, pmid = {38022117}, issn = {2168-8184}, abstract = {Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.}, } @article {pmid38031465, year = {2024}, author = {Ghasemi, A and Sadedel, M and Moghaddam, MM}, title = {A wearable system to assist impaired-neck patients: Design and evaluation.}, journal = {Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine}, volume = {238}, number = {1}, pages = {63-77}, doi = {10.1177/09544119231211362}, pmid = {38031465}, issn = {2041-3033}, mesh = {Humans ; *Robotics ; Electromyography/methods ; *Stroke ; Movement ; *Wearable Electronic Devices ; }, abstract = {Patients with neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease, and cerebral palsy, often face challenges due to head-neck immobility. The conventional treatment approach involves using a neck collar to maintain an upright head position, but this can be cumbersome and restricts head-neck movements over prolonged periods. This study introduces a wearable robot capable of providing three anatomical head motions for training and assistance. The primary contributions of this research include the design of an optimized structure and the incorporation of human-robot interaction. Based on human head motion data, our primary focus centered on developing a robot capable of accommodating a significant range of neutral head movements. To ensure safety, impedance control was employed to facilitate human-robot interaction. A human study was conducted involving 10 healthy subjects who participated in an experiment to assess the robot's assistance capabilities. Passive and active modes were used to evaluate the robot's effectiveness, taking into account head-neck movement error and muscle activity levels. Surface electromyography signals (sEMG) were collected from the splenius capitis muscles during the experiment. The results demonstrated that the robot covered nearly 85% of the overall range of head rotations. Importantly, using the robot during rehabilitation led to reduced muscle activation, highlighting its potential for assisting individuals with post-stroke movement impairments.}, } @article {pmid38033869, year = {2023}, author = {Vukolova, MN and Yen, LY and Khmyz, MI and Sobolevsky, AI and Yelshanskaya, MV}, title = {Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis-emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1252953}, pmid = {38033869}, issn = {2296-634X}, support = {R37 NS083660/NS/NINDS NIH HHS/United States ; R01 NS107253/NS/NINDS NIH HHS/United States ; R01 NS083660/NS/NINDS NIH HHS/United States ; R01 AR078814/AR/NIAMS NIH HHS/United States ; R01 CA206573/CA/NCI NIH HHS/United States ; }, abstract = {Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.}, } @article {pmid38036035, year = {2024}, author = {Wang, X and Zhu, Z and Sun, J and Jia, L and Cai, L and Chen, Q and Yang, W and Wang, Y and Zhang, Y and Guo, S and Liu, W and Yang, Z and Zhao, P and Wang, Z and Lv, H}, title = {Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {129}, number = {}, pages = {110903}, doi = {10.1016/j.pnpbp.2023.110903}, pmid = {38036035}, issn = {1878-4216}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Iron ; Genome-Wide Association Study ; Magnetic Resonance Imaging/methods ; Brain/diagnostic imaging/pathology ; *Alzheimer Disease/pathology ; *Parkinson Disease ; *Multiple Sclerosis ; }, abstract = {The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.}, } @article {pmid38037913, year = {2024}, author = {Zhong, G and Wang, X and Li, J and Xie, Z and Wu, Q and Chen, J and Wang, Y and Chen, Z and Cao, X and Li, T and Liu, J and Wang, Q}, title = {Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.}, journal = {Current neuropharmacology}, volume = {22}, number = {10}, pages = {1650-1671}, pmid = {38037913}, issn = {1875-6190}, support = {81973918, 82274616//National Natural Science Foundation of China/ ; 2019KSYS005//Key laboratory project of colleges and universities in Guangdong Province/ ; 2020A0505100052//Guangdong province science and technology plan international cooperation project/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Copper/metabolism ; Animals ; Biological Products/therapeutic use/pharmacology ; Homeostasis/drug effects ; Chelating Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.}, } @article {pmid38046608, year = {2023}, author = {Wang, R and Sun, Y and Lan, Y and Wei, S and Huang, H and Li, X and Huang, Z}, title = {ALS gene overexpression and enhanced metabolism conferring Digitaria sanguinalis resistance to nicosulfuron in China.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1290600}, pmid = {38046608}, issn = {1664-462X}, abstract = {Crabgrass (Digitaria sanguinalis) is a common malignant weed in corn fields in China. Recently, the acetolactate synthase (ALS) inhibitor, nicosulfuron, has shown decreasing efficacy against crabgrass. In order to elucidate the molecular basis of resistance to nicosulfuron in crabgrass, we conducted bioassays, combined with gene sequence analysis, relative expression and relative copy number analysis, to characterize resistance in crabgrass populations collected from Beijing, Heilongjiang, Jilin and Anhui provinces. Whole-plant dose-response results indicated that only population collected in Heilongjiang province (HLJ) had developed low level of resistance to nicosulfuron compared with the sensitive population (SD22). No known resistant mutation of ALS gene was found in HLJ population. The real-time fluorescence quantitative PCR results showed that the ALS gene copy number did not differ significantly between the HLJ and SD22 populations. However, the ALS gene expression in the HLJ was 2.07-fold higher than that of the SD22 population at 24 h after treatment with nicosulfuron. Pretreatment with the cytochrome P450 (CYP450) inhibitor malathion, piperonyl butoxide (PBO), and the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) all partially reversed HLJ resistance. Among them, the synergistic effect of PBO and nicosulfuron is the most significant. This is the first report of resistance to nicosulfuron in crabgrass through ALS gene overexpression and possible metabolic resistance.}, } @article {pmid38049068, year = {2024}, author = {Wang, B and Huang, Y and Li, J}, title = {Response to John et al's comments of "paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the prospective rosacea refractory erythema randomized clinical trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e143-e144}, doi = {10.1016/j.jaad.2023.11.050}, pmid = {38049068}, issn = {1097-6787}, mesh = {Humans ; *Paroxetine/therapeutic use ; Prospective Studies ; *Rosacea/drug therapy ; Erythema/drug therapy/etiology ; Treatment Outcome ; }, } @article {pmid38050066, year = {2024}, author = {Bowser, R and An, J and Mehta, L and Chen, J and Timmons, J and Cudkowicz, M and Paganoni, S}, title = {Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {7}, pages = {605-608}, pmid = {38050066}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/drug therapy ; *Biomarkers/blood ; *Chitinase-3-Like Protein 1/blood ; *C-Reactive Protein/analysis ; *Phenylbutyrates/therapeutic use ; Female ; Male ; Middle Aged ; Hexosaminidases/blood ; Aged ; Double-Blind Method ; Chitinases/blood ; }, abstract = {BACKGROUND: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR.

METHODS: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients.

RESULTS: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups.

CONCLUSIONS: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies.

TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/study/NCT03127514.}, } @article {pmid38052188, year = {2024}, author = {Crowe, AL and Kerr, K and McAneney, H and McMullan, J and Duffy, G and McKnight, AJ}, title = {Stakeholder Perceptions of Complementary and Integrative Medicines from People Living with Rare Diseases in Northern Ireland: A Mixed Methods Study.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {107-115}, pmid = {38052188}, issn = {2504-2106}, mesh = {Humans ; Northern Ireland ; *Complementary Therapies/statistics & numerical data/psychology ; *Rare Diseases/therapy ; *Integrative Medicine ; Female ; Surveys and Questionnaires ; Male ; Adult ; Middle Aged ; Health Personnel/psychology ; *Stakeholder Participation ; }, abstract = {INTRODUCTION: Only 5% of rare diseases have an approved treatment available, therefore patients often utilise complementary and integrative medicines (CIMs) to help manage their condition. Limited high-quality evidence-based studies are available which support the effectiveness of CIM, as it is difficult to show that an outcome is a direct result of the CIM intervention and not due to bias. Patients and healthcare professionals must weigh up the evidence quality, safety, efficacy, practical logistics, and financial implications of utilising CIM for rare diseases. This study aimed to elucidate perspectives of stakeholders (individuals with rare diseases, carers, family members, CIM practitioners and healthcare professionals), on the usage of CIM for rare diseases across Northern Ireland.

METHODS: This was a mixed methods study. An online survey was open from January to February 2019 (n = 29 responses). Themes identified from the survey were then discussed with stakeholders in a semi-structured discussion workshop in March 2019.

RESULTS: A limited number of participants responded to the survey (n = 29). Some individuals with rare diseases reported CIM as effective in the management of their condition, in particular acupuncture, dietary supplements, herbal medicines, homoeopathy, hydrotherapy, kinesiology, mindfulness, pilates, reflexology, tai chi, and yoga. However, a number of respondents (n = 7) experienced a negative side effect from CIM. Workshop participants raised concerns over the lack of information available about CIM and rare disease. Both the survey and workshop identified inequality of access with participants reporting CIM to be expensive.

CONCLUSIONS: More information, high-quality research, and education about CIM are required for patients and healthcare professionals to help make informed decisions about the usage of CIM for rare diseases. Improved communication, information, and health and social care in general would help individuals be more confident and knowledgeable about therapeutic options in relation to their rare disease(s).

UNLABELLED: EinleitungNur für fünf Prozent der seltenen Erkrankungen existiert eine zugelassene Behandlung, weshalb Patienten häufig komplementäre und integrative Medizin (CIM) nutzen, um ihre Krankheit zu behandeln. Es liegen nur wenige qualitativ hochwertige evidenzbasierte Studien vor, die die Wirksamkeit von CIM stützen, da sich schwer nachweisen lässt, dass ein Behandlungsergebnis direkt durch die CIM-Intervention bedingt und nicht Folge einer Verzerrung ist. Patienten und Angehörige der Gesundheitsberufe müssen die Qualität der Evidenz, die Sicherheit und Wirksamkeit sowie praktische logistische Aspekte und die finanziellen Folgen der Anwendung von CIM bei seltenen Erkrankungen abwägen. Mit der vorliegenden Studie sollte die Perspektive der Betroffenen (Menschen mit seltenen Erkrankungen, Betreuungspersonen, Familienangehörige, CIM-Praktiker und Angehörige der Gesundheitsberufe) in Bezug auf die Anwendung von CIM bei seltenen Erkrankungen in Nordirland untersucht werden.MethodenEs handelte sich um eine Studie mit gemischten Methoden. Eine Online-Umfrage war von Januar bis Februar 2019 geöffnet (n = 29 Antworten). Die in der Umfrage ermittelten Themen wurden anschließend im März 2019 im Rahmen eines halbstrukturierten Diskussionsworkshops mit den Betroffenen erörtert.ErgebnisseEine begrenzte Anzahl von Teilnehmern antwortete auf die Umfrage (n = 29). Einige Personen mit seltenen Erkrankungen gaben an, dass CIM bei der Behandlung ihrer Erkrankung wirksam war, insbesondere Akupunktur, Nahrungsergänzungsmittel, pflanzliche Arzneimittel, Homöopathie, Hydrotherapie, Kinesiologie, Achtsamkeit, Pilates, Reflexologie, Tai Chi und Yoga. Einige Befragte (n = 7) berichteten jedoch über negative Nebenwirkungen der CIM. Die Workshop-Teilnehmer äußerten Bedenken in Bezug auf den Mangel an Informationen über CIM und seltene Erkrankungen. Sowohl in der Umfrage als auch im Workshop zeigte sich eine Ungleichheit beim Zugang zu CIM und die Teilnehmer berichteten, dass CIM teuer sei.SchlussfolgerungenPatienten und Angehörige der Gesundheitsberufe benötigen mehr Informationen, qualitativ hochwertige Forschung und Aufklärung über CIM, um fundierte Entscheidungen über die Anwendung von CIM bei seltenen Erkrankungen treffen zu können. Eine bessere Kommunikation, Information sowie gesundheitliche und soziale Versorgung im Allgemeinen würden zu mehr Selbstvertrauen und Wissen der Betroffenen über die therapeutischen Möglichkeiten im Zusammenhang mit ihrer seltenen Erkrankung beitragen.}, } @article {pmid38053196, year = {2023}, author = {Lombardo, FL and Spila Alegiani, S and Mayer, F and Cipriani, M and Lo Giudice, M and Ludolph, AC and McDermott, CJ and Corcia, P and Van Damme, P and Van den Berg, LH and Hardiman, O and Nicolini, G and Vanacore, N and Dickie, B and Albanese, A and Puopolo, M and , }, title = {A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {792}, pmid = {38053196}, issn = {1745-6215}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Riluzole ; *Neuroprotective Agents/adverse effects ; Reproducibility of Results ; Double-Blind Method ; Treatment Outcome ; Disease Progression ; Taurochenodeoxycholic Acid ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities.

METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023.

DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.}, } @article {pmid38068696, year = {2023}, author = {Sun, J and Yu, X and Xu, H and Yang, Y and Liu, M and Zhang, Y and Lu, Y and Tang, W}, title = {Post-Emergence Water-Dispersal Application Provides Equal Herbicidal Activity against Echinochloa crus-galli and Rice Safety as Foliar Spraying of Penoxsulam.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {23}, pages = {}, pmid = {38068696}, issn = {2223-7747}, support = {LGN21C140003//Zhejiang Provincial Natural Science Foundation/ ; 32071508//National Natural Science Foundation of China/ ; CARS-01//the China Agriculture Research System/ ; }, abstract = {Penoxsulam is an acetolactate synthase (ALS)-inhibiting herbicide usually applied by post-emergence foliar spraying (PFS) for the control of Echinochloa crus-galli and numerous annual weeds in paddy fields. Herbicides applied by foliar spraying can have negative impacts on the environment, ecosystems, and human health. In this study, the response of E. crus-galli and rice to the PFS and post-emergence water-dispersal (PWD) applications of penoxsulam, and the differences in the detoxification displayed by them between the two treatment methods were compared. The results showed that the PWD application of penoxsulam provides a similar control efficacy against E. crus-galli as PFS at the 1-, 3-, and 5-leaf stages. Meanwhile, the PWD application had a higher safety for the rice. After being treated with 30 g a.i. ha[-1] penoxsulam, residues were not detected in the rice treated by the PWD application method, whereas, with the PFS treatment, there was 59.0 µg/kg penoxsulam remaining. With the PFS application, there were many more residues of penoxsulam in the E. crus-galli than with the PWD method; the amount of residues was 32-fold higher 12 h after treatment. The in vitro enzyme activity assays revealed that the activities of ALS, glutathione-S-transferase (GST), and cytochrome P450 monooxygenases (P450) were increased in the PWD treatments, and were 1.5-, 1.3-, and 2.3-fold higher than with PFS 72 h after treatment. The real-time quantitative PCR (qRT-PCR) revealed that the GST1 and P450 genes, CYP81A14, CYP81A12, CYP81A18, and CYP81A21 were upregulated with the PWD application versus PFS in the E. crus-galli. In summary, these results demonstrate that the herbicidal activity was not affected by the upregulation of target and metabolic enzyme activities with the PWD application of penoxsulam. This research could contribute to application strategies reducing the risk of rice injury and environmental impacts by using water-dispersal formulations of penoxsulam.}, } @article {pmid38069154, year = {2023}, author = {Belosludtseva, NV and Matveeva, LA and Belosludtsev, KN}, title = {Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069154}, issn = {1422-0067}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Energy Metabolism ; Disease Progression ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.}, } @article {pmid38082598, year = {2023}, author = {Zhang, C and Deng, F and Li, Y and Hall, T and Goldys, E}, title = {Paper-based lateral flow assay for the point-of-care detection of neurofilament light chain.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10340109}, pmid = {38082598}, issn = {2694-0604}, mesh = {Humans ; *Point-of-Care Systems ; Intermediate Filaments/metabolism ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers ; }, abstract = {Neurofilament light chain (NF-L) is a protein found in neurons of the nervous system and is widely used as a biomarker for neurological disorders. However, the current methods for detecting NF-L levels are complicated, expensive, and require specialized equipment, making it challenging to implement in a point-of-care (POC) setting. In this study, we developed a gold nanoshell (AuNS)-assisted lateral flow assay (LFA) based test strip for the POC detection of NF-L at a low ng/mL level (8 ng/mL = 117.65 pM). The test strip is a simple, rapid, and cost-effective method for detecting NF-L, making it suitable for use in a POC setting for the diagnosis and treatment of various neurological disorders. With its ease of use and reliability, the paper-based LFA is a valuable tool for the diagnosis and management of neurological conditions.Clinical Relevance- The AuNS-assisted LFA test strip developed in this study offers a rapid, cost-effective, and simple method for detecting NF-L levels, making it of great interest to practicing clinicians for the diagnosis of various neurological diseases such as HIV-associated dementia (HID), Amyotrophic Lateral Sclerosis (ALS), and Creutzfeldt-Jakob disease (CJD).}, } @article {pmid38086800, year = {2023}, author = {Wei, J and Li, M and Ye, Z and Hu, X and He, X and Wang, J and Chen, G and Zou, C and Xu, D and Zhang, H and Yuan, J and Zha, Y}, title = {Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {451}, pmid = {38086800}, issn = {2059-3635}, support = {WJ2021M257//Health and Family Planning Commission of Hubei Province (Hubei Provincial Health Department)/ ; 2019SHZDZX02//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 32070737//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82188101, 91849204, 21837004, 92049303 and 32170755//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20JC1411600//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; 20QA1411500//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Biomarkers ; Interleukin-8/genetics ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism ; Primidone/metabolism/pharmacology/therapeutic use ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism/pharmacology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1[G93A] mice and ALS patients. SOD1[G93A] mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).}, } @article {pmid38087359, year = {2023}, author = {Nayab, DE and Din, FU and Ali, H and Kausar, WA and Urooj, S and Zafar, M and Khan, I and Shabbir, K and Khan, GM}, title = {Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {477}, pmid = {38087359}, issn = {1477-3155}, support = {20-14604/NRPU/R&D/HEC/2021//Higher Education Commision, Pakistan/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Brain ; Blood-Brain Barrier ; Drug Delivery Systems/methods ; Nanotechnology ; }, abstract = {Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.}, } @article {pmid38090405, year = {2023}, author = {Gupta, D and Vagha, S and Dhingra, H and Shirsath, H}, title = {Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48691}, pmid = {38090405}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly CNS neurodegenerative disease. The way ALS is now managed, from diagnosis to prognosis, is still not ideal despite many studies. Early diagnosis can help ALS patients live longer since prompt treatment can halt the disease's development. Two medications, riluzole and edaravone, have recently been licensed for use in therapy, and they very slightly increase life expectancy. Still, a lot of cutting-edge experimental medications are being developed. In the following article, we give a synopsis of the innovative medications and genetic remodeling that have emerged recently and help to halt the course of the illness. Studies have also been conducted on a few symptomatic and rehabilitative therapies that enhance the quality of life for ALS patients.}, } @article {pmid38093670, year = {2024}, author = {Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Current challenges in primary lateral sclerosis diagnosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {1}, pages = {45-53}, doi = {10.1080/14737175.2023.2295010}, pmid = {38093670}, issn = {1744-8360}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnosis ; Neuroimaging ; Diagnosis, Differential ; Biomarkers ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Primary lateral sclerosis (PLS) is a rare, adult-onset and slowly progressive motor neuron disorder whose clinical core is characterized by upper motor neuron (UMN) dysfunction. Its formal diagnosis is clinically based and disease duration-dependent. Differentiating PLS from other disorders involving UMN can be challenging, particularly in the early stages.

AREAS COVERED: Our review covers and discusses different aspects of the PLS field, including the diagnostic criteria and its limitations, its differential diagnosis and their major pitfalls, and the actual role of neurophysiology, neuroimaging, genetics, and molecular biomarkers. Symptomatic treatment of the different manifestations is also addressed. The authors searched MEDLINE and Scopus. They also searched the reference lists of articles identified by our search strategy and reviewed and selected those deemed relevant. They selected papers and studies based on the quality of the report, significance of the findings, and on the author's critical appraise and expertise.

EXPERT OPINION: It is important to investigate novel molecular biomarkers and plan multicenter clinical trials for PLS. However, this will require a large international project to recruit enough patients, particularly given the diagnostic uncertainty of the current clinical criteria. A better understanding of PLS pathophysiology is crucial for designing disease-targeted therapies.}, } @article {pmid38100267, year = {2024}, author = {Qi, S and Peng, Y and Wang, G and Zhang, X and Liu, M and He, L}, title = {A tale of dual functions of SERF family proteins in regulating amyloid formation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {5}, pages = {e202300727}, doi = {10.1002/cbic.202300727}, pmid = {38100267}, issn = {1439-7633}, support = {2018YFE0202301//National Key R&D Program of China/ ; 2018YFE0202300//National Key R&D Program of China/ ; 22174151//National Natural Sciences Foundation of China/ ; 21991080//National Natural Sciences Foundation of China/ ; XDB0540000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 2023AFA041//Hubei Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; Caenorhabditis elegans ; *Neurodegenerative Diseases ; Amyloidogenic Proteins ; Amyloid beta-Peptides ; *Alzheimer Disease ; *Caenorhabditis elegans Proteins ; }, abstract = {The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and β-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.}, } @article {pmid38105307, year = {2024}, author = {Hamad, AA and Amer, BE and Hawas, Y and Mabrouk, MA and Meshref, M}, title = {Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {1861-1873}, pmid = {38105307}, issn = {1590-3478}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Benzamides/pharmacology/therapeutic use ; *Thiazoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; *Pyridines/pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {OBJECTIVES: Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib's neuroprotective activities from preclinical to clinical studies.

METHODS: This scoping review was conducted following the guidelines described by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies.

RESULTS: A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer's disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity.

CONCLUSION: The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use.}, } @article {pmid38108952, year = {2024}, author = {Xiao, X and Rui, Y and Jin, Y and Chen, M}, title = {Relationship of Sleep Disorder with Neurodegenerative and Psychiatric Diseases: An Updated Review.}, journal = {Neurochemical research}, volume = {49}, number = {3}, pages = {568-582}, pmid = {38108952}, issn = {1573-6903}, support = {82371541//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; Brain/metabolism ; *Huntington Disease/metabolism ; *Sleep Wake Disorders/metabolism ; }, abstract = {Sleep disorders affect many people worldwide and can accompany neurodegenerative and psychiatric diseases. Sleep may be altered before the clinical manifestations of some of these diseases appear. Moreover, some sleep disorders affect the physiological organization and function of the brain by influencing gene expression, accelerating the accumulation of abnormal proteins, interfering with the clearance of abnormal proteins, or altering the levels of related hormones and neurotransmitters, which can cause or may be associated with the development of neurodegenerative and psychiatric diseases. However, the detailed mechanisms of these effects are unclear. This review mainly focuses on the relationship between and mechanisms of action of sleep in Alzheimer's disease, depression, and anxiety, as well as the relationships between sleep and Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This summary of current research hotspots may provide researchers with better clues and ideas to develop treatment solutions for neurodegenerative and psychiatric diseases associated with sleep disorders.}, } @article {pmid38110144, year = {2024}, author = {Hafner, C and Manschein, V and Klaus, DA and Schaubmayr, W and Tiboldi, A and Scharner, V and Gleiss, A and Thal, B and Krammel, M and Hamp, T and Willschke, H and Hermann, M}, title = {Live stream of prehospital point-of-care ultrasound during cardiopulmonary resuscitation - A feasibility trial.}, journal = {Resuscitation}, volume = {194}, number = {}, pages = {110089}, doi = {10.1016/j.resuscitation.2023.110089}, pmid = {38110144}, issn = {1873-1570}, support = {21044//Medical Scientific Fund of the Mayor of the City of Vienna/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services/methods ; Feasibility Studies ; *Out-of-Hospital Cardiac Arrest/diagnostic imaging/therapy ; Point-of-Care Systems ; }, abstract = {BACKGROUND: Current resuscitation guidelines recommend that skilled persons could use ultrasound to detect reversible causes during cardiopulmonary resuscitation (CPR) where the examination can be safely integrated into the Advanced Life Support (ALS) algorithm. However, in a prehospital setting performing and rapidly interpreting ultrasound can be challenging for physicians. Implementing remote, expert-guided, and real-time transmissions of ultrasound examinations offers the opportunity for tele-support, even during an out-of-hospital cardiac arrest (OHCA). The aim of this feasibility study was to evaluate the impact of tele-supported ultrasound in ALS on hands-off time during an OHCA.

METHODS: In an urban setting, physicians performed point-of-care ultrasound (POCUS) on patients during OHCA using a portable device, either with tele-support (n = 30) or without tele-support (n = 12). Where tele-support was used, the ultrasound image was transmitted via a remote real-time connection to an on-call specialist in anaesthesia and intensive care medicine with an advanced level of critical care ultrasound expertise. The primary safety endpoint of this study was to evaluate whether POCUS can be safely integrated into the algorithm, and to provide an analysis of hands-off time before, during, and after POCUS during OHCA.

RESULTS: In all 42 cases it was possible to perform POCUS during regular rhythm analyses, and no additional hands-off time was required. In 40 of these 42 cases, the physicians were able to perform POCUS during a single regular rhythm analysis, with two periods required only in two cases. The median hands-off time during these rhythm analyses for POCUS with tele-support was 10 (8-13) seconds, and 11 (9-14) seconds for POCUS without tele-support. Furthermore, as a result of POCUS, in a quarter of all cases the physician on scene altered their diagnosis of the primary suspected cause of cardiac arrest, leading to a change in treatment strategy.

CONCLUSIONS: This feasibility study demonstrated that POCUS with tele-support can be safely performed during OHCA in an urban environment. Trial Registration (before patient enrolment): ClinicalTrials.gov, NCT04817475.}, } @article {pmid38110502, year = {2023}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22497}, pmid = {38110502}, issn = {2045-2322}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Suspensions ; Europe ; *Airway Obstruction ; Tablets ; *Neuroprotective Agents ; }, abstract = {The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies.}, } @article {pmid38112345, year = {2024}, author = {Battaglini, M and Marino, A and Montorsi, M and Carmignani, A and Ceccarelli, MC and Ciofani, G}, title = {Nanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders.}, journal = {Advanced healthcare materials}, volume = {13}, number = {12}, pages = {e2304180}, doi = {10.1002/adhm.202304180}, pmid = {38112345}, issn = {2192-2659}, mesh = {*Microglia/drug effects/metabolism ; Humans ; *Nanostructures/chemistry ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Microglia play a pivotal role in the central nervous system (CNS) homeostasis, acting as housekeepers and defenders of the surrounding environment. These cells can elicit their functions by shifting into two main phenotypes: pro-inflammatory classical phenotype, M1, and anti-inflammatory alternative phenotype, M2. Despite their pivotal role in CNS homeostasis, microglia phenotypes can influence the development and progression of several CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injuries, and even brain cancer. It is thus clear that the possibility of modulating microglia activation has gained attention as a therapeutic tool against many CNS pathologies. Nanomaterials are an unprecedented tool for manipulating microglia responses, in particular, to specifically target microglia and elicit an in situ immunomodulation activity. This review focuses the discussion on two main aspects: analyzing the possibility of using nanomaterials to stimulate a pro-inflammatory response of microglia against brain cancer and introducing nanostructures able to foster an anti-inflammatory response for treating neurodegenerative disorders. The final aim is to stimulate the analysis of the development of new microglia nano-immunomodulators, paving the way for innovative and effective therapeutic approaches for the treatment of CNS disorders.}, } @article {pmid38112783, year = {2024}, author = {Libonati, L and Cambieri, C and Colavito, D and Moret, F and D'Andrea, E and Del Giudice, E and Leon, A and Inghilleri, M and Ceccanti, M}, title = {Genetics screening in an Italian cohort of patients with Amyotrophic Lateral Sclerosis: the importance of early testing and its implication.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {1921-1936}, pmid = {38112783}, issn = {1432-1459}, mesh = {Humans ; Mutation ; *Amyotrophic Lateral Sclerosis/epidemiology ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; *Neurodegenerative Diseases ; Italy ; Heat-Shock Proteins/genetics ; Molecular Chaperones/genetics ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease.

MATERIALS AND METHODS: 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups.

RESULTS: Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients.

DISCUSSION: The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives.

CONCLUSION: This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development.}, } @article {pmid38127305, year = {2023}, author = {Lester, EG and Vitolo, OV and Flaherty, A and Beaussant, Y and Cramer, M and Harley, R and Cohen, JN}, title = {"When Will All of This End?": A 65-Year-Old Man With Amyotrophic Lateral Sclerosis and Psychiatric Distress.}, journal = {The Journal of clinical psychiatry}, volume = {85}, number = {1}, pages = {}, doi = {10.4088/JCP.23ct15038}, pmid = {38127305}, issn = {1555-2101}, mesh = {Aged ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Cognitive Behavioral Therapy ; Psychotherapy ; *Psychological Distress ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) are impacted both physically and psychiatrically during their illness. Emotional distress (ie, anxiety, depression, stress) is common in patients diagnosed with ALS, as prognosis is poor and there are very few effective treatments. The progression of symptoms is unpredictable, and all cases are terminal. Neuropsychiatric symptoms are also increasingly recognized as part of ALS symptomatology. There are currently no empirically supported interventions or best practices for adjustment to ALS. This case presents both the psychological and pharmacologic aspects of caring for a patient with ALS. Psychotherapy utilized a cognitive behavioral therapy-informed approach, and pharmacotherapy was tailored to the specific needs of the patient. We explore how these approaches impacted our patient, as well as how ALS-specific challenges presented throughout the course of treatment.}, } @article {pmid38129934, year = {2023}, author = {Marriott, H and Kabiljo, R and Hunt, GP and Khleifat, AA and Jones, A and Troakes, C and , and , and Pfaff, AL and Quinn, JP and Koks, S and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {208}, pmid = {38129934}, issn = {2051-5960}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Motor Neurone Disease Association/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Unsupervised Machine Learning ; *Motor Cortex/metabolism ; Brain/pathology ; Autopsy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their use in clinical and research settings. We overcame these issues by performing hierarchical clustering on the 5000 most variably expressed autosomal genes from motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N = 112). Three molecular phenotypes linked to ALS pathogenesis were identified: synaptic and neuropeptide signalling, oxidative stress and apoptosis, and neuroinflammation. Cluster validation was achieved by applying linear discriminant analysis models to cases from TargetALS US motor cortex (N = 93), as well as Italian (N = 15) and Dutch (N = 397) blood expression datasets, for which there was a high assignment probability (80-90%) for each molecular subtype. The ALS and motor cortex specificity of the expression signatures were tested by mapping KCL BrainBank controls (N = 59), and occipital cortex (N = 45) and cerebellum (N = 123) samples from TargetALS to each cluster, before constructing case-control and motor cortex-region logistic regression classifiers. We found that the signatures were not only able to distinguish people with ALS from controls (AUC 0.88 ± 0.10), but also reflect the motor cortex-based disease process, as there was perfect discrimination between motor cortex and the other brain regions. Cell types known to be involved in the biological processes of each molecular phenotype were found in higher proportions, reinforcing their biological interpretation. Phenotype analysis revealed distinct cluster-related outcomes in both motor cortex datasets, relating to disease onset and progression-related measures. Our results support the hypothesis that different mechanisms underpin ALS pathogenesis in subgroups of patients and demonstrate potential for the development of personalised treatment approaches. Our method is available for the scientific and clinical community at https://alsgeclustering.er.kcl.ac.uk .}, } @article {pmid38135852, year = {2024}, author = {Huang, J and Yu, Y and Pang, D and Li, C and Wei, Q and Cheng, Y and Cui, Y and Ou, R and Shang, H}, title = {Lnc-HIBADH-4 Regulates Autophagy-Lysosome Pathway in Amyotrophic Lateral Sclerosis by Targeting Cathepsin D.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4768-4782}, pmid = {38135852}, issn = {1559-1182}, support = {81871000//National Natural Science Foundation of China/ ; 82101485//National Natural Science Foundation of China/ ; 2022ZYD0051//Sichuan Province Science and Technology Support Program/ ; No.2022NSFSC0750//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Humans ; *Autophagy/physiology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Lysosomes/metabolism ; *Cathepsin D/metabolism/genetics ; Male ; Female ; Signal Transduction ; MicroRNAs/genetics/metabolism ; Apoptosis/genetics ; Middle Aged ; Cell Proliferation ; Down-Regulation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent and lethal class of severe motor neuron diseases (MND) with no efficacious treatment. The pathogenic mechanisms underlying ALS remain unclear. Nearly 90% of patients exhibit sporadic onset (sALS). Therefore, elucidating the pathophysiology of ALS is imperative. Long non-coding RNA (lncRNA) is a large class of non-coding RNAs that regulate transcription, translation, and post-translational processes. LncRNAs contribute to the pathogenesis of diverse neurodegenerative disorders and hold promise as targets for interference in the realm of neurodegeneration. However, the mechanisms of which lncRNAs are involved in ALS have not been thoroughly investigated. We identified and validated a downregulated lncRNA, lnc-HIBADH-4, in ALS which correlated with disease severity and overall survival. Lnc-HIBADH-4 acted as a "molecular sponge" regulating lysosomal function through the lnc-HIBADH-4/miR-326/CTSD pathway, thereby impacting autophagy-lysosome dynamics and the levels of cell proliferation and apoptosis. Therefore, this study discovered and revealed the role of lnc-HIBADH-4 in the pathogenesis of ALS. With further research, lnc-HIBADH-4 is expected to provide a new biomarker in the diagnosis and treatment of ALS.}, } @article {pmid38143551, year = {2023}, author = {Kasindi, A and Carstarphen, KJ}, title = {Bulbar Onset Amyotrophic Lateral Sclerosis in an African American Older Adult.}, journal = {Ochsner journal}, volume = {23}, number = {4}, pages = {353-356}, pmid = {38143551}, issn = {1524-5012}, abstract = {Background: Amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, affects the motor tracts and anterior horn cells of the spinal cord, causing both upper and lower motor neuron dysfunction. ALS typically involves progressive peripheral weakness and mobility issues. Case Report: An African American male in his early 70s presented to his primary care provider (PCP) with bulbar weakness and urinary tract symptoms. At presentation, and even later in the disease course, he ambulated well and did not report any limb issues. After some months of worsening symptoms of dyspnea, dysarthria, dysphagia, and urinary incontinence, a diagnosis of ALS was made via collaborative work between the PCP, a medical student, and various medical specialists including a neurosurgeon and neurologist. Because of the absence of limb abnormalities, the patient had difficulty accepting a diagnosis of ALS, thus delaying treatment onset. Conclusion: Clinicians must consider the patient's presentation holistically so that they do not miss insidious, complex, or unique presentations. ALS can present with bulbar symptoms early in the disease course with no upper motor neuron/lower motor neuron involvement. Older adult African American males can present with ALS. Mistrust of health care systems and resistance to science based on religious beliefs can impact patient acceptance of diagnoses and engagement in treatments. Having a long-term relationship with a PCP who also represents the patient's community can influence patient willingness to accept diagnoses, especially those that are life-limiting.}, } @article {pmid38148559, year = {2024}, author = {Gautam, S and Latif, S and Kang, YS}, title = {Effect of Various Pathological Conditions on Nitric Oxide Level and L-Citrulline Uptake in Motor Neuron-Like (NSC-34) Cell Lines.}, journal = {Biomolecules & therapeutics}, volume = {32}, number = {1}, pages = {154-161}, pmid = {38148559}, issn = {1976-9148}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that causes progressive paralysis. L-Citrulline is a non-essential neutral amino acid produced by L-arginine via nitric oxide synthase (NOS). According to previous studies, the pathogenesis of ALS entails glutamate toxicity, oxidative stress, protein misfolding, and neurofilament disruption. In addition, L-citrulline prevents neuronal cell death in brain ischemia; therefore, we investigated the change in the transport of L-citrulline under various pathological conditions in a cell line model of ALS. We examined the uptake of [[14]C]L-citrulline in wild-type (hSOD1wt/WT) and mutant NSC-34/ SOD1[G93A] (MT) cell lines. The cell viability was determined via MTT assay. A transport study was performed to determine the uptake of [[14]C]L-citrulline. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to determine the expression levels of rat large neutral amino acid transported 1 (rLAT1) in ALS cell lines. Nitric oxide (NO) assay was performed using Griess reagent. L-Citrulline had a restorative effect on glutamate induced cell death, and increased [[14]C]L-citrulline uptake and mRNA levels of the large neutral amino acid transporter (LAT1) in the glutamate-treated ALS disease model (MT). NO levels increased significantly when MT cells were pretreated with glutamate for 24 h and restored by co-treatment with L-citrulline. Co-treatment of MT cells with L-arginine, an NO donor, increased NO levels. NSC-34 cells exposed to high glucose conditions showed a significant increase in [[14]C]L-citrulline uptake and LAT1 mRNA expression levels, which were restored to normal levels upon co-treatment with unlabeled L-citrulline. In contrast, exposure of the MT cell line to tumor necrosis factor alpha, lipopolysaccharides, and hypertonic condition decreased the uptake significantly which was restored to the normal level by co-treating with unlabeled L-citrulline. L-Citrulline can restore NO levels and cellular uptake in ALS-affected cells with glutamate cytotoxicity, pro-inflammatory cytokines, or other pathological states, suggesting that L-citrulline supplementation in ALS may play a key role in providing neuroprotection.}, } @article {pmid38151482, year = {2024}, author = {Taha, MA and Morren, JA}, title = {The role of artificial intelligence in electrodiagnostic and neuromuscular medicine: Current state and future directions.}, journal = {Muscle & nerve}, volume = {69}, number = {3}, pages = {260-272}, doi = {10.1002/mus.28023}, pmid = {38151482}, issn = {1097-4598}, mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain ; Electromyography ; }, abstract = {The rapid advancements in artificial intelligence (AI), including machine learning (ML), and deep learning (DL) have ushered in a new era of technological breakthroughs in healthcare. These technologies are revolutionizing the way we utilize medical data, enabling improved disease classification, more precise diagnoses, better treatment selection, therapeutic monitoring, and highly accurate prognostication. Different ML and DL models have been used to distinguish between electromyography signals in normal individuals and those with amyotrophic lateral sclerosis and myopathy, with accuracy ranging from 67% to 99.5%. DL models have also been successfully applied in neuromuscular ultrasound, with the use of segmentation techniques achieving diagnostic accuracy of at least 90% for nerve entrapment disorders, and 87% for inflammatory myopathies. Other successful AI applications include prediction of treatment response, and prognostication including prediction of intensive care unit admissions for patients with myasthenia gravis. Despite these remarkable strides, significant knowledge, attitude, and practice gaps persist, including within the field of electrodiagnostic and neuromuscular medicine. In this narrative review, we highlight the fundamental principles of AI and draw parallels with the intricacies of human brain networks. Specifically, we explore the immense potential that AI holds for applications in electrodiagnostic studies, neuromuscular ultrasound, and other aspects of neuromuscular medicine. While there are exciting possibilities for the future, it is essential to acknowledge and understand the limitations of AI and take proactive steps to mitigate these challenges. This collective endeavor holds immense potential for the advancement of healthcare through the strategic and responsible integration of AI technologies.}, } @article {pmid38157256, year = {2023}, author = {Kang, Q and Jiang, S and Min, J and Hu, F and Xu, R}, title = {Parvalbumin interneurons dysfunction is potentially associated with FαMNs decrease and NRG1-ErbB4 signaling inhibition in spinal cord in amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {15}, number = {24}, pages = {15324-15339}, pmid = {38157256}, issn = {1945-4589}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Interneurons/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; Parvalbumins/metabolism ; Receptor, ErbB-4/genetics/metabolism ; Neuregulin-1/genetics/metabolism ; }, abstract = {OBJECTIVE: To investigate the alteration of PV interneurons in ALS mainly focusing its dynamic changes and its relationship with motor neurons and ErbB4 signaling.

METHODS: SOD1G93A mice were used as ALS model. ALS animals were divided into different groups according to birth age: symptomatic prophase (50~60 days), symptomatic phase (90~100 days), and symptomatic progression (130~140 days). Immunofluorescence was performed for measurement of PV-positive interneurons, MMP-9, ChAT, NeuN and ErbB4. RT-qPCR and western blot were used to determine the expression of PV and MMP-9.

RESULTS: PV expression was remarkably higher in the anterior horn of gray matter compared with posterior horn and area in the middle of gray matter in control mice. In ALS mice, PV, MMP-9 and ErbB4 levels were gradually decreased along with onset. PV, MMP-9 and ErbB4 levels in ALS mice were significantly down-regulated than control mice after onset, indicating the alteration of PV interneurons, FαMNs and ErbB4. SαMNs levels only decreased remarkably at symptomatic progression in ALS mice compared with control mice, while γMNs levels showed no significant change during whole period in all mice. MMP-9 and ErbB4 were positively correlated with PV. NRG1 treatment significantly enhanced the expression of ErBb4, PV and MMP-9 in ALS mice.

CONCLUSION: PV interneurons decrease is along with FαMNs and ErbB4 decrease in ALS mice.}, } @article {pmid38157654, year = {2024}, author = {Halseth, M and Mahoney, R and Hsiou, J and Jones, HN and Kimonis, V}, title = {Remote respiratory resistance exercise training improves respiratory function in individuals with VCP multisystem proteinopathy.}, journal = {Neuromuscular disorders : NMD}, volume = {34}, number = {}, pages = {68-74}, doi = {10.1016/j.nmd.2023.12.001}, pmid = {38157654}, issn = {1873-2364}, mesh = {Adult ; Humans ; Valosin Containing Protein/genetics ; *Resistance Training ; *Muscular Diseases ; Respiration ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Mutation ; Cell Cycle Proteins/genetics ; }, abstract = {Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.}, } @article {pmid38158673, year = {2023}, author = {Luo, S and Yang, L and Ma, B and Wang, X and Lu, Y and Ma, S and Wang, D and Qu, H and Zou, L}, title = {Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {69}, number = {13}, pages = {156-161}, doi = {10.14715/cmb/2023.69.13.24}, pmid = {38158673}, issn = {1165-158X}, mesh = {Humans ; Network Pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases/genetics ; Proto-Oncogene Proteins c-akt ; Medicine, Chinese Traditional ; Technology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.}, } @article {pmid38174670, year = {2023}, author = {Maksymowicz-Śliwińska, A and Lulé, D and Nieporęcki, K and Ciećwierska, K and Ludolph, AC and Kuźma-Kozakiewicz, M}, title = {Attitudes of caregivers towards prolonging and shortening life in advanced stages of amyotrophic lateral sclerosis.}, journal = {Folia neuropathologica}, volume = {61}, number = {4}, pages = {349-359}, doi = {10.5114/fn.2023.130444}, pmid = {38174670}, issn = {1509-572X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Caregivers ; Death ; Disease Progression ; }, abstract = {INTRODUCTION: Inevitable disease progression in amyotrophic lateral sclerosis (ALS) forces patients and their caregivers (CGs) to reflect on end-of-life treatment. The CGs are often heavily burdened with their role of surrogate decision-makers. The aim of the study was to analyze attitudes of CGs and presumable attitudes of ALS patients from the CGs' perspective towards palliative care in advanced disease stages.

MATERIAL AND METHODS: One hundred and sixty four CGs from Germany and Poland were interviewed regarding their own preferences and patients' ideational attitudes towards life-prolonging (invasive and non-invasive ventilation, tube feeding) and life-shortening methods (termination of measures, active measures if permitted by law). The data were correlated with patient- and CG-related factors: demographic and clinical data, care commitment, depression and quality of life (QoL).

RESULTS: The CGs were mostly female spouses of ALS patients, with secondary/higher education. Nearly 70% (81% in Poland, 57% in Germany; p = 0.0001) reported positive attitudes towards life-prolonging methods, which positively correlated with religiousness and negatively with patients' age. Approximately 40% of CGs (25% and 51% respectively; p = 0.001) reported positive attitudes towards life-shortening methods. It positively correlated with time since diagnosis and negatively with the CG's QoL, religiosity and religious/spiritual faith as factors that significantly influenced end-of-life decisions. There was a strongly positive correlation between CGs' positive attitudes towards life-shortening methods and presumed positive patients' attitudes assessed by their CGs (p < 0.000001).

CONCLUSIONS: Although attitudes towards treatment differed between countries, the CGs of ALS patients were generally positive towards life-prolonging treatment. A greater acceptance of life-shortening methods in the case of longer disease duration and poorer QoL may indicate worse coping with disease progression and weaker adaptation mechanisms in CGs compared to those previously reported in ALS patients. A close resemblance of the CGs' answers to probable patients' attitudes reported by the CGs indicates that many GCs might actually express their own culturally shaped attitudes towards end-of-life methods. In light of earlier-reported discrepancies between presumed opinions of the CGs and of patients themselves, a greater focus should be placed on thorough discussions on future treatment options with ALS patients in the presence of their CGs, to stay in line with the patient's authentic will.}, } @article {pmid38177242, year = {2024}, author = {Shi, Y and Huang, L and Dong, H and Yang, M and Ding, W and Zhou, X and Lu, T and Liu, Z and Zhou, X and Wang, M and Zeng, B and Sun, Y and Zhong, S and Wang, B and Wang, W and Yin, C and Wang, X and Wu, Q}, title = {Decoding the spatiotemporal regulation of transcription factors during human spinal cord development.}, journal = {Cell research}, volume = {34}, number = {3}, pages = {193-213}, pmid = {38177242}, issn = {1748-7838}, support = {81891001//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32122037//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; Humans ; *Transcription Factors/genetics ; *Amyotrophic Lateral Sclerosis ; Neurogenesis ; Central Nervous System ; }, abstract = {The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10× Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.}, } @article {pmid38178841, year = {2023}, author = {Zhao, S and Chen, R and Gao, Y and Lu, Y and Bai, X and Zhang, J}, title = {Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1319706}, pmid = {38178841}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons (MNs) in the brain and spinal cord. It is caused by multiple factors, including mutations in any one of several specific genes. Optineurin (OPTN) mutation is an essential cause of some familial and sporadic ALS. Besides, as a multifunctional protein, OPTN is highly expressed and conserved in the central nervous system. OPTN exerts its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more core proteins related to autophagy and inflammation, etc. OPTN mutation mainly results in its function deficiency, which alters these interactions, leading to functional impairment in many processes. Meanwhile, OPTN immunopositive inclusions are also confirmed in the cases of ALS due to C9ORF72, FUS, TARDBP, and SOD1 mutations. Therefore, OPTN gene may play fundamental roles in the molecular pathology of ALS in addition to OPTN mutation. In this review, we summarize the recent advances in the ALS pathology of OPTN defect, such as mitophagy disorder, neuroinflammation, neuronal axonal degeneration, vesicular transport dysfunction, etc., which will provide a reference for research on the pathogenesis and treatment of ALS.}, } @article {pmid38179776, year = {2023}, author = {Yang, EJ and Lee, SH}, title = {Anti-Inflammatory Effects of Chaenomeles sinensis Extract in an ALS Animal Model.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {12}, pages = {326}, doi = {10.31083/j.fbl2812326}, pmid = {38179776}, issn = {2768-6698}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea, South Korea/ ; KSN2212010//KIOM, South Korea/ ; C18040//KIOM, South Korea/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Mice, Transgenic ; Disease Models, Animal ; Spinal Cord ; *Rosaceae/chemistry ; Antioxidants/pharmacology/therapeutic use ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress. Despite many studies seeking to identify and develop effective therapies, effective ALS treatment has yet to be approved. Hence, patients with ALS ultimately experience muscle atrophy and loss of motor neurons. Herbal medicines have been used to treat numerous diseases by modulating multiple biological processes and exerting pharmacological effects, including anti-inflammatory and antioxidant properties. In particular, Chaenomeles sinensis Koehne (CS) exhibits anti-hyperuricemic and nephroprotective effects and is used to treat anaphylaxis, viral infections, and neurodegenerative diseases, such as Alzheimer's disease. This study monitored the effects of CS supplementation on muscle function and motor neurons in hSOD1G93A mice, an established ALS animal model.

METHODS: Body weight measurements and behavioral tests were performed; additionally, western blotting and immunohistochemistry analyses were conducted using the mice gastrocnemius, tibialis anterior, and spinal cord.

RESULTS: CS augmented anti-inflammatory and antioxidant effects in the muscle and spinal cord of hSOD1G93A mice. Furthermore, CS improved motor function and regulated autophagy in the muscles of the hSOD1G93A mice.

CONCLUSIONS: CS might represent a promising supplement for improving motor function and delaying ALS progression. However, its development for clinical use warrants further investigation.}, } @article {pmid38180358, year = {2024}, author = {Ferguson, R and van Es, MA and van den Berg, LH and Subramanian, V}, title = {Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.}, journal = {The Journal of pathology}, volume = {262}, number = {4}, pages = {410-426}, doi = {10.1002/path.6244}, pmid = {38180358}, issn = {1096-9896}, support = {084562/Z/07/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/pathology ; *Neural Stem Cells/metabolism ; Mutation ; Homeostasis ; *Ribonuclease, Pancreatic ; }, abstract = {Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.}, } @article {pmid38180612, year = {2024}, author = {Lin, CY and Wu, HE and Weng, EF and Wu, HC and Su, TP and Wang, SM}, title = {Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5282-5294}, pmid = {38180612}, issn = {1559-1182}, mesh = {*Sigma-1 Receptor ; *Fluvoxamine/pharmacology ; *Receptors, sigma/metabolism ; *Autophagy/drug effects ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Humans ; *Active Transport, Cell Nucleus/drug effects ; Animals ; Mice ; Cell Nucleus/metabolism/drug effects ; C9orf72 Protein/metabolism/genetics ; Cell Line ; }, abstract = {Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.}, } @article {pmid38185101, year = {2024}, author = {Huber, T and Krüerke, D and Simões-Wüst, AP}, title = {How Physicians and Nursing Staff Perceive Effectiveness and Tolerability of Bryophyllum Preparations: An Online Survey in an Anthroposophic Hospital.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {116-123}, pmid = {38185101}, issn = {2504-2106}, mesh = {Humans ; Male ; Surveys and Questionnaires ; Female ; Adult ; Switzerland ; *Kalanchoe ; Anthroposophy ; Middle Aged ; *Attitude of Health Personnel ; *Nursing Staff, Hospital/psychology/statistics & numerical data ; *Physicians/psychology ; *Phytotherapy ; *Plant Extracts/therapeutic use ; *Medical Staff, Hospital/psychology ; }, abstract = {BACKGROUND: Bryophyllum preparations are widely used in anthroposophic medicine, most often for mental and behavioural disorders. Three prospective studies have revealed positive effects of Bryophyllum pinnatum on sleep quality, and various trials have shown very good tolerability. Results from animal models have indicated CNS depressant and anxiolytic effects. This survey was conducted at the hospital "Klinik Arlesheim" in Switzerland to find out how the physicians and the nursing staff perceive the effectiveness and the tolerability of the Bryophyllum preparations they most frequently use.

DESIGN: Internal, anonymous online survey of healthcare professionals (April 8-May 31, 2022). The questionnaire comprised 105 multiple-choice questions. Answering the questions was taken as consent to participate in the survey.

PARTICIPANTS AND METHODS: All physicians and nursing staff with a valid email address at the hospital "Klinik Arlesheim AG" were invited via email to participate in this REDCap survey. The data were analysed descriptively.

RESULTS: Out of 266 invited participants, 48 answered some and 36 answered all questions (response rate between 18.0% and 13.5%). The participants had long experience with Bryophyllum preparations and were comprised approximately equal numbers of physicians and nursing staff. Various Bryophyllum preparations from the hospital's own production and Wala Heilmittel GmbH (in both cases produced from the species B. daigremontianum) and from Weleda AG (species B. pinnatum) were used. The indications for which most participants had prescribed or administered Bryophyllum preparations "very frequently" were anxiety, sleep disorders, crisis situations in oncology, posttraumatic stress disorder, benzodiazepine dependence/withdrawal, and depression. Improvements such as relief from restlessness, decreased anxiety, balance, easier falling asleep, better sleeping through, increased resilience, mood elevation, and less urge to move one's legs were reported "frequently" or "very frequently." Almost all participants agreed that Bryophyllum can be used to reduce the intake of synthetic sedatives or psychotropic drugs, but only approximately half believed that it could replace them. The majority of participants mentioned good tolerability of the various products, but a few reported occasional stomach or intestinal irritation, daytime fatigue, drowsiness, diarrhoea, and nausea.

CONCLUSION: Bryophyllum preparations are perceived as helpful in the treatment of various mental disorders, particularly anxiety, and are generally well tolerated. Most of these preparations are used for indications that have not yet been clinically investigated.

UNLABELLED: HintergrundBryophyllum-Präparate werden in der Anthroposophischen Medizin sehr häufig zur Behandlung von psychischen und Verhaltensstörungen eingesetzt. Drei prospektive Studien zeigten zudem positive Wirkungen von Bryophyllum pinnatum (BP) auf die Schlafqualität. Auch die Verträglichkeit wurde in allen bisherigen Studien als sehr gut bewertet. In Tiermodellen wurden ZNS-depressive und anxiolytische Effekte von BP festgestellt. Die hier durchgeführte Umfrage fand an der Klinik Arlesheim (Schweiz) statt. Sie diente dazu herauszufinden, wie Ärztinnen und Ärzte sowie das Pflegepersonal die Wirksamkeit und Verträglichkeit der von ihnen am häufigsten verwendeten Bryophyllum-Präparate wahrnehmen.DesignInterne, anonyme, Online-Befragung unter ärztlichen und pflegerischen Fachkräften (8. April–31. Mai 2022). Der Fragebogen umfasste 105 Multiple-Choice-Fragen. Die Beantwortung der Fragen wurde als Zustimmung zur Teilnahme an der Umfrage interpretiert.Teilnehmende und MethodenAlle Ärztinnen, Ärzte und Pflegefachpersonen mit einer gültigen E-Mail-Adresse der “Klinik Arlesheim AG” wurden per E-Mail eingeladen, an dieser REDCap-Umfrage teilzunehmen. Die Daten wurden deskriptiv ausgewertet.ErgebnisseVon den 266 eingeladenen Teilnehmenden beantworteten 48 einige und 36 alle Fragen (Antwortquote zwischen 18.0% und 13.5%). Die Teilnehmenden hatten langjährige Erfahrung mit Bryophyllum-Präparaten und setzten sich etwa zu gleichen Teilen aus ärztlichen und pflegerischen Fachkräften zusammen. Die Resultate zeigen, dass verschiedenste Bryophyllum-Präparate aus klinikeigener Herstellung, von der Wala Heilmittel GmbH (Art B. daigremontianum) und von der Weleda AG (Art B. pinnatum) verwendet werden. Zu den Indikationen, bei denen die meisten Teilnehmenden Bryophyllum-Präparate “sehr häufig” verordnet oder angewendet haben, gehören Angstzustände, Schlafstörungen, Krisensituationen in der Onkologie, Posttraumatische Belastungsstörung, Benzodiazepin-Abhängigkeit/Entzug und Depressionen. Gesundheitsverbesserungen wie Linderung von Unruhe, verminderte Angst, Ausgeglichenheit, leichteres Einschlafen, besseres Durchschlafen, erhöhte Belastbarkeit, Stimmungsaufhellung und weniger Drang, die Beine zu bewegen, wurden als “häufig” oder “sehr häufig” angegeben. Fast alle Teilnehmenden waren sich einig, dass Bryophyllum verwendet werden kann, um die Einnahme von synthetischen Beruhigungsmitteln oder Psychopharmaka zu reduzieren, aber nur etwa die Hälfte gab an, dass es diese ersetzen kann. Die Mehrheit der Teilnehmenden spricht von einer guten Verträglichkeit der verschiedenen Produkte. Einige wenige berichteten von gelegentlicher Magen- oder Darmreizung, Tagesmüdigkeit, Schläfrigkeit, Durchfall und Übelkeit.SchlussfolgerungBryophyllum-Präparate werden als hilfreich bei der Behandlung verschiedener psychischen Störungen, insbesondere bei Angstzuständen, angesehen und im Allgemeinen gut vertragen. Die meisten der angegebenen Präparate werden für Indikationen verwendet, die noch nicht klinisch untersucht worden sind.}, } @article {pmid38185999, year = {2024}, author = {Liu, Z and Qiang, Y and Shan, S and Wang, S and Song, F}, title = {Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {2}, pages = {}, doi = {10.1093/cercor/bhad526}, pmid = {38185999}, issn = {1460-2199}, support = {82173552//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Rats ; Animals ; *Carbon Disulfide/metabolism ; *Neuroblastoma/metabolism/pathology ; Cytoplasm/metabolism ; DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/chemically induced/pathology ; Spinal Cord/pathology ; *Neurodegenerative Diseases/metabolism ; *Mitochondrial Diseases/metabolism/pathology ; }, abstract = {The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.}, } @article {pmid38187158, year = {2023}, author = {Yang, J and Liu, T and Zhang, L and Li, X and Du, FP and Liu, Q and Dong, H and Liu, Y}, title = {Eosinophils at diagnosis are elevated in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1289467}, pmid = {38187158}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons. To date, no effective treatment or reliable biomarker for ALS has been developed. In recent years, many factors have been proposed as possible biomarkers of ALS; however, no consensus has been reached. Therefore, a reliable biomarker is urgently needed. Eosinophils may play a crucial role in healthy humans and diseases, and serve as a biomarker for many chronic diseases.

METHODS: Routine blood test results were collected from 66 healthy controls and 59 patients with ALS. The percentages and total numbers of each cell population were analyzed, and the correlation between these indicators and patient ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score) was analyzed.

RESULTS: Compared to healthy controls, the number of blood leukocytes, neutrophils, monocytes, and basophils was significantly decreased in patients with ALS (p = 0.002, p = 0.001, p = 0.049, and p < 0.0001, respectively). There was an increase in the number of eosinophils (p < 0.0001), but no difference in the number of lymphocytes between patients with ALS and healthy controls was found (p = 0.563). Compared to healthy controls, the percentage of neutrophils was decreased and the percentage of lymphocytes and eosinophils was increased in patients with ALS (p = 0.01, p = 0.012, and p = 0.001, respectively). There was no difference between patients with ALS and healthy controls in the percentage of monocytes and basophils (p = 0.622 and p = 0.09, respectively). However, only the percentage and number of eosinophils had a correlation with the ΔFS score. Further multivariate analysis revealed a significant correlation between the disease duration, eosinophil count and percentage, and the disease progression rate (p < 0.0001, p = 0.048, and p = 0.023, respectively). The neutrophil-to-eosinophil ratio (NER), lymphocyte-to-eosinophil ratio (LER), and monocyte-to-eosinophil ratio (MER) were significantly lower in patients with ALS than in healthy controls. However, only the LER was significantly correlated with the ΔFS score.

CONCLUSION: These observations implicate neutrophils, lymphocytes, and eosinophils as important factors, and increasing eosinophil counts were negatively correlated with the ΔFS score in patients with ALS.}, } @article {pmid38188011, year = {2023}, author = {Ansari, U and Chen, V and Sedighi, R and Syed, B and Muttalib, Z and Ansari, K and Ansari, F and Nadora, D and Razick, D and Lui, F}, title = {Role of the UNC13 family in human diseases: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {388-400}, pmid = {38188011}, issn = {2373-7972}, abstract = {This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC13C, and UNC13D, in the pathogenesis of various human diseases. These proteins, which are evolutionarily conserved and crucial for synaptic vesicle priming and exocytosis, have been implicated in a range of disorders, spanning from neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) to immune-related conditions such as familial hemophagocytic lymphohistiocytosis (FHL). The involvement of UNC13A in neurotransmitter release and synaptic plasticity is linked to ALS and FTD, with genetic variations affecting disease progression. UNC13B, which is closely related to UNC13A, plays a role in autism spectrum disorders (ASD), epilepsy, and schizophrenia. UNC13C is implicated in oral squamous cell carcinoma (OSCC) and hepatocellular carcinoma (HCC), and has a neuroprotective role in Alzheimer's disease (AD). UNC13D has an essential role in immune cell function, making it a key player in FHL. This review highlights the distinct molecular functions of each UNC13 family member and their implications in disease contexts, shedding light on potential therapeutic strategies and avenues for future research. Understanding these proteins' roles offers new insights into the management and treatment of neurological and immunological disorders.}, } @article {pmid38196621, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38196621}, issn = {2693-5015}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; MC_PC_15080/MRC_/Medical Research Council/United Kingdom ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10[-39]; OR=4.73, p = 2 × 10[-10]; OR=2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38198547, year = {2024}, author = {Perlegos, AE and Durkin, J and Belfer, SJ and Rodriguez, A and Shcherbakova, O and Park, K and Luong, J and Bonini, NM and Kayser, MS}, title = {TDP-43 impairs sleep in Drosophila through Ataxin-2-dependent metabolic disturbance.}, journal = {Science advances}, volume = {10}, number = {2}, pages = {eadj4457}, pmid = {38198547}, issn = {2375-2548}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; T32 HL007953/HL/NHLBI NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; F31 AG063470/AG/NIA NIH HHS/United States ; T32 MH014654/MH/NIMH NIH HHS/United States ; R01 AG071777/AG/NIA NIH HHS/United States ; R56 AG071777/AG/NIA NIH HHS/United States ; R01 GM084947/GM/NIGMS NIH HHS/United States ; F30 AG058409/AG/NIA NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; F32 NS117785/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis ; Ataxin-2 ; DNA-Binding Proteins/genetics ; Drosophila ; *Neurodegenerative Diseases ; Drosophila Proteins ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.}, } @article {pmid38200398, year = {2024}, author = {Stenson, K and Fecteau, TE and O'Callaghan, L and Bryden, P and Mellor, J and Wright, J and Earl, L and Thomas, O and Iqbal, H and Barlow, S and Parvanta, S}, title = {Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2390-2404}, pmid = {38200398}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications ; *Quality of Life ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Disease Progression ; Aged ; Adult ; Severity of Illness Index ; Surveys and Questionnaires ; Caregivers/psychology ; Neurologists ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS).

METHODS: Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States.

RESULTS: Neurologists (n = 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in HRQoL and increased burden.

CONCLUSIONS: Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.}, } @article {pmid38201932, year = {2023}, author = {Sharma, H and Sharma, N and An, SSA}, title = {Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.}, journal = {Nutrients}, volume = {16}, number = {1}, pages = {}, pmid = {38201932}, issn = {2072-6643}, support = {RS-2023-00251396 and 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {*Neuroprotective Agents/pharmacology ; *Cordyceps ; *Agaricales ; Neuroprotection ; Adenosine ; }, abstract = {Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N[6]-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.}, } @article {pmid38202163, year = {2023}, author = {Ueha, R and Cotaoco, C and Kondo, K and Yamasoba, T}, title = {Management and Treatment for Dysphagia in Neurodegenerative Disorders.}, journal = {Journal of clinical medicine}, volume = {13}, number = {1}, pages = {}, pmid = {38202163}, issn = {2077-0383}, abstract = {Patients with neurodegenerative disorders (NDDs) often experience functional dysphagia, which may involve dysfunction in a specific phase of swallowing or in the entire process. This review outlines the approach to dysphagia in the setting of NDDs. Distinguishing the etiology of dysphagia can be difficult, and it is important to always look out for signs pointing to NDD as the cause. Thorough diagnostic work-up is essential, and it includes a comprehensive history and physical examination, alongside swallowing function tests, such as fiberoptic endoscopic evaluation of swallowing, videofluoroscopic swallowing study, and high-resolution manometry. Management requires a multidisciplinary approach with a treatment plan tailored to each patient. This involves dietary guidance, swallowing rehabilitation, and surgery in cases in which improvement with rehabilitation is inadequate. Surgery may involve altering certain pharyngolaryngeal structures to facilitate swallowing and reduce the risk of aspiration (swallowing improvement surgery) or separating the airway and digestive tract while sacrificing laryngeal function, with the main goal of preventing aspiration (aspiration prevention surgery). Proper management stems from recognizing the impact of these disorders on swallowing and consistently finding ways to improve the quality of life of patients.}, } @article {pmid38203300, year = {2023}, author = {Wei, J and Wong, LC and Boland, S}, title = {Lipids as Emerging Biomarkers in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203300}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Alzheimer Disease/diagnosis ; *Parkinson Disease ; Biomarkers ; Monoglycerides ; }, abstract = {Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.}, } @article {pmid38216448, year = {2024}, author = {Van Daele, SH and Masrori, P and Van Damme, P and Van Den Bosch, L}, title = {The sense of antisense therapies in ALS.}, journal = {Trends in molecular medicine}, volume = {30}, number = {3}, pages = {252-262}, doi = {10.1016/j.molmed.2023.12.003}, pmid = {38216448}, issn = {1471-499X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Oligonucleotides, Antisense/therapeutic use ; RNA Splicing ; }, abstract = {Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.}, } @article {pmid38218077, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Bączyk, M and de Carvalho, M and Dileone, M and Dubbioso, R and Fernandes, S and Kozak, G and Motolese, F and Ziemann, U}, title = {Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {114-136}, doi = {10.1016/j.clinph.2023.12.012}, pmid = {38218077}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Transcranial Direct Current Stimulation ; *Motor Neuron Disease/diagnosis/therapy ; Motor Neurons/physiology ; Brain ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.}, } @article {pmid38218903, year = {2024}, author = {Lee, MH and Kang, S and Um, KH and Lee, SW and Hwang, H and Baek, K and Choi, JW}, title = {Brain-targeted delivery of neuroprotective survival gene minimizing hematopoietic cell contamination: implications for Parkinson's disease treatment.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {53}, pmid = {38218903}, issn = {1479-5876}, support = {NRF-2017R1A5A2014768//Ministry of Science and ICT, South Korea/ ; NRF-2022R1A2C2009281//Ministry of Science and ICT, South Korea/ ; NRF-2019R1A2C1006752//Ministry of Science and ICT, South Korea/ ; 21153MFDS601//Ministry of Food and Drug Safety/ ; }, mesh = {Animals ; *Parkinson Disease/genetics/therapy ; Leukocytes, Mononuclear ; Brain/metabolism ; Genetic Therapy/methods ; Transgenes ; Genetic Vectors ; Dependovirus/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases, including Parkinson's disease, Amyotropic Lateral Sclerosis (ALS) and Alzheimer's disease, present significant challenges for therapeutic development due to drug delivery restrictions and toxicity concerns. Prevailing strategies often employ adeno-associated viral (AAV) vectors to deliver neuroprotective survival genes directly into the central nervous system (CNS). However, these methods have been limited by triggering immunogenic responses and risk of tumorigenicity, resulting from overexpression of survival genes in peripheral blood mononuclear cells (PBMC), thereby increasing the risk of tumorigenicity in specific immune cells. Thus, by coding selectively suppressive microRNA (miRNA) target sequences in AAV genome, we designed CNS-targeted neuroprotective gene expression vector system without leakage to blood cells.

METHODS: To minimize the potential for transgene contamination in the blood, we designed a CNS-specific AAV system. Our system utilized a self-complementary AAV (scAAV), encoding a quadruple repeated target sequence of the hematopoietic cell-specific miR142-3p at the 3' untranslated region (UTR). As a representative therapeutic survival gene for Parkinson's disease treatment, we integrated DX2, an antagonistic splice variant of the apoptotic gene AIMP2, known to be implicated in Parkinson's disease, into the vector.

RESULTS: This configuration ensured that transgene expression was stringently localized to the CNS, even if the vector found its way into the blood cells. A single injection of scAAV-DX2 demonstrated marked improvement in behavior and motor activity in animal models of Parkinson's disease induced by either Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, comprehensive preclinical data adhering to Good Laboratory Practice (GLP) standards revealed no adverse effects in the treated animals.

CONCLUSIONS: Our CNS-specific vector system, which encodes a survival transgene DX2, signifies a promising avenue for safe gene therapy, avoiding unintended expression of survival gene in blood cells, applicable to various neurodegenerative diseases.}, } @article {pmid38225062, year = {2024}, author = {Xu, X and Zhao, B and Li, B and Shen, B and Qi, Z and Wang, J and Cui, H and Chen, S and Wang, G and Liu, X}, title = {Trp-574-Leu mutation and metabolic resistance by cytochrome P450 gene conferred high resistance to ALS-inhibiting herbicides in Descurainia sophia.}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105708}, doi = {10.1016/j.pestbp.2023.105708}, pmid = {38225062}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/metabolism ; *Arylsulfonates ; *Brassicaceae/drug effects/genetics ; Cytochrome P-450 Enzyme System/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; }, abstract = {Descurainia sophia (flixweed) is a troublesome weed in winter wheat fields in North China. Resistant D. sophia populations with different acetolactate synthetase (ALS) mutations have been reported in recent years. In addition, metabolic resistance to ALS-inhibiting herbicides has also been identified. In this study, we collected and purified two resistant D. sophia populations (R1 and R2), which were collected from winter wheat fields where tribenuron-methyl provided no control of D. sophia at 30 g a.i. ha[-1]. Whole plant bioassay and ALS activity assay results showed the R1 and R2 populations had evolved high-level resistance to tribenuron-methyl and florasulam and cross-resistance to imazethapyr and pyrithiobac‑sodium. The two ALS genes were cloned from the leaves of R1 and R2 populations, ALS1 (2004 bp) and ALS2 (1998 bp). A mutation of Trp 574 to Leu in ALS1 was present in both R1 and R2. ALS1 and ALS2 were cloned from R1 and R2 populations respectively and transferred into Arabidopsis thaliana. Homozygous T3 transgenic seedlings with ALS1 of R1 or R2 were resistant to ALS-inhibiting herbicides and the resistant levels were the same. Transgenic seedlings with ALS2 from R1 or R2 were susceptible to ALS-inhibiting herbicides. Treatment with cytochrome P450 inhibitor malathion decreased the resistant levels to tribenuron-methyl in R1 and R2. RNA-Seq was used to identify target cytochrome P450 genes possibly involved in resistance to ALS-inhibiting herbicides. There were five up-regulated differentially expressed cytochrome P450 genes: CYP72A15, CYP83B1, CYP81D8, CYP72A13 and CYP71A12. Among of them, CYP72A15 had the highest expression level in R1 and R2 populations. The R1 and R2 populations of D. sophia have evolved resistance to ALS-inhibiting herbicides due to Trp 574 Leu mutation in ALS1 and possibly other mechanisms. The resistant function of CYP72A15 needs further research.}, } @article {pmid38225089, year = {2024}, author = {Unan, R and Azapoglu, O and Deligoz, İ and Mennan, H and Al-Khatib, K}, title = {Gene flow and spontaneous mutations are responsible for imidazolinone herbicide-resistant weedy rice (Oryza sativa L.).}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105746}, doi = {10.1016/j.pestbp.2023.105746}, pmid = {38225089}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Oryza/genetics ; Gene Flow ; Plant Weeds/genetics ; Herbicide Resistance/genetics ; Mutation ; }, abstract = {For more than two decades, weedy rice (Oryza sativa L.) has been controlled in rice fields by using imidazolinone (IMI) herbicide-resistant rice technology (Clearfield®). Outcrossing in weedy rice populations and spontaneous mutations are potential problems with herbicide-resistant crop management technologies, such as the IMI-resistant rice. The aim of this study was to characterize the mechanism of IMI herbicide resistance in weedy rice through dose-response bioassay study and evaluating amino acid substitutions in acetolactate synthase (ALS) protein. A total of 118 suspected IMI-resistant weedy rice samples, which survived in the field after an IMI herbicide application, were collected at harvest time from Türkiye in 2020 and 2021. Single-dose imazamox application experiment revealed that 38 plants survived herbicide treatment. The imazamox resistance of the surviving plants was confirmed by dose-response experiment. ALS gene region underwent a sanger DNA partial sequencing. No substitution was found in 10 samples, however, amino acid substitutions were found in 26 samples with S563N, one sample with S653T, and one sample with E630D. The S653N point is the same substitution point that serves as the origin of resistance for the Clearfield® rice varieties that are commonly cultivated in the region. It has been hypothesized that the gene flow from IMI-resistant rice may be the cause of resistance in the IMI resistant weedy rice samples with S653N. The other substitution, S653T, were considered spontaneous mutation to IMI resistance. Interestingly, the S653T mutation was detected for the first time in weedy rice. The mechanism of resistance of 10 resistant weedy rice was not confirmed in this study, however, it may be a non-target resistance or another mutation point in target site, but evidently, they did not acquire resistance by gene flow from IMI-resistant rice. It has been concluded that the effectiveness of IMI-resistant rice technology in controlling weedy rice has drastically decreased due to possible gene flow, spontaneous mutation and non-target resistance. In addition to cultural controls like clean seed, clean machinery and crop rotation, other herbicide-tolerant rice systems such as Provisia® and Roxy-RPS® rice are needed to create a diverse weedy rice management ensemble available for rice production and move towards sustainable rice farming.}, } @article {pmid38229740, year = {2024}, author = {Rosse, G}, title = {Novel Pyrazolopyridine Inhibitors of Monoacylglycerol Lipase for the Treatment of Neurodegenerative Diseases and Neuroinflammation.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {1}, pages = {19-20}, pmid = {38229740}, issn = {1948-5875}, abstract = {This work highlights the use of bicyclic heterocyclic compounds as monoacylglycerol lipase inhibitors potentially in the treatment of Alzheimer's disease, Parkinson's disease, ALS, traumatic brain injury, and multiple sclerosis.}, } @article {pmid38235589, year = {2024}, author = {Gebrehiwet, P and Aggarwal, S and Topaloglu, O and Chiò, A}, title = {Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis.}, journal = {Expert review of pharmacoeconomics & outcomes research}, volume = {24}, number = {3}, pages = {447-458}, doi = {10.1080/14737167.2024.2306819}, pmid = {38235589}, issn = {1744-8379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Cost-Benefit Analysis ; Feasibility Studies ; Mitochondria Associated Membranes ; Disease Progression ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS).

METHODS: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate.

RESULTS: A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively.

CONCLUSION: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.}, } @article {pmid38235844, year = {2024}, author = {Zhang, L and Li, Y and Niu, J and Hu, N and Ding, J and Cui, L and Liu, M}, title = {Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16202}, pmid = {38235844}, issn = {1468-1331}, support = {CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 2016YFC0905103//National Key Research and Development Program of China/ ; grant XDB39040000//the Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy ; Nerve Conduction Studies ; Neural Conduction/physiology ; Motor Neurons ; *Polyneuropathies ; *Motor Neuron Disease ; }, abstract = {BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients.

METHODS: Between January 2019 and May 2022, 102 consecutive treatment-naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS).

RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively.

CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.}, } @article {pmid38240416, year = {2024}, author = {Schuster, J and Dreyhaupt, J and Mönkemöller, K and Dupuis, L and Dieterlé, S and Weishaupt, JH and Kassubek, J and Petri, S and Meyer, T and Grosskreutz, J and Schrank, B and Boentert, M and Emmer, A and Hermann, A and Zeller, D and Prudlo, J and Winkler, AS and Grehl, T and Heneka, MT and Johannesen, S and Göricke, B and Witzel, S and Dorst, J and Ludolph, AC and , }, title = {In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16204}, pmid = {38240416}, issn = {1468-1331}, support = {//Teva Pharmaceutical Industries/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Indans/therapeutic use ; Disease Progression ; }, abstract = {BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data.

METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system.

RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects.

CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.}, } @article {pmid38244886, year = {2024}, author = {DSouza, AA and Kulkarni, P and Ferris, CF and Amiji, MM and Bleier, BS}, title = {Mild repetitive TBI reduces brain-derived neurotrophic factor (BDNF) in the substantia nigra and hippocampus: A preclinical model for testing BDNF-targeted therapeutics.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114696}, pmid = {38244886}, issn = {1090-2430}, support = {P30 EY003790/EY/NEI NIH HHS/United States ; R01 NS108968/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Rats ; *Brain Concussion/complications ; *Brain Injuries, Traumatic/drug therapy/complications ; Brain-Derived Neurotrophic Factor/metabolism ; Hippocampus/metabolism ; Substantia Nigra/metabolism ; }, abstract = {Clinical studies have consistently shown that neurodegenerative diseases (NDs) such as Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease show absent or low levels of brain-derived neurotrophic factor (BDNF). Despite this relationship between BDNF and ND, only a few ND animal models have been able to recapitulate the low BDNF state, thereby hindering research into the therapeutic targeting of this important neurotrophic factor. In order to address this unmet need, we sought to develop a reproducible model of BDNF reduction by inducing traumatic brain injury (TBI) using a closed head momentum exchange injury model in mature 9-month-old male and female rats. Head impacts were repetitive and varied in intensity from mild to severe. BDNF levels, as assessed by ELISA, were significantly reduced in the hippocampus of both males and females as well as in the substantia nigra of males 12 days after mild TBI. However, we observed significant sexual dimorphism in multiple sequelae, including magnetic resonance imaging-determined vasogenic edema, astrogliosis (GFAP-activation), and microgliosis (Iba1 activation). This study provides an opportunity to investigate the mechanism of BDNF reduction in rodent models and provides a reliable paradigm to test BDNF-targeted therapeutics for the treatment of ND.}, } @article {pmid38249102, year = {2024}, author = {Bakaeva, M and Chetverikov, S and Starikov, S and Kendjieva, A and Khudaygulov, G and Chetverikova, D}, title = {Effect of Plant Growth-Promoting Bacteria on Antioxidant Status, Acetolactate Synthase Activity, and Growth of Common Wheat and Canola Exposed to Metsulfuron-Methyl.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {79-95}, pmid = {38249102}, issn = {2039-4713}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {Metsulfuron-methyl, a widely used herbicide, could cause damage to the sensitive plants in crop-rotation systems at extremely low levels in the soil. The potential of plant growth-promoting bacteria (PGPB) for enhancing the resistance of plants against herbicide stress has been discovered recently. Therefore, it is poorly understood how physiological processes occur in plants, while PGPB reduce the phytotoxicity of herbicides for agricultural crops. In greenhouse studies, the effect of strains Pseudomonas protegens DA1.2 and Pseudomonas chlororaphis 4CH on oxidative damage, acetolactate synthase (ALS), enzymatic and non-enzymatic antioxidants in canola (Brassica napus L.), and wheat (Triticum aestivum L.) were investigated under two levels (0.05 and 0.25 mg∙kg[-1]) of metsulfuron-methyl using spectrophotometric assays. The inoculation of herbicide-exposed wheat with bacteria significantly increased the shoots fresh weight (24-28%), amount of glutathione GSH (60-73%), and flavonoids (5-14%), as well as activity of ascorbate peroxidase (129-140%), superoxide dismutase SOD (35-49%), and ALS (50-57%). Bacterial treatment stimulated the activity of SOD (37-94%), ALS (65-73%), glutathione reductase (19-20%), and the accumulation of GSH (61-261%), flavonoids (17-22%), and shoots weight (27-33%) in herbicide-exposed canola. Simultaneous inoculation prevented lipid peroxidation induced by metsulfuron-methyl in sensitive plants. Based on the findings, it is possible that the protective role of bacterial strains against metsulfuron-metil is linked to antioxidant system activation.}, } @article {pmid38249293, year = {2023}, author = {Krishnamurthy, K and Pradhan, RK}, title = {Emerging perspectives of synaptic biomarkers in ALS and FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1279999}, pmid = {38249293}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.}, } @article {pmid38249592, year = {2023}, author = {Jiang, Q and Guo, Y and Yang, T and Li, S and Hou, Y and Lin, J and Xiao, Y and Ou, R and Wei, Q and Shang, H}, title = {Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1309568}, pmid = {38249592}, issn = {1662-4548}, abstract = {BACKGROUND: Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.

METHODS: A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis.

RESULTS: CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant.

CONCLUSION: CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.}, } @article {pmid38250776, year = {2024}, author = {Du, P and Zhang, X and Lian, X and Hölscher, C and Xue, G}, title = {O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {3}, pages = {1051-1068}, doi = {10.3233/JAD-230955}, pmid = {38250776}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Processing, Post-Translational ; Proteins/metabolism ; *Alzheimer Disease/pathology ; Acetylglucosamine/metabolism ; Disease Progression ; N-Acetylglucosaminyltransferases/metabolism ; }, abstract = {As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.}, } @article {pmid38256050, year = {2024}, author = {Bruno, A and Milillo, C and Anaclerio, F and Buccolini, C and Dell'Elice, A and Angilletta, I and Gatta, M and Ballerini, P and Antonucci, I}, title = {Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256050}, issn = {1422-0067}, mesh = {Female ; Pregnancy ; Humans ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Huntington Disease/therapy ; *Parkinson Disease/therapy ; Stem Cells ; }, abstract = {Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.}, } @article {pmid38260713, year = {2023}, author = {Geraci, J and Bhargava, R and Qorri, B and Leonchyk, P and Cook, D and Cook, M and Sie, F and Pani, L}, title = {Machine learning hypothesis-generation for patient stratification and target discovery in rare disease: our experience with Open Science in ALS.}, journal = {Frontiers in computational neuroscience}, volume = {17}, number = {}, pages = {1199736}, pmid = {38260713}, issn = {1662-5188}, abstract = {INTRODUCTION: Advances in machine learning (ML) methodologies, combined with multidisciplinary collaborations across biological and physical sciences, has the potential to propel drug discovery and development. Open Science fosters this collaboration by releasing datasets and methods into the public space; however, further education and widespread acceptance and adoption of Open Science approaches are necessary to tackle the plethora of known disease states.

MOTIVATION: In addition to providing much needed insights into potential therapeutic protein targets, we also aim to demonstrate that small patient datasets have the potential to provide insights that usually require many samples (>5,000). There are many such datasets available and novel advancements in ML can provide valuable insights from these patient datasets.

PROBLEM STATEMENT: Using a public dataset made available by patient advocacy group AnswerALS and a multidisciplinary Open Science approach with a systems biology augmented ML technology, we aim to validate previously reported drug targets in ALS and provide novel insights about ALS subpopulations and potential drug targets using a unique combination of ML methods and graph theory.

METHODOLOGY: We use NetraAI to generate hypotheses about specific patient subpopulations, which were then refined and validated through a combination of ML techniques, systems biology methods, and expert input.

RESULTS: We extracted 8 target classes, each comprising of several genes that shed light into ALS pathophysiology and represent new avenues for treatment. These target classes are broadly categorized as inflammation, epigenetic, heat shock, neuromuscular junction, autophagy, apoptosis, axonal transport, and excitotoxicity. These findings are not mutually exclusive, and instead represent a systematic view of ALS pathophysiology. Based on these findings, we suggest that simultaneous targeting of ALS has the potential to mitigate ALS progression, with the plausibility of maintaining and sustaining an improved quality of life (QoL) for ALS patients. Even further, we identified subpopulations based on disease onset.

CONCLUSION: In the spirit of Open Science, this work aims to bridge the knowledge gap in ALS pathophysiology to aid in diagnostic, prognostic, and therapeutic strategies and pave the way for the development of personalized treatments tailored to the individual's needs.}, } @article {pmid38261982, year = {2024}, author = {Moglia, C and Calvo, A and Canosa, A and Manera, U and Vasta, R and Di Pede, F and Daviddi, M and Matteoni, E and Brunetti, M and Sbaiz, L and Cabras, S and Gallone, S and Grassano, M and Peotta, L and Palumbo, F and Mora, G and Iazzolino, B and Chio, A}, title = {Cognitive and Behavioral Features of Patients With Amyotrophic Lateral Sclerosis Who Are Carriers of the TARDBP Pathogenic Variant.}, journal = {Neurology}, volume = {102}, number = {4}, pages = {e208082}, pmid = {38261982}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; *Apathy ; Cognition ; *Frontotemporal Dementia ; Memory, Short-Term ; Male ; DNA-Binding Proteins ; }, abstract = {BACKGROUND AND OBJECTIVES: TARDBP patients are considered particularly prone to cognitive involvement, but no systematic studies of cognitive impairment in TARDBP patients are available. The aim of this article was to depict in depth the cognitive-behavioral characteristics of a cohort of patients with amyotrophic lateral sclerosis (ALS) carrying TARDBP pathogenetic variants followed by an ALS referral center.

METHODS: We enrolled all patients with ALS seen at the Turin ALS expert center in the 2009-2021 period who underwent extensive genetic testing and a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, nonverbal intelligence, cognitive flexibility, social cognition, and behavior. Tests were compared with the Mann-Whitney U test on age-corrected, sex-corrected, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci), that is, evidence of executive and/or language dysfunction; isolated behavioral impairment (ALSbi), that is, identification of apathy; cognitive and behavioral impairment (ALScbi), that is, evidence meeting the criteria for both ALSci and ALSbi; and frontotemporal dementia (ALS-FTD).

RESULTS: This study includes 33 patients with TARDBP pathogenetic variants (TARDBP-ALS) (median age 61 years [interquartile range (IQR) 53-67], 8 female [24.2%]) and 928 patients with ALS not carrying the pathogenic variant (WT-ALS) (median age 67 years [IQR 59-74], 386 female [41.6%]). TARDBP-ALS cases were also compared with 129 matched controls (median age 66 years [IQR 57.5-71.5], 55 female [42.6%]). TARDBP-ALS and WT-ALS patients were cognitively classified as ALS-CN (54% vs 58.8%, respectively), ALSci (21.2% vs 18.3%), ALSci (9.1% vs 9.5%), ALScbi (6.1% vs 6.0%), and ALS-FTD (9.1 vs 6.7%), with no significant difference (p = 0.623). Compared with controls, TARDBP-ALS had a worse performance in executive functions, visual memory, visuoconstructive abilities, verbal fluency, and the apathy behavioral component of FrSBe. The scores of performed tests, including all Edinburgh Cognitive and Behavioral ALS Screen subdomains, were similar in TARDBP-ALS and WT-ALS.

DISCUSSION: TARDBP-ALS patients were significantly more impaired than controls in most examined domains but do not show any specific pattern of cognitive impairment compared with WT-ALS. Our findings are relevant both clinically, considering the effect of cognitive impairment on patients' decision-making and caregivers' burden, and in designing clinical trials for the treatment of patients carrying TARDBP pathogenetic variants.}, } @article {pmid38262101, year = {2024}, author = {Masegosa, VM and Navarro, X and Herrando-Grabulosa, M}, title = {ICA-27243 improves neuromuscular function and preserves motoneurons in the transgenic SOD1[G93A] mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {2}, pages = {e00319}, pmid = {38262101}, issn = {1878-7479}, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Motor Neurons ; Spinal Cord ; Disease Models, Animal ; Superoxide Dismutase ; *Benzamides ; *Pyridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons (MNs). Excessive neuronal excitability has been implicated in MN degeneration; thus, modulation of hyperexcitability appears as a promising therapeutic strategy. Potassium channels are attractive targets since they can be activated at subthreshold voltages and can regulate neuronal excitability. In this study, we assayed the effects of N-(6-Chloro-pyridin-3-yl)-3,4-difluorobenzamide compound, known as ICA-27243, as a potential treatment for ALS. ICA-27243 is a highly selective Kv7.2/7.3 opener used mainly in epilepsy models. In the in vitro model of spinal cord organotypic cultures (SCOCs) exposed to acute excitotoxicity, ICA-27243 prevented MN degeneration at a dose-of 10 μM. Administration of ICA-27243 to transgenic SOD1[G93A] ALS mice improved the decline of neuromuscular function, maintained locomotion and coordination in the rotarod, decreased spinal MN death and attenuated glial reactivity. In conclusion, we report here for the first time that ICA-27243 is an effective treatment for ALS, emphasizing the potential of targeting Kv channels to reduce neuronal hyperexcitability.}, } @article {pmid38264389, year = {2023}, author = {Gouveia, C and Araújo, L and Freitas, S and Correia, J and Passos, V and Camacho, G and Gomes, L and Fragoeiro, H and Camacho, C and Chambino, B}, title = {A Palliative Care Approach to Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51048}, pmid = {38264389}, issn = {2168-8184}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease characterized by motor dysfunction. Currently, treatment options are limited and management is based mostly on symptom control and quality of life optimization, so palliative care plays a fundamental role. Our objective was to characterize the ALS population in Madeira Island that was referenced and/or followed by a palliative care unit over a five-year period.

METHODS: Longitudinal, retrospective, descriptive, and observational study to analyze patients with ALS who were referred and/or followed by a palliative care unit during a five-year period, between 2017 and 2021. Patient's medical electronic and physical records were analyzed to gather data. Descriptive and inferential statistical analysis was done using Microsoft Excel and Statistical Package for the Social Sciences (version 28.0.1).

RESULTS: During this five-year period, a total of 38 patients were diagnosed with ALS in Madeira Island and 23 (60.53%) were referred to palliative care. Three patients died before assessment, so 20 (50.63%) were followed by the palliative care team. They had a median life expectancy of 425 days and the median time spent in palliative care was 137 days. Of this population, 56.52% (n=13) was male with an average age of 64 years. The median period from diagnosis to referral was 167 days, with most referrals being made by family medicine (39.13%; n=9) motivated by uncontrolled symptoms (95.65%; n=22). The median period from referral to first assessment by a palliative care physician was 19 days. The Palliative Performance Scale (PPS) and Confusion Assessment Method (CAM) applied on the first visit had a median score of 40% in the former and was negative in 95.00% (n=19) of patients in the latter. Advanced care directives were present in 55.00% (n=11) of patients and all provided care was in accordance with the patient's wishes. The most common symptoms were dysphagia, dyspnea, pain, anxiety, and sialorrhea. The most used drugs were morphine, riluzole, butylscopolamine, bisacodyl, and midazolam. As for other interventions, 55.00% (n=11) of patients underwent noninvasive ventilation (NIV), 15.00% (n=3) were submitted to percutaneous endoscopic gastrostomy (PEG), and one patient (5.00%) was nasogastrically intubated. The death rate was 95.00% (n=19) with 73.68% (n=14) of deaths occurring in the palliative care unit.

CONCLUSION: Literature has shown that there are many advantages to the early inclusion of palliative care in ALS management, achieving effective symptom control and greater quality of life, but also reducing caregiver burden. However, in this study, we found that referrals to palliative care were late and included mostly cases of advanced disease with uncontrolled symptoms.}, } @article {pmid38265475, year = {2024}, author = {Xiang, Y and Song, X and Long, D}, title = {Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.}, journal = {Archives of toxicology}, volume = {98}, number = {3}, pages = {579-615}, pmid = {38265475}, issn = {1432-0738}, support = {81673227//National Natural Science Foundation of China/ ; 2020JJ4080//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; NF-E2-Related Factor 2/metabolism ; *Ferroptosis ; Oxidative Stress/physiology ; Antioxidants/metabolism ; }, abstract = {This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.}, } @article {pmid38267984, year = {2024}, author = {Irwin, KE and Sheth, U and Wong, PC and Gendron, TF}, title = {Fluid biomarkers for amyotrophic lateral sclerosis: a review.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {9}, pmid = {38267984}, issn = {1750-1326}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; P01NS084974/NH/NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Biomarkers ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.}, } @article {pmid38270442, year = {2024}, author = {Smith, R and Hovren, H and Bowser, R and Bakkar, N and Garruto, R and Ludolph, A and Ravits, J and Gaertner, L and Murphy, D and Lebovitz, R}, title = {Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16206}, pmid = {38270442}, issn = {1468-1331}, mesh = {Humans ; *alpha-Synuclein/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Lewy Bodies/metabolism/pathology ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.

METHODS: Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS.

RESULTS: Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.

CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.}, } @article {pmid38283317, year = {2022}, author = {Cheung, K and Mitsumoto, H}, title = {Evaluating Personalized (N-of-1) Trials in Rare Diseases: How Much Experimentation Is Enough?.}, journal = {Harvard data science review}, volume = {2022}, number = {Spec Iss 3}, pages = {}, pmid = {38283317}, issn = {2644-2353}, support = {P30 AG063786/AG/NIA NIH HHS/United States ; R01 LM012836/LM/NLM NIH HHS/United States ; R01 MH109496/MH/NIMH NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {For rare diseases, conducting large, randomized trials of new treatments can be infeasible due to limited sample size, and it may answer the wrong scientific questions due to heterogeneity of treatment effects. Personalized (N-of-1) trials are multi-period crossover studies that aim to estimate individual treatment effects, thereby identifying the optimal treatments for individuals. This article examines the statistical design issues of evaluating a personalized (N-of-1) treatment program in people with amyotrophic lateral sclerosis (ALS). We propose an evaluation framework based on an analytical model for longitudinal data observed in a personalized trial. Under this framework, we address two design parameters: length of experimentation in each trial and number of trials needed. For the former, we consider patient-centric design criteria that aim to maximize the benefits of enrolled patients. Using theoretical investigation and numerical studies, we demonstrate that, from a patient's perspective, the duration of an experimentation period should be no longer than one-third of the entire follow-up period of the trial. For the latter, we provide analytical formulae to calculate the power for testing quality improvement due to personalized trials in a randomized evaluation program and hence determine the required number of trials needed for the program. We apply our theoretical results to design an evaluation program for ALS treatments informed by pilot data and show that the length of experimentation has a small impact on power relative to other factors such as the degree of heterogeneity of treatment effects.}, } @article {pmid38284068, year = {2024}, author = {Sunildutt, N and Ahmed, F and Chethikkattuveli Salih, AR and Lim, JH and Choi, KH}, title = {Integrating Transcriptomic and Structural Insights: Revealing Drug Repurposing Opportunities for Sporadic ALS.}, journal = {ACS omega}, volume = {9}, number = {3}, pages = {3793-3806}, pmid = {38284068}, issn = {2470-1343}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, resulting in debilitating muscle weakness and atrophy. Currently, there are no effective treatments available for ALS, posing significant challenges in managing the disease that affects approximately two individuals per 100,000 people annually. To address the urgent need for effective ALS treatments, we conducted a drug repurposing study using a combination of bioinformatics tools and molecular docking techniques. We analyzed sporadic ALS-related genes from the GEO database and identified key signaling pathways involved in sporadic ALS pathogenesis through pathway analysis using DAVID. Subsequently, we utilized the Clue Connectivity Map to identify potential drug candidates and performed molecular docking using AutoDock Vina to evaluate the binding affinity of short-listed drugs to key sporadic ALS-related genes. Our study identified Cefaclor, Diphenidol, Flubendazole, Fluticasone, Lestaurtinib, Nadolol, Phenamil, Temozolomide, and Tolterodine as potential drug candidates for repurposing in sporadic ALS treatment. Notably, Lestaurtinib demonstrated high binding affinity toward multiple proteins, suggesting its potential as a broad-spectrum therapeutic agent for sporadic ALS. Additionally, docking analysis revealed NOS3 as the gene that interacts with all the short-listed drugs, suggesting its possible involvement in the mechanisms underlying the therapeutic potential of these drugs in sporadic ALS. Overall, our study provides a systematic framework for identifying potential drug candidates for sporadic ALS therapy and highlights the potential of drug repurposing as a promising strategy for discovering new therapies for neurodegenerative diseases.}, } @article {pmid38286111, year = {2024}, author = {Wang, M and Wang, T and Gu, F}, title = {Efficacy of Huanglian Jiedu Decoction for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {187-200}, doi = {10.1159/000536453}, pmid = {38286111}, issn = {2504-2106}, mesh = {*Diabetes Mellitus, Type 2/drug therapy ; Humans ; *Drugs, Chinese Herbal/therapeutic use ; Blood Glucose/drug effects ; Glycated Hemoglobin ; Randomized Controlled Trials as Topic ; *Hypoglycemic Agents/therapeutic use ; }, abstract = {OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, and there is an increasing interest in the potential benefits of traditional Chinese medicine, such as Huanglian Jiedu decoction (HJD), for its management. This meta-analysis aimed to determine the efficacy and safety of HJD in the treatment of T2DM.

METHODS: A systematic review was conducted across six databases including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang, from their inception to August 24, 2023. We focused on randomized controlled trials (RCTs) that evaluated HJD as both a monotherapy and in combination treatments for T2DM patients. Data analysis was performed using RevMan 5.3 and Stata 17.0, with evaluations for heterogeneity and publication bias. Additionally, subgroup analyses were stratified based on the duration of treatment.

RESULTS: A total of 40 studies involving 3,934 participants were included in the meta-analysis. Both HJD monotherapy and combined with other therapies significantly reduced hemoglobin A1C (HbA1c) fasting blood glucose (FBG) and 2-h postprandial glucose (2hPG) levels, as well as improved insulin resistance. Furthermore, combination therapy enhanced the efficacy rate and favorably altered lipid profiles, including increasing HDL-C and decreasing LDL-C, TC, and TG levels. It was worth noting that the results of the subgroup analysis indicated that, in terms of reducing HbA1c and 2hPG, the efficacy of HJD alone for a duration of less than 3 months was found to be potentially superior to that observed in treatments exceeding 3 months. Adverse event assessment suggested that HJD did not increase the incidence of side effects, including diarrhea, affirming its safety.

CONCLUSION: HJD appears to be an effective and safe alternative or adjunctive therapy for T2DM, showing significant improvements in glycemic control and lipid profiles without increasing adverse events. Further rigorous, multicenter RCTs outside China are warranted to validate these findings.

UNLABELLED: ZielDiabetes mellitus Typ 2 (DMT2) ist eine weit verbreitete Stoffwechselerkrankung, und es besteht ein steigendes Interesse an den potenziellen Vorteilen der traditionellen chinesischen Medizin, wie beispielsweise Huanglian Jiedu-Dekokt (HJD), zu seiner Behandlung. Mit dieser Metaanalyse sollten die Wirksamkeit und Sicherheit von HJD zur Behandlung von DMT2 ermittelt werden.MethodenEs wurde eine systematische Recherche in sechs Datenbanken durchgeführt, darunter PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI) und Wanfang, für die Zeit vom Beginn der Datenbank bis zum 24. August 2023. Dabei lag unser Hauptaugenmerk auf randomisierten kontrollierten Studien (RCTs), die HJD sowohl als Monotherapie als auch in Kombinationstherapien bei Patienten mit DMT2 untersuchten. Die Datenanalyse erfolgte mithilfe von RevMan 5.3 und Stata 17.0 mit Untersuchungen auf Heterogenität und Publikationsverzerrungen. Darüber hinaus wurden Subgruppenanalysen stratifiziert nach Behandlungsdauer durchgeführt.ErgebnisseInsgesamt wurden 40 Studien mit 3.934 Teilnehmern in die Metaanalyse eingeschlossen. HJD führte sowohl als Monotherapie als auch in Kombination mit anderen Therapien zu einer signifikanten Senkung des HbA1c-Nüchternblutzuckerspiegels (fasting blood glucose, FBG) und der postprandialen Blutzuckerwerte 2 Stunden nach dem Essen (2-h postprandial glucose, 2hPG) sowie zu einer Verbesserung der Insulinresistenz. Darüber hinaus verbesserte die Kombinationstherapie die Wirksamkeitsrate und führte zu einer positiven Veränderung der Lipidprofile, die eine Erhöhung der HDL-Cholesterinwerte und eine Senkung der LDL-, Gesamtcholesterin- und Trigylceridwerte einschloss. Erwähnenswert ist, dass nach den Ergebnissen der Subgruppenanalyse die Wirksamkeit von HJD als Monotherapie in Hinblick auf die Senkung der HbA1c- und 2hPG-Werte bei einer Behandlungsdauer von weniger als drei Monaten gegenüber derjenigen von Behandlungen, die länger als drei Monate dauerten, potenziell überlegen war. Die Bewertung der unerwünschten Ereignisse zeigte, dass HJD nicht zu einem Anstieg der Nebenwirkungen wie Durchfall führte, was seine Sicherheit bestätigte.SchlussfolgerungHJD scheint eine wirksame und sichere Alternative oder Zusatztherapie bei DMT2 zu sein, die signifikante Verbesserungen der Blutzuckerkontrolle und der Lipidprofile ohne Zunahme der unerwünschten Ereignisse bewirkt. Weitere rigorose, multizentrische RCTs außerhalb Chinas sind erforderlich, um diese Ergebnisse zu validieren.}, } @article {pmid38286113, year = {2024}, author = {Dutta, A and Manna, A and Ghosh, S and Mundle, M and Saha, M and Gourav, K and Maiti, S and Chattopadhyay, B}, title = {Prespecified Homeopathic Medicines in the Prevention of Confirmed and Suspected Cases of COVID-19: A Community-Based, Double-Blind, Randomized, Placebo-Controlled Prophylaxis Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {140-148}, doi = {10.1159/000536395}, pmid = {38286113}, issn = {2504-2106}, mesh = {Humans ; Double-Blind Method ; *COVID-19/prevention & control ; Male ; Female ; Adult ; *Homeopathy/methods ; Middle Aged ; India/epidemiology ; *Materia Medica/therapeutic use ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {INTRODUCTION: Homeopathic medicines have been used for decades in the prevention and treatment of infectious diseases. However, the preventive efficacy of specific homeopathic medicines in COVID-19 is not well characterized. This study aimed to evaluate the comparative efficacy of prespecified homeopathic medicines in preventing COVID-19.

METHODS: A community-based, double-blind, randomized, placebo-controlled trial was conducted on 4,034 participants residing in Ward No. 27 of the Howrah Municipal Corporation in India. Participants were randomized to receive one of three prespecified homeopathic medicines [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)], or placebo. The outcomes were the incidence of laboratory-confirmed and suspected cases of COVID-19 during a follow-up period of 1 month.

RESULTS: During the follow-up period, a total of 13 new laboratory-confirmed COVID-19 cases were reported in the study population. Among these, 5 cases in Influenzinum group, 2 cases in Arsenicum album group, 1 case in Oscillococcinum® group, and 5 cases in Placebo group were reported. On the other hand, number of suspected COVID-19 cases was significantly less in all the three homeopathic medicine groups compared to placebo. The least number of suspected cases reported in the Oscillococcinum® group (aOR: 0.058; 95% confidence interval [CI]: 0.029, 0.114), followed by the Arsenicum album (aOR: 0.337; 95% CI: 0.238, 0.475) and Influenzinum (aOR: 0.539; 95% CI: 0.401, 0.726) groups.

CONCLUSION: Prespecified homeopathic medicines, particularly Oscillococcinum® and Arsenicum album 30C, may have a role in preventing COVID-19, especially in reducing the incidence of suspected or COVID-19-like respiratory illnesses. However, the result failed to demonstrate a statistically significant difference in the occurrence of confirmed cases of COVID-19 between the study groups. Further research is needed to evaluate the efficacy of these medicines in different populations and settings.

UNLABELLED: EinleitungHomöopathische Arzneimittel werden seit Jahrzehnten zur Prävention und Behandlung von Infektionskrankheiten eingesetzt. Die Wirksamkeit spezifischer homöopathischer Arzneimittel zur Prophylaxe von COVID-19 ist jedoch nicht gut untersucht. Mit dieser Studie sollte die vergleichende Wirksamkeit spezifischer homöopathischer Arzneimittel bei der Prävention von COVID-19 untersucht werden.MethodenEs handelte sich um eine gemeindebasierte, doppelblinde, randomisierte, placebokontrollierte Studie mit 4.034 Teilnehmern, die im Bezirk Nr. 27 der Howrah Municipal Corporation in Indien lebten. Die Teilnehmer erhielten randomisiert eines von drei zuvor festgelegten homöopathischen Arzneimitteln [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)] oder Placebo. Zielkriterien waren die Inzidenz von laborchemisch bestätigten und vermuteten COVID-19-Fällen während des Follow-up-Zeitraums von einem Monat.ErgebnisseWährend des Follow-up-Zeitraums wurden insgesamt 13 neue, laborchemisch bestätigte COVID-19-Fälle in der Studienpopulation berichtet, davon 5 Fälle in der Influenzinum-Gruppe, 2 Fälle in der Arsenicum album-Gruppe, 1 Fall in der Oscillococcinum®-Gruppe und 5 Fälle in der Placebo-Gruppe. Demgegenüber fiel Zahl der COVID-19-Verdachtsfälle in allen drei homöopathischen Arzneimittelgruppen signifikant geringer aus als in der Placebogruppe. Die wenigsten Verdachtsfälle wurden in der Oscillococcinum®-Gruppe berichtet (aOR: 0.058; 95%-KI: 0.029, 0.114), gefolgt von der Arsenicum album- (aOR: 0.337; 95%-KI: 0.238, 0.475) und der Influenzinum- (aOR: 0.539; 95%-KI: 0.401, 0.726) Gruppe.SchlussfolgerungSpezifische homöopathische Arzneimittel, insbesondere Oscillococcinum® und Arsenicum album 30C, könnten bei der Prävention von COVID-19 eine Rolle spielen, vor allem bei der Senkung der Inzidenz von COVID-19-Verdachtsfällen oder COVID-19-ähnlichen Atemwegserkrankungen. Allerdings war kein statistisch signifikanter Unterschied im Auftreten von bestätigten COVID-19-Fällen zwischen den Studiengruppen nachweisbar. Weitere Untersuchungen sind erforderlich, um die Wirksamkeit dieser Arzneimittel in verschiedenen Populationen und Umgebungen zu bewerten.}, } @article {pmid38286832, year = {2024}, author = {Lu, J and He, AX and Jin, ZY and Zhang, M and Li, ZX and Zhou, F and Ma, L and Jin, HM and Wang, JY and Shen, X}, title = {Desloratadine alleviates ALS-like pathology in hSOD1[G93A] mice via targeting 5HTR2A on activated spinal astrocytes.}, journal = {Acta pharmacologica Sinica}, volume = {45}, number = {5}, pages = {926-944}, pmid = {38286832}, issn = {1745-7254}, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Astrocytes/drug effects/metabolism/pathology ; Disease Models, Animal ; *Loratadine/analogs & derivatives/pharmacology/therapeutic use ; Mice, Inbred C57BL ; *Mice, Transgenic ; Receptor, Serotonin, 5-HT2A/genetics/metabolism ; Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; *Spinal Cord/drug effects/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1[G93A] (hSOD1[G93A]) ALS model mice, and elucidated the underlying mechanisms. HSOD1[G93A] mice were administered DLT (20 mg·kg[-1]·d[-1], i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1[G93A] mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1[G93A] mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice.}, } @article {pmid38288843, year = {2024}, author = {Fatima, J and Siddique, YH}, title = {Application of Nanocomposites and Nanoparticles in Treating Neurodegenerative Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {10}, pages = {1217-1233}, pmid = {38288843}, issn = {1996-3181}, support = {211610179057//University Grants Commission/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Nanoparticles/therapeutic use ; *Nanocomposites/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Blood-Brain Barrier/drug effects/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.}, } @article {pmid38289969, year = {2024}, author = {Hossain, MA and Sarin, R and Donnelly, DP and Miller, BC and Weiss, A and McAlary, L and Antonyuk, SV and Salisbury, JP and Amin, J and Conway, JB and Watson, SS and Winters, JN and Xu, Y and Alam, N and Brahme, RR and Shahbazian, H and Sivasankar, D and Padmakumar, S and Sattarova, A and Ponmudiyan, AC and Gawde, T and Verrill, DE and Yang, W and Kannapadi, S and Plant, LD and Auclair, JR and Makowski, L and Petsko, GA and Ringe, D and Agar, NYR and Greenblatt, DJ and Ondrechen, MJ and Chen, Y and Yerbury, JJ and Manetsch, R and Hasnain, SS and Brown, RH and Agar, JN}, title = {Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.}, journal = {PLoS biology}, volume = {22}, number = {1}, pages = {e3002462}, pmid = {38289969}, issn = {1545-7885}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; R01 NS065263/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Cysteine/genetics ; Mutation ; Superoxide Dismutase/genetics/chemistry/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.}, } @article {pmid38292603, year = {2024}, author = {Weerawarna, PM and Schiefer, IT and Soares, P and Fox, S and Morimoto, RI and Melani, RD and Kelleher, NL and Luan, CH and Silverman, RB}, title = {Target Identification of a Class of Pyrazolone Protein Aggregation Inhibitor Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {ACS central science}, volume = {10}, number = {1}, pages = {87-103}, pmid = {38292603}, issn = {2374-7943}, support = {P41 GM108569/GM/NIGMS NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure, and current treatment options are very limited. Previously, we performed a high-throughput screen to identify small molecules that inhibit protein aggregation caused by a mutation in the gene that encodes superoxide dismutase 1 (SOD1), which is responsible for about 25% of familial ALS. This resulted in three hit series of compounds that were optimized over several years to give three compounds that were highly active in a mutant SOD1 ALS model. Here we identify the target of two of the active compounds (6 and 7) with the use of photoaffinity labeling, chemical biology reporters, affinity purification, proteomic analysis, and fluorescent/cellular thermal shift assays. Evidence is provided to demonstrate that these two pyrazolone compounds directly interact with 14-3-3-E and 14-3-3-Q isoforms, which have chaperone activity and are known to interact with mutant SOD1[G93A] aggregates and become insoluble in the subcellular JUNQ compartment, leading to apoptosis. Because protein aggregation is the hallmark of all neurodegenerative diseases, knowledge of the target compounds that inhibit protein aggregation allows for the design of more effective molecules for the treatment of ALS and possibly other neurodegenerative diseases.}, } @article {pmid38308282, year = {2024}, author = {Cai, R and Yang, J and Wu, L and Liu, Y and Wang, X and Zheng, Q and Li, L}, title = {Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {40}, pmid = {38308282}, issn = {1750-1172}, support = {82174229//the National Natural Science Funds of China/ ; 2022YFC3502000//China national key research and development program/ ; ZY [2021-2023]-0401//Shanghai 3-year Action Plan for Inheritance, Innovation, and Development of traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; *Riluzole/therapeutic use ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development.

METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points.

RESULTS: In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months.

CONCLUSIONS: The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.}, } @article {pmid38314277, year = {2024}, author = {Mohan, S and Alhazmi, HA and Hassani, R and Khuwaja, G and Maheshkumar, VP and Aldahish, A and Chidambaram, K}, title = {Role of ferroptosis pathways in neuroinflammation and neurological disorders: From pathogenesis to treatment.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24786}, pmid = {38314277}, issn = {2405-8440}, abstract = {Ferroptosis is a newly discovered non-apoptotic and iron-dependent type of cell death. Ferroptosis mainly takes place owing to the imbalance of anti-oxidation and oxidation in the body. It is regulated via a number of factors and pathways both inside and outside the cell. Ferroptosis is closely linked with brain and various neurological disorders (NDs). In the human body, the brain contains the highest levels of polyunsaturated fatty acids, which are known as lipid peroxide precursors. In addition, there is also a connection of glutathione depletion and lipid peroxidation with NDs. There is growing evidence regarding the possible link between neuroinflammation and multiple NDs, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and stroke. Recent studies have demonstrated that disruptions of lipid reactive oxygen species (ROS), glutamate excitatory toxicity, iron homeostasis, and various other manifestations linked with ferroptosis can be identified in various neuroinflammation-mediated NDs. It has also been reported that damage-associated molecular pattern molecules including ROS are generated during the events of ferroptosis and can cause glial activation via activating neuroimmune pathways, which subsequently leads to the generation of various inflammatory factors that play a role in various NDs. This review summarizes the regulation pathways of ferroptosis, the link between ferroptosis as well as inflammation in NDs, and the potential of a range of therapeutic agents that can be used to target ferroptosis and inflammation in the treatment of neurological disorders.}, } @article {pmid38314348, year = {2023}, author = {Watts, ME and Giadone, RM and Ordureau, A and Holton, KM and Harper, JW and Rubin, LL}, title = {Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1327361}, pmid = {38314348}, issn = {1662-5102}, support = {F32 AG079593/AG/NIA NIH HHS/United States ; R01 NS083524/NS/NINDS NIH HHS/United States ; R01 NS110395/NS/NINDS NIH HHS/United States ; R37 NS083524/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities conferred by ALS patient genetics in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). In doing so, we found that thapsigargin and tunicamycin exposure recapitulated ALS-associated degeneration, and that we could rescue this degeneration via MAP4K4 inhibition (MAP4K4i). We subsequently identified mechanisms underlying MAP4K4i-mediated protection by performing phosphoproteomics on iPSC-derived MNs treated with ER stressors ±MAP4K4i. Through these analyses, we found JNK, PKC, and BRAF to be differentially modulated in MAP4K4i-protected MNs, and that inhibitors to these proteins could also rescue MN toxicity. Collectively, this study highlights the value of utilizing ER stressors in ALS patient MNs to identify novel druggable targets.}, } @article {pmid38317225, year = {2024}, author = {Liddell, JR and Hilton, JBW and Kysenius, K and Billings, JL and Nikseresht, S and McInnes, LE and Hare, DJ and Paul, B and Mercer, SW and Belaidi, AA and Ayton, S and Roberts, BR and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Crouch, PJ}, title = {Microglial ferroptotic stress causes non-cell autonomous neuronal death.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {14}, pmid = {38317225}, issn = {1750-1326}, mesh = {Mice ; Animals ; Humans ; Microglia/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Neurodegenerative Diseases/metabolism ; Cell Death ; Disease Models, Animal ; }, abstract = {BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.

METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1[G37R] mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.

RESULTS: We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1[G37R] mouse model where treatment with a CNS-permeant ferroptosis inhibitor, Cu[II](atsm), ameliorated these markers and was neuroprotective.

CONCLUSIONS: By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.}, } @article {pmid38318827, year = {2024}, author = {Motamedy, S and Soltani, B and Kameshki, H and Kermani, AA and Amleshi, RS and Nazeri, M and Shabani, M}, title = {The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex[®] - A Cannabis-derived Spray.}, journal = {Mini reviews in medicinal chemistry}, volume = {24}, number = {15}, pages = {1427-1448}, pmid = {38318827}, issn = {1875-5607}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cannabidiol/pharmacology/therapeutic use/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Dronabinol/pharmacology/chemistry/therapeutic use ; Animals ; Multiple Sclerosis/drug therapy ; Cannabis/chemistry ; Drug Combinations ; }, abstract = {Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.}, } @article {pmid38318860, year = {2024}, author = {Jhooty, S and Barkhaus, P and Brown, A and Mascias Cadavid, J and Carter, GT and Crayle, J and Heiman-Patterson, T and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Pattee, G and Ratner, D and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #74: Withania Somnifera (Ashwagandha).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {805-808}, doi = {10.1080/21678421.2024.2311721}, pmid = {38318860}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Withania ; Animals ; *Plant Extracts/therapeutic use ; Phytotherapy/methods ; }, abstract = {ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS (PALS) who ask about them. Here, we review withania somnifera (WS) commonly known as ashwagandha or winter cherry. WS has plausible mechanisms for slowing ALS progression because of its effects on inflammation, oxidative stress, autophagy, mitochondrial function, and apoptosis. Preclinical trials demonstrate that WS slows disease progression in multiple different animal models of ALS. Of the five individuals we found who described using WS for their ALS, two individuals reported moderate benefit while none reported experiencing any significant side effects. There is currently one clinical trial using WS to treat PALS; the results are not yet published. There are no serious side effects associated with WS and the associated cost of this treatment is low. Based on the above information, WS appears to us to be a good candidate for future ALS trials.}, } @article {pmid38325382, year = {2024}, author = {Yan, J and Wang, YM and Hellwig, A and Bading, H}, title = {TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {2}, pages = {101413}, pmid = {38325382}, issn = {2666-3791}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; *TRPM Cation Channels ; }, abstract = {Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1[G93A] ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.}, } @article {pmid38325473, year = {2024}, author = {Xu, Y and Nie, J and Lu, C and Hu, C and Chen, Y and Ma, Y and Huang, Y and Lu, L}, title = {Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.}, journal = {The Science of the total environment}, volume = {919}, number = {}, pages = {170670}, doi = {10.1016/j.scitotenv.2024.170670}, pmid = {38325473}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/chemically induced ; *Alzheimer Disease ; *Parkinson Disease/etiology/metabolism ; Brain/metabolism ; Oxidative Stress/physiology ; }, abstract = {Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.}, } @article {pmid38330475, year = {2024}, author = {Stavros, K}, title = {Genetic Myelopathies.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {1}, pages = {119-132}, pmid = {38330475}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Muscular Atrophy, Spinal/diagnosis ; *Spastic Paraplegia, Hereditary/diagnosis ; *Spinal Cord Diseases/diagnosis/genetics/therapy ; }, abstract = {OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy.

LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia.

ESSENTIAL POINTS: Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.}, } @article {pmid38330924, year = {2024}, author = {Leedasawat, P and Sangvatanakul, P and Tungsukruthai, P and Kamalashiran, C and Phetkate, P and Patarajierapun, P and Sriyakul, K}, title = {The Efficacy and Safety of Chinese Eye Exercise of Acupoints in Dry Eye Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {149-159}, doi = {10.1159/000536516}, pmid = {38330924}, issn = {2504-2106}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture Points ; *Acupuncture Therapy/methods ; *Dry Eye Syndromes/therapy ; Single-Blind Method ; Thailand ; Treatment Outcome ; }, abstract = {INTRODUCTION: Dry eye disorder (DED) is a growing global issue linked to excessive digital screen time. Chinese eye exercise of acupoint (CEA), a set of self-massages on shared Chinese acupuncture (CA), has been used to reduce visual-related ocular symptoms and possibly as an alternative treatment for DED. This study aimed to assess the efficacy and safety of CEA.

METHODS: A single-blind randomized controlled trial was conducted at Thammasat University Hospital in Thailand, recruiting 56 participants aged 20-60 years, equally divided into two groups: the treatment group with CEA and the control group with standard lid hygiene treatment (STD). The intervention program lasted 12 weeks.

MAIN OUTCOME MEASURES: Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), Schirmer-I test (SIT), corneal surface staining (CSS), and self-recorded forms for safety and adverse effects were measured at baseline, week 4, and week 12. An independent sample t test, paired t test, and repeated measures (ANOVA) were used to compare results between both groups, study visits, and primary and secondary outcome measurements, respectively. The p values <0.05 were considered statistically significant.

RESULTS: The characteristics were not statistically different between both groups at the baseline. The mean OSDI scores were significantly reduced in both groups at week 4 and week 12 compared to baseline (p value <0.05). Additionally, both CEA and STD showed significant improvement in TBUT and SIT (p value <0.05). CSS was significantly improved only in the CEA groups (p value <0.05). No significant differences were observed between the study groups, except for SIT at week 12 (p value <0.05). For the safety, there were no adverse side effects in either group.

CONCLUSION: CEA seemed to be as effective as STD in improving the OSDI, TBUT, and SIT of DED without causing any side effects.

UNLABELLED: EinleitungDas Trockene Auge (Dry eye disorder, DED) ist weltweit ein zunehmendes Problem, das mit übermässiger Bildschirmarbeit zusammenhängt. Die chinesische Augenübung der Akupunkturpunkte (Chinese eye exercise of acupoint, CEA), eine Reihe von Selbstmassagen an gemeinsamen CA-Akupunkturpunkten, wird zur Linderung visusbezogener Augensymptome und als mögliche alternative Behandlung für DED eingesetzt. Mit dieser Studie sollte die Wirksamkeit und Sicherheit von CEA bewertet werden.MethodenAm Thammasat-Universitätsklinikum in Thailand wurde eine einfach verblindete, randomisierte, kontrollierte Studie mit 56 Teilnehmern im Alter von 20 bis 60 Jahren durchgeführt, die zu gleichen Teilen zwei Gruppen zugewiesen wurden: die Behandlungsgruppe mit CEA und die Kontrollgruppe, die die Standard-Lidhygienebehandlung erhielt (STD). Das Interventionsprogramm dauerte 12 Wochen. Die Haupt-Zielkriterien, der Ocular Surface Disease Index (OSDI), die Tränenfilmaufreisszeit (tear break-up time, TBUT), der Schirmer-I-Test (SIT), das Corneal Surface Staining (CSS) und Selbstauskunftsformulare zur Sicherheit und zu unerwünschten Wirkungen wurden zu Beginn der Behandlung, in Woche 4 und in Woche 12 ermittelt. Für den Vergleich der Ergebnisse zwischen den beiden Gruppen, den Studienvisiten bzw. den primären und sekundären Zielkriterien wurden ein t Test für unabhängige Stichproben, ein t Test für paarige Stichproben und eine ANOVA mit Messwiederholungen verwendet. p-Werte <0,05 galten als statistisch signifikant.ErgebnisseHinsichtlich der Merkmale bestand zwischen den beiden Gruppen kein statistischer Unterschied bei Studienbeginn. In beiden Gruppen fielen die mittleren OSDI-Scores in Woche 4 und Woche 12 im Vergleich zum Ausgangswert signifikant geringer aus (p-Wert <0,05). Darüber hinaus zeigten sowohl die CEA- als auch die STD-Gruppe eine signifikante Verbesserung der TBUT- und SIT-Werte (p-Wert <0,05). Das CSS verbesserte sich nur in der CEA-Gruppe signifikant (p-Wert <0,05). Zwischen den Studiengruppen waren keine signifikanten Unterschiede zu beobachten, ausser beim SIT in Woche 12 (p-Wert <0,05). Was die Sicherheit betrifft, so traten in beiden Gruppen keine unerwünschten Nebenwirkungen auf.SchlussfolgerungDie CEA schien die OSDI-, TBUT- und SIT-Werte bei DED ebenso wirksam zu verbessern wie die Standardbehandlung, ohne Nebenwirkungen zu verursachen.}, } @article {pmid38330934, year = {2024}, author = {Yang, L and Li, Y and Zhang, S and Qian, H and Xu, W and Yu, J}, title = {Efficacy of Acupuncture Combined with Traditional Chinese Medicine Fumigation Therapy in Sequelae of Pelvic Inflammatory Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {175-186}, doi = {10.1159/000536101}, pmid = {38330934}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Fumigation/methods ; *Medicine, Chinese Traditional/methods ; *Pelvic Inflammatory Disease/therapy ; Combined Modality Therapy ; Female ; }, abstract = {BACKGROUND AND OBJECTIVE: Acupuncture combined with traditional Chinese medicine fumigation is increasingly being used in treating sequelae of pelvic inflammatory disease (SPID). However, there is a lack of meta-analysis on the effectiveness of acupuncture combined with traditional Chinese medicine fumigation in treating SPID. The aim of this study was to assess the feasibility of combining acupuncture with traditional Chinese medicine fumigation in the treatment of SPID.

METHODS: We searched eight databases for studies on acupuncture combined with traditional Chinese medicine fumigation for the treatment of SPID from the date of establishment to October 29, 2022. We assessed the quality of included studies by using the Cochrane bias risk tool. Pooled results were expressed as risk ratios (RRs), with a 95% confidence interval (CI). In addition, we identified sources of heterogeneity by sensitivity analysis, assessed publication bias by Egger's test, and assessed the quality of the evidence by Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). All statistical analyses were performed by Review Manager 5.3 and Stata 14.

RESULTS: Finally, seven studies with a total of 663 participants were included. We found a significant difference in the total effective rate in the acupuncture combined with the fumigation group compared with the acupuncture group in the treatment of SPID (RR = 1.17, 95% CI [1.09, 1.25], p = 0.0001 < 0.05; I2 = 0%; 6 trials), and a significant difference in the total effective rate in the acupuncture combined with fumigation group compared with the fumigation group in the treatment of SPID (RR = 1.42, 95% CI [1.21, 1.66], p = 0.0001 < 0.05; 5 trials).

CONCLUSION: The clinical efficacy of acupuncture combined with herbal fumigation in the treatment of SPID is relatively good. Larger scale studies are needed in the future.

UNLABELLED: Hintergrund und ZielAkupunktur in Kombination mit Fumigation, einem Verfahren der Traditionellen Chinesischen Medizin, wird zunehmend in der Behandlung von Folgeerscheinungen von Beckenentzündungen (SPID; sequelae of pelvic inflammatory disease) eingesetzt. Es mangelt jedoch an Metaanalysen zur Wirksamkeit der Akupunktur in Kombination mit Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von SPID. Das Ziel dieser Studie ist die Beurteilung der Machbarkeit der Kombination aus Akupunktur und Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von SPID.MethodenWir durchsuchten acht Datenbanken nach Studien zur Akupunktur in Kombination mit Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von Folgeerscheinungen von SPID von der Einrichtung bis zum 29. Oktober 2022. Wir beurteilten die Qualität der eingeschlossenen Studien mit dem Cochrane-Tool zur Bewertung des Bias-Risikos. Die gepoolten Ergebnisse wurden als Risikoquotient (RR; risk ratio) mit 95%-Konfidenzintervall (KI) ausgedrückt. Zusätzlich identifizierten wir Quellen für Heterogenität mittels Sensitivitätsanalyse, beurteilten den Publikations-Bias mittels Egger-Test und bewerteten die Qualität der Evidenz nach Grad der Empfehlungsstärke, Beurteilung, Entwicklung und Evaluierung (GRADE). Alle statistischen Analysen erfolgten mit Review Manager 5.3 und Stata 14.ErgebnisseIm Endeffekt wurden 7 Studien mit insgesamt 663 Teilnehmern eingeschlossen. Wir fanden einen signifikanten Unterschied in der Gesamt-Effektivitätsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Akupunkturgruppe (RR = 1,17; 95%-KI [1,09; 1,25]; p = 0,0001 < 0,05; I2-Wert = 0%; 6 Studien), und einen signifikanten Unterschied in der Gesamt-Effektivitätsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Fumigationsgruppe (RR = 1,42; 95%-KI [1,21; 1,66]; p = 0,0001 < 0,05; 5 Studien).SchlussfolgerungDie klinische Wirksamkeit der Akupunktur in Kombination mit Kräuter-Fumigation zur Behandlung von SPID ist relativ gut. Zukünftig sind größere Studien erforderlich.}, } @article {pmid38332489, year = {2024}, author = {Dandl, S and Bender, A and Hothorn, T}, title = {Heterogeneous treatment effect estimation for observational data using model-based forests.}, journal = {Statistical methods in medical research}, volume = {33}, number = {3}, pages = {392-413}, pmid = {38332489}, issn = {1477-0334}, mesh = {Humans ; *Treatment Effect Heterogeneity ; Riluzole ; *Amyotrophic Lateral Sclerosis ; Linear Models ; }, abstract = {The estimation of heterogeneous treatment effects has attracted considerable interest in many disciplines, most prominently in medicine and economics. Contemporary research has so far primarily focused on continuous and binary responses where heterogeneous treatment effects are traditionally estimated by a linear model, which allows the estimation of constant or heterogeneous effects even under certain model misspecifications. More complex models for survival, count, or ordinal outcomes require stricter assumptions to reliably estimate the treatment effect. Most importantly, the noncollapsibility issue necessitates the joint estimation of treatment and prognostic effects. Model-based forests allow simultaneous estimation of covariate-dependent treatment and prognostic effects, but only for randomized trials. In this paper, we propose modifications to model-based forests to address the confounding issue in observational data. In particular, we evaluate an orthogonalization strategy originally proposed by Robinson (1988, Econometrica) in the context of model-based forests targeting heterogeneous treatment effect estimation in generalized linear models and transformation models. We found that this strategy reduces confounding effects in a simulated study with various outcome distributions. We demonstrate the practical aspects of heterogeneous treatment effect estimation for survival and ordinal outcomes by an assessment of the potentially heterogeneous effect of Riluzole on the progress of Amyotrophic Lateral Sclerosis.}, } @article {pmid38334639, year = {2024}, author = {Cunha-Oliveira, T and Montezinho, L and Simões, RF and Carvalho, M and Ferreiro, E and Silva, FSG}, title = {Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334639}, issn = {2073-4409}, support = {PTDC/MED-FAR/29391/2017//Fundação para a Ciência e Tecnologia/ ; POCI-01-0145-FEDER-029391//Fundação para a Ciência e Tecnologia/ ; PTDC/BTM-SAL/29297/2017//Fundação para a Ciência e Tecnologia/ ; POCI-01-0145-FEDER-029297//Fundação para a Ciência e Tecnologia/ ; PTDC/BTM-ORG/0055/2021//Fundação para a Ciência e Tecnologia/ ; DL57/2016/CP1448/CT0016//Fundação para a Ciência e Tecnologia/ ; CEECIND/00322/2017//Fundação para a Ciência e Tecnologia/ ; 2022.00011.CEECIND//Fundação para a Ciência e Tecnologia/ ; UIDP/04539/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/04539/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/00081/2020//Fundação para a Ciência e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; Motor Neurons/pathology ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.}, } @article {pmid38334818, year = {2024}, author = {Hoek, AG and Dal Canto, E and Wenker, E and Bindraban, N and Handoko, ML and Elders, PJM and Beulens, JWJ}, title = {Epidemiology of heart failure in diabetes: a disease in disguise.}, journal = {Diabetologia}, volume = {67}, number = {4}, pages = {574-601}, pmid = {38334818}, issn = {1432-0428}, support = {91718304/ZONMW_/ZonMw/Netherlands ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/complications ; *Heart Failure/epidemiology/physiopathology ; Incidence ; Prevalence ; Stroke Volume/physiology ; Ventricular Dysfunction, Left/epidemiology/physiopathology ; Echocardiography ; }, abstract = {Left ventricular diastolic dysfunction (LVDD) without symptoms, and heart failure (HF) with preserved ejection fraction (HFpEF) represent the most common phenotypes of HF in individuals with type 2 diabetes mellitus, and are more common than HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and left ventricular systolic dysfunction (LVSD) in these individuals. However, diagnostic criteria for HF have changed over the years, resulting in heterogeneity in the prevalence/incidence rates reported in different studies. We aimed to give an overview of the diagnosis and epidemiology of HF in type 2 diabetes, using both a narrative and systematic review approach; we focus narratively on diagnosing (using the 2021 European Society of Cardiology [ESC] guidelines) and screening for HF in type 2 diabetes. We performed an updated (2016-October 2022) systematic review and meta-analysis of studies reporting the prevalence and incidence of HF subtypes in adults ≥18 years with type 2 diabetes, using echocardiographic data. Embase and MEDLINE databases were searched and data were assessed using random-effects meta-analyses, with findings presented as forest plots. From the 5015 studies found, 209 were screened using the full-text article. In total, 57 studies were included, together with 29 studies that were identified in a prior meta-analysis; these studies reported on the prevalence of LVSD (n=25 studies, 24,460 individuals), LVDD (n=65 studies, 25,729 individuals), HFrEF (n=4 studies, 4090 individuals), HFmrEF (n=2 studies, 2442 individuals) and/or HFpEF (n=8 studies, 5292 individuals), and on HF incidence (n=7 studies, 17,935 individuals). Using Hoy et al's risk-of-bias tool, we found that the studies included generally had a high risk of bias. They showed a prevalence of 43% (95% CI 37%, 50%) for LVDD, 17% (95% CI 7%, 35%) for HFpEF, 6% (95% CI 3%, 10%) for LVSD, 7% (95% CI 3%, 15%) for HFrEF, and 12% (95% CI 7%, 22%) for HFmrEF. For LVDD, grade I was found to be most prevalent. Additionally, we reported a higher incidence rate of HFpEF (7% [95% CI 4%, 11%]) than HFrEF 4% [95% CI 3%, 7%]). The evidence is limited by the heterogeneity of the diagnostic criteria over the years. The systematic section of this review provides new insights on the prevalence/incidence of HF in type 2 diabetes, unveiling a large pre-clinical target group with LVDD/HFpEF in which disease progression could be halted by early recognition and treatment.Registration PROSPERO ID CRD42022368035.}, } @article {pmid38336286, year = {2024}, author = {Lomeli, N and Pearre, DC and Cruz, M and Di, K and Ricks-Oddie, JL and Bota, DA}, title = {Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity.}, journal = {Experimental neurology}, volume = {375}, number = {}, pages = {114717}, pmid = {38336286}, issn = {1090-2430}, support = {TL1 TR001415/TR/NCATS NIH HHS/United States ; T32 NS082174/NS/NINDS NIH HHS/United States ; R01 CA263806/CA/NCI NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; T32 CA060396/CA/NCI NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; K08 NS072234/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Female ; *Cisplatin/toxicity ; *Brain-Derived Neurotrophic Factor/metabolism ; Rats, Sprague-Dawley ; Down-Regulation ; Quality of Life ; Riluzole/pharmacology ; Hippocampus/metabolism ; Disks Large Homolog 4 Protein ; }, abstract = {Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.}, } @article {pmid38337058, year = {2024}, author = {Choi, BJ and Park, MH and Jin, HK and Bae, JS}, title = {Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.}, journal = {Experimental & molecular medicine}, volume = {56}, number = {2}, pages = {301-310}, pmid = {38337058}, issn = {2092-6413}, mesh = {Animals ; Humans ; Mice ; *Alzheimer Disease/drug therapy ; Brain ; *Multiple Sclerosis ; *Nervous System Diseases ; Sphingomyelin Phosphodiesterase/genetics ; }, abstract = {Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.}, } @article {pmid38338912, year = {2024}, author = {Duranti, E and Cordani, N and Villa, C}, title = {Edaravone: A Novel Possible Drug for Cancer Treatment?.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338912}, issn = {1422-0067}, mesh = {Humans ; Edaravone/therapeutic use ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; *Neoplasms/drug therapy/chemically induced ; Free Radical Scavengers/pharmacology ; }, abstract = {Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.}, } @article {pmid38339026, year = {2024}, author = {Potenza, RL and Armida, M and Popoli, P}, title = {Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339026}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease ; *Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.}, } @article {pmid38347315, year = {2024}, author = {Huang, SL and Shen, YL and Peng, WY and Ye, K and Zheng, H}, title = {Edaravone for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {3}, pages = {895-904}, pmid = {38347315}, issn = {2240-2993}, support = {no. 2021JDTD0007//Sichuan Province Science and Technology Support Program/ ; }, mesh = {*Edaravone/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Free Radical Scavengers/therapeutic use ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone.

METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach.

RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p = 0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p = 0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty.

CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.}, } @article {pmid38347638, year = {2024}, author = {Li, W and Li, HL and Wang, JZ and Liu, R and Wang, X}, title = {Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.}, journal = {Cell & bioscience}, volume = {14}, number = {1}, pages = {22}, pmid = {38347638}, issn = {2045-3701}, support = {92049107//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; 31929002//National Natural Science Foundation of China/ ; }, abstract = {Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.}, } @article {pmid38349395, year = {2024}, author = {Soni, S and Lukhey, MS and Thawkar, BS and Chintamaneni, M and Kaur, G and Joshi, H and Ramniwas, S and Tuli, HS}, title = {A current review on P2X7 receptor antagonist patents in the treatment of neuroinflammatory disorders: a patent review on antagonists.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {7}, pages = {4643-4656}, pmid = {38349395}, issn = {1432-1912}, mesh = {*Patents as Topic ; Humans ; *Receptors, Purinergic P2X7/metabolism ; *Purinergic P2X Receptor Antagonists/therapeutic use/pharmacology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Chronic inflammation is defined by an activated microglial state linked to all neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (a motor neuron disease that affects the brain and spinal cord). P2X7 receptors (P2X7R) are ATP-activated ion-gated channels present on microglial surfaces. Prolonged ATP release under pathological settings results in sustained P2X7R activation, which leads to inflammasome development and cytokine release. P2X7R and its enabling roles have recently been linked to neurodegenerative diseases, making it a potential research subject. This research provides an overview of current patents for chemicals, biologics, and medicinal applications. The World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), and the United States Patent and Trademark Office (USPTO) databases were searched for patents using the keywords "P2X7R and Neuroinflammation." During the study period from 2015 to 2021, 103 patents were examined. The countries that protected these innovations were the United States, PCT (Patent Cooperation Treaty states), Europe, Canada, Australia, and India. Janssen Pharmaceutica NV had the most applications, followed by Acetelion Pharmaceuticals LTD., Renovis Inc., Kelly Michael G, Kincaid Jhon, Merck Patent GMBH, H Lundbeck A/S, and many more. The P2X7R is a possible diagnostic and therapeutic target for cancer, pain disorders, and inflammation. For P2X7 R, several compounds have been discovered and are presently the subject of clinical trial investigations. This study featured patents for P2X7R antagonists, which help treat conditions including neuroinflammation.}, } @article {pmid38349516, year = {2024}, author = {Xin, Z and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Neuroprotective Effect of a Multistrain Probiotic Mixture in SOD1[G93A] Mice by Reducing SOD1 Aggregation and Targeting the Microbiota-Gut-Brain Axis.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10051-10071}, pmid = {38349516}, issn = {1559-1182}, support = {H2021206310//the Natural Science Foundation of Hebei Province/ ; zh2018004//the Key Project of Technical Health Research and Achievement Transformation of Hebei Provincial Department of Health/ ; }, mesh = {Animals ; *Probiotics/pharmacology ; *Gastrointestinal Microbiome/drug effects ; *Superoxide Dismutase-1/metabolism/genetics ; *Mice, Transgenic ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/pathology ; Brain-Gut Axis/drug effects/physiology ; Mice ; Autophagy/drug effects ; Brain/drug effects/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Protein Aggregates/drug effects ; Mice, Inbred C57BL ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. A bidirectional communication system known as the "microbiota-gut-brain" axis has a regulatory function in neurodegenerative disorders. The impact of probiotics on ALS through the "microbiota-gut-brain" axis remains uncertain. A longitudinal investigation was conducted to examine the alterations in the structure of the ileum and colon in mutant superoxide dismutase 1 (SOD1[G93A]) transgenic mice models of ALS by using immunofluorescence and Western blotting. Subsequently, the mice were administered a multistrain probiotic mixture (LBE) or vehicle orally, starting from 60 days of age until the terminal stage of the disease. The effects of these agents on the behavior, gut microbiota, microbial metabolites, and pathological processes of the spinal and intestine of SOD1[G93A] mice were analyzed, with a focus on exploring potential protective mechanisms. SOD1[G93A] mice exhibit various structural abnormalities in the intestine. Oral administration of LBE improved the proinflammatory response, reduced aberrant superoxide dismutase 1 (SOD1) aggregation, and protected neuronal cells in the intestine and spinal cord of SOD1[G93A] mice. Furthermore, LBE treatment resulted in a change in intestinal microbiota, an increase in short-chain fatty acid levels, and an enhancement in autophagy flux. SOD1[G93A] mice exhibited various structural abnormalities in the intestine. LBE can improve the proinflammatory response, reduce aberrant SOD1 aggregation, and protect neuronal cells in the spinal cord and intestine of SOD1[G93A] mice. The positive effect of LBE can be attributed to increased short-chain fatty acids and enhanced autophagy flux.}, } @article {pmid38352376, year = {2024}, author = {Amado, DA and Robbins, AB and Smith, AR and Whiteman, KR and Chillon Bosch, G and Chen, Y and Fuller, JA and Izda, A and Nelson, S and Dichter, AI and Monteys, AM and Davidson, BL}, title = {AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578314}, pmid = {38352376}, issn = {2692-8205}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.}, } @article {pmid38358553, year = {2024}, author = {Brakemeier, S and Lipka, J and Schlag, M and Kleinschnitz, C and Hagenacker, T}, title = {Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2649-2657}, pmid = {38358553}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *Deglutition Disorders/etiology/physiopathology/drug therapy ; Pyrimidines/therapeutic use/pharmacology ; Aged ; Spinal Muscular Atrophies of Childhood/drug therapy/physiopathology/complications ; Treatment Outcome ; Deglutition/physiology/drug effects ; Prospective Studies ; Muscular Atrophy, Spinal/drug therapy/physiopathology ; Young Adult ; *Azo Compounds ; }, abstract = {BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality.

METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM).

RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline.

CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.}, } @article {pmid38359044, year = {2024}, author = {Vieira, FG and Tassinari, VR and Kidd, JD and Moreno, A and Thompson, K and Perrin, S and Gill, A and Hatzipetros, T}, title = {PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.}, journal = {PloS one}, volume = {19}, number = {2}, pages = {e0292190}, pmid = {38359044}, issn = {1932-6203}, mesh = {Mice ; Humans ; Animals ; *Guanabenz/pharmacology/therapeutic use/*analogs & derivatives ; eIF-2 Kinase/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Clonidine ; Unfolded Protein Response ; Adrenergic alpha-2 Receptor Agonists ; Adenine/*analogs & derivatives ; *Cinnamates ; *Indoles ; Thiourea/*analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.}, } @article {pmid38360060, year = {2024}, author = {El-Ghazouly, DE and Yassien, RI}, title = {Bisphosphonate's effect on the tongue in adult male albino rats and the possible protective role of rutin: light and scanning electron microscopic study.}, journal = {Anatomy & cell biology}, volume = {57}, number = {1}, pages = {129-142}, pmid = {38360060}, issn = {2093-3665}, abstract = {Alendronate sodium (ALS) is a nitrogen-containing bisphosphonate used for the treatment of different bone disorders. However, its adverse effect on oral soft tissue has been detected. Rutin (RUT) is natural flavonoid with antioxidant and anti-inflammatory properties. This work aimed to investigate the possible effect of ALS on the tongue of adult male albino rats and to evaluate the possible protective role of RUT. Forty adult male albino rats were equally divided into four groups: group I (control), group II (RUT): Received RUT 50 mg/kg, group III (ALS): Received ALS 1 mg/kg, group IV (ALS+RUT): Received ALS and RUT with the same doses as pervious groups. The drugs were given once daily for 5 weeks. Tongue specimens were taken and processed for light and scanning electron microscopic inspection. ALS treated group revealed structural changes in the tongue in the form of decrease in the height of the filiform papillae with blunt ends, marked atrophy in some papillae with areas of focal loss, loss of some epithelial cells, pyknotic nuclei and cytoplasmic vacuoles in some epithelial cells. The lamina propria showed inflammatory cellular infiltration with congested blood vessels. Statistically, there were highly significant decrease in the number of proliferating cell nuclear antigen immunopositive cells, area percentage of Bcl-2 immunoexpression and highly significant increase in the collagen content compared to control group. Administration of RUT with ALS minimizes these changes. RUT protected the rat tongue against the histological and immunohistochemical changes induced by ALS through its antioxidant and anti-inflammatory properties.}, } @article {pmid38366598, year = {2024}, author = {Ke, YD and van Hummel, A and Au, C and Chan, G and Lee, WS and van der Hoven, J and Przybyla, M and Deng, Y and Sabale, M and Morey, N and Bertz, J and Feiten, A and Ippati, S and Stevens, CH and Yang, S and Gladbach, A and Haass, NK and Kril, JJ and Blair, IP and Delerue, F and Ittner, LM}, title = {Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice.}, journal = {Neuron}, volume = {112}, number = {8}, pages = {1249-1264.e8}, doi = {10.1016/j.neuron.2024.01.022}, pmid = {38366598}, issn = {1097-4199}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/metabolism ; Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy.}, } @article {pmid38372421, year = {2024}, author = {Miquel, E and Villarino, R and Martínez-Palma, L and Cassina, A and Cassina, P}, title = {Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration.}, journal = {Glia}, volume = {72}, number = {5}, pages = {999-1011}, doi = {10.1002/glia.24516}, pmid = {38372421}, issn = {1098-1136}, support = {//Programa de Desarrollo de las Ciencias Básicas (PEDECIBA)/ ; FCE_1_2019_1_156461//Agencia Nacional de Investigación e Innovación/ ; }, mesh = {Animals ; Rats ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Astrocytes/metabolism ; Cells, Cultured ; Disease Models, Animal ; Motor Neurons/metabolism ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics/metabolism ; Respiration ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.}, } @article {pmid38378992, year = {2024}, author = {Song, M and Qiang, Y and Zhao, X and Song, F}, title = {Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7287-7302}, pmid = {38378992}, issn = {1559-1182}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/metabolism ; *Cyclin-Dependent Kinase 5/metabolism ; Animals ; Oxidative Stress/physiology ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.}, } @article {pmid38382647, year = {2024}, author = {Huang, TN and Shih, YT and Yen, TL and Hsueh, YP}, title = {Vcp overexpression and leucine supplementation extend lifespan and ameliorate neuromuscular junction phenotypes of a SOD1G93A-ALS mouse model.}, journal = {Human molecular genetics}, volume = {33}, number = {11}, pages = {935-944}, pmid = {38382647}, issn = {1460-2083}, support = {AS-CFII-108-104//Transgenic Core Facility/ ; //Animal Facility of the Institute of Molecular Biology, Academia Sinica/ ; }, mesh = {Animals ; *Valosin Containing Protein/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Neuromuscular Junction/metabolism ; Female ; Male ; *Longevity/genetics ; *Mice, Transgenic ; *Leucine/pharmacology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Phenotype ; Superoxide Dismutase/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Humans ; Adenosine Triphosphatases/genetics/metabolism ; }, abstract = {Many genes with distinct molecular functions have been linked to genetically heterogeneous amyotrophic lateral sclerosis (ALS), including SuperOxide Dismutase 1 (SOD1) and Valosin-Containing Protein (VCP). SOD1 converts superoxide to oxygen and hydrogen peroxide. VCP acts as a chaperon to regulate protein degradation and synthesis and various other cellular responses. Although the functions of these two genes differ, in the current report we show that overexpression of wild-type VCP in mice enhances lifespan and maintains the size of neuromuscular junctions (NMJs) of both male and female SOD1G93A mice, a well-known ALS mouse model. Although VCP exerts multiple functions, its regulation of ER formation and consequent protein synthesis has been shown to play the most important role in controlling dendritic spine formation and social and memory behaviors. Given that SOD1 mutation results in protein accumulation and aggregation, it may direct VCP to the protein degradation pathway, thereby impairing protein synthesis. Since we previously showed that the protein synthesis defects caused by Vcp deficiency can be improved by leucine supplementation, to confirm the role of the VCP-protein synthesis pathway in SOD1-linked ALS, we applied leucine supplementation to SOD1G93A mice and, similar to Vcp overexpression, we found that it extends SOD1G93A mouse lifespan. In addition, the phenotypes of reduced muscle strength and fewer NMJs of SOD1G93A mice are also improved by leucine supplementation. These results support the existence of crosstalk between SOD1 and VCP and suggest a critical role for protein synthesis in ASL. Our study also implies a potential therapeutic treatment for ALS.}, } @article {pmid38382884, year = {2024}, author = {Jiao, LL and Dong, HL and Liu, MM and Wu, PL and Cao, Y and Zhang, Y and Gao, FG and Zhu, HY}, title = {The potential roles of salivary biomarkers in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106442}, doi = {10.1016/j.nbd.2024.106442}, pmid = {38382884}, issn = {1095-953X}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Reproducibility of Results ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Huntington Disease/diagnosis ; Biomarkers ; }, abstract = {Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, β-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.}, } @article {pmid38383503, year = {2024}, author = {Vidovic, M and Menschikowski, M and Freigang, M and Lapp, HS and Günther, R}, title = {Macrophage inclusions in cerebrospinal fluid following treatment initiation with antisense oligonucleotide therapies in motor neuron diseases.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {11}, pmid = {38383503}, issn = {2524-3489}, abstract = {5q-associated spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are two distinct neurological disorders leading to degeneration of lower motor neurons. The antisense oligonucleotides (ASOs) nusinersen and tofersen are novel disease-modifying agents for these diseases, respectively. In the context of ASO treatment, the cytological characteristics and composition of cerebrospinal fluid (CSF) have recently garnered particular interest. This report presents a case series of CSF cytology findings in two patients with SMA and ALS revealing comparable unspecified macrophage inclusions following treatment initiation with nusinersen and tofersen. Yet, the presence of these "asophages" in the treatment course of two different ASOs is of unclear significance. While both treatments have been well tolerated, this phenomenon warrants attention, given the long-term nature of these treatments.}, } @article {pmid38384337, year = {2024}, author = {Wiesenfarth, M and Dorst, J and Brenner, D and Elmas, Z and Parlak, Ö and Uzelac, Z and Kandler, K and Mayer, K and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Bachhuber, F and Simak, T and Günther, K and Fröhlich, E and Knehr, A and Regensburger, M and German, A and Petri, S and Grosskreutz, J and Klopstock, T and Reilich, P and Schöberl, F and Hagenacker, T and Weyen, U and Günther, R and Vidovic, M and Jentsch, M and Haarmeier, T and Weydt, P and Valkadinov, I and Hesebeck-Brinckmann, J and Conrad, J and Weishaupt, JH and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Senel, M and Tumani, H and Ludolph, AC}, title = {Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.}, journal = {EClinicalMedicine}, volume = {69}, number = {}, pages = {102495}, pmid = {38384337}, issn = {2589-5370}, abstract = {BACKGROUND: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.

METHODS: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.

FINDINGS: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.

INTERPRETATION: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.

FUNDING: No funding was received towards this study.}, } @article {pmid38389786, year = {2024}, author = {Berthiaume, AA and Reda, SM and Kleist, KN and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Moebius, HJ and Church, KJ}, title = {ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1348157}, pmid = {38389786}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS.

METHODS: In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice.

RESULTS: In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS.

DISCUSSION: The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.}, } @article {pmid38390945, year = {2024}, author = {Fukatsu, S and Sashi, H and Shirai, R and Takagi, N and Oizumi, H and Yamamoto, M and Ohbuchi, K and Miyamoto, Y and Yamauchi, J}, title = {Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {1}, pages = {100-116}, pmid = {38390945}, issn = {1873-149X}, abstract = {Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.}, } @article {pmid38391754, year = {2024}, author = {Leão Batista Simões, J and Webler Eichler, S and Raitz Siqueira, ML and de Carvalho Braga, G and Bagatini, MD}, title = {Amyotrophic Lateral Sclerosis in Long-COVID Scenario and the Therapeutic Potential of the Purinergic System in Neuromodulation.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391754}, issn = {2076-3425}, support = {Proj. No 404256/2021-0 and 310606/2021-7).//National Council for Scientific and Technological Development/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves the degeneration of motor neurons and debilitating and possibly fatal symptoms. The COVID-19 pandemic directly affected the quality of life of this group, and the SARS-CoV-2 infection accelerated the present neuroinflammatory process. Furthermore, studies indicate that the infection may have led to the development of the pathology. Thus, the scenario after this pandemic presents "long-lasting COVID" as a disease that affects people who have been infected. From this perspective, studying the pathophysiology behind ALS associated with SARS-CoV-2 infection and possible supporting therapies becomes necessary when we understand the impact on the quality of life of these patients. Thus, the purinergic system was trained to demonstrate how its modulation can add to the treatment, reduce disease progression, and result in better prognoses. From our studies, we highlight the P2X7, P2X4, and A2AR receptors and how their activity can directly influence the ALS pathway.}, } @article {pmid38399373, year = {2024}, author = {Cha, Y and Kagalwala, MN and Ross, J}, title = {Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399373}, issn = {1424-8247}, abstract = {Recent advances in machine learning hold tremendous potential for enhancing the way we develop new medicines. Over the years, machine learning has been adopted in nearly all facets of drug discovery, including patient stratification, lead discovery, biomarker development, and clinical trial design. In this review, we will discuss the latest developments linking machine learning and CNS drug discovery. While machine learning has aided our understanding of chronic diseases like Alzheimer's disease and Parkinson's disease, only modest effective therapies currently exist. We highlight promising new efforts led by academia and emerging biotech companies to leverage machine learning for exploring new therapies. These approaches aim to not only accelerate drug development but to improve the detection and treatment of neurodegenerative diseases.}, } @article {pmid38399458, year = {2024}, author = {Al Shaer, D and Al Musaimi, O and Albericio, F and de la Torre, BG}, title = {2023 FDA TIDES (Peptides and Oligonucleotides) Harvest.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399458}, issn = {1424-8247}, abstract = {A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.}, } @article {pmid38399543, year = {2024}, author = {Karagul, S and Senol, S and Karakose, O and Uzunoglu, K and Kayaalp, C}, title = {One Anastomosis Gastric Bypass versus Roux-en-Y Gastric Bypass: A Randomized Prospective Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {2}, pages = {}, pmid = {38399543}, issn = {1648-9144}, mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; *Gastric Bypass/methods ; Prospective Studies ; *Obesity, Morbid/surgery ; Comorbidity ; Weight Loss ; Retrospective Studies ; }, abstract = {Background and Objectives: One anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB) surgeries are effective methods used in bariatric surgery. There are limited randomized studies comparing these procedures over more than 2 years. Here, we aimed to compare the 3-year results of two bariatric procedures. Materials and Methods: Patients included in this randomized prospective study were compared in OAGB and RYGB groups. A total of 55 patients, aged between 18 and 65, were eligible for the study. Thirteen patients who did not accept randomization were excluded. Patients were evaluated at 6, 12, 24, and 36 months postoperatively. Results: Three patients were excluded from the study due to loss of communication during the clinical follow-up and one due to death by amyotrophic lateral sclerosis, which started in the eighth month after surgery. The study was completed with a total of 38 patients (OAGB; n = 20, RYGB; n = 18). Patients in the two groups were similar in terms of age, gender, body mass index (BMI), and obesity-related comorbidities. At the end of 3-year follow-up, BMI in the OAGB and RYGB groups was 28.80 ± 4.53 kg/m[2] and 29.17 ± 5.36 kg/m[2], respectively (p = 0.822). Percentage total weight loss (TWL%) was similar. No significant differences were found between the groups regarding percentage excess weight loss (EWL%). Remission of comorbidities was similar. De novo refluxes developed in four OAGB patients; there were no occurrences of these in RYGB patients (p = 0.066). Conclusions: Both OAGB and RYGB are effective in the treatment of morbid obesity. The two procedures are similarly successful in terms of obesity-related comorbidities.}, } @article {pmid38405076, year = {2024}, author = {Dittlau, KS and Chandrasekaran, A and Freude, K and Van Den Bosch, L}, title = {Generation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Astrocytes for Amyotrophic Lateral Sclerosis and Other Neurodegenerative Disease Studies.}, journal = {Bio-protocol}, volume = {14}, number = {4}, pages = {e4936}, pmid = {38405076}, issn = {2331-8325}, abstract = {Astrocytes are increasingly recognized for their important role in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). In ALS, astrocytes shift from their primary function of providing neuronal homeostatic support towards a reactive and toxic role, which overall contributes to neuronal toxicity and cell death. Currently, our knowledge on these processes is incomplete, and time-efficient and reproducible model systems in a human context are therefore required to understand and therapeutically modulate the toxic astrocytic response for future treatment options. Here, we present an efficient and straightforward protocol to generate human induced pluripotent stem cell (hiPSC)-derived astrocytes implementing a differentiation scheme based on small molecules. Through an initial 25 days, hiPSCs are differentiated into astrocytes, which are matured for 4+ weeks. The hiPSC-derived astrocytes can be cryopreserved at every passage during differentiation and maturation. This provides convenient pauses in the protocol as well as cell banking opportunities, thereby limiting the need to continuously start from hiPSCs. The protocol has already proven valuable in ALS research but can be adapted to any desired research field where astrocytes are of interest. Key features • This protocol requires preexisting experience in hiPSC culturing for a successful outcome. • The protocol relies on a small molecule differentiation scheme and an easy-to-follow methodology, which can be paused at several time points. • The protocol generates >50 × 10[6] astrocytes per differentiation, which can be cryopreserved at every passage, ensuring a large-scale experimental output.}, } @article {pmid38410712, year = {2024}, author = {Moretti, A and Pietersen, PI and Hassan, M and Shafiek, H and Prosch, H and Tarnoki, AD and Annema, JT and Munavvar, M and Bonta, PI and de Wever, W and Juul, AD}, title = {ERS International Congress 2023: highlights from the Clinical Techniques, Imaging and Endoscopy Assembly.}, journal = {ERJ open research}, volume = {10}, number = {1}, pages = {}, pmid = {38410712}, issn = {2312-0541}, abstract = {The Clinical Techniques, Imaging and Endoscopy Assembly is involved in the diagnosis and treatment of several pulmonary diseases, as demonstrated at the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. From interventional pulmonology, the congress included several exciting results for the use of bronchoscopy in lung cancer, including augmented fluoroscopy, robotic-assisted bronchoscopy and cryobiopsies. In obstructive lung disease, the latest results on bronchoscopic treatment of emphysema with hyperinflation and chronic bronchitis were presented. Research on using cryobiopsies to diagnose interstitial lung disease was further explored, with the aims of elevating diagnostic yield and minimising risk. For imaging, the latest updates in using artificial intelligence to overcome the increased workload of radiologists were of great interest. Novel imaging in sarcoidosis explored the use of magnetic resonance imaging, photon-counting computed tomography and positron emission tomography/computed tomography in the diagnostic work-up. Lung cancer screening is still a hot topic and new results were presented regarding incorporation of biomarkers, identifying knowledge gaps and improving screening programmes. The use of ultrasound in respiratory medicine is an expanding field, which was demonstrated by the large variety in studies presented at the 2023 ERS Congress. Ultrasound of the diaphragm in patients with amyotrophic lateral sclerosis and myasthenia gravis was used to assess movements and predict respiratory fatigue. Furthermore, studies using ultrasound to diagnose or monitor pulmonary disease were presented. The congress also included studies regarding the training and assessment of competencies as an important part of implementing ultrasound in clinical practice.}, } @article {pmid38413232, year = {2024}, author = {Chun, C and Lee, JH and Bothwell, M and Nghiem, P and Smith, AST and Mack, DL}, title = {Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {16}, pages = {}, pmid = {38413232}, issn = {1529-2401}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; R03 TR004009/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; B7-H1 Antigen/metabolism ; Biomarkers ; DNA-Binding Proteins/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Interferon-gamma/metabolism/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.}, } @article {pmid38416402, year = {2024}, author = {Wolff, AW and Peine, J and Höfler, J and Zurek, G and Hemker, C and Lingor, P}, title = {SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.}, journal = {CNS drugs}, volume = {38}, number = {4}, pages = {291-302}, pmid = {38416402}, issn = {1179-1934}, support = {2017_T05//Else Kröner-Fresenius-Stiftung/ForTra GmbH/ ; }, mesh = {Male ; Humans ; Female ; *rho-Associated Kinases ; Biological Availability ; Healthy Volunteers ; *Protein Kinase Inhibitors/adverse effects ; Chronic Disease ; Administration, Oral ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives ; }, abstract = {BACKGROUND: The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.

OBJECTIVE: The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.

METHODS: This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).

RESULTS: Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC0-tz) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.

CONCLUSIONS: Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to considered. The results presented here lay grounds for future trials of fasudil in chronic diseases, which require an oral long-term application. This trial was registered with EudraCT (no. 2019-001805-26).}, } @article {pmid38421827, year = {2024}, author = {Zhang, Y and Li, Y and Bin, S and Cheng, X and Niu, Q}, title = {A Neglected Gene: The Role of the ANG Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {16}, number = {1}, pages = {13-32}, pmid = {38421827}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a poor prognosis. To date, more than 40 ALS-related genes have been identified. However, there is still a lack of targeted therapeutic drugs for the treatment of ALS, especially for patients with acute onset and severe disease. A series of studies reported missense heterozygous mutations with loss of function in the coding region of the ANG gene in ALS patients. ANG deficiency is related to the pathogenesis of ALS, but the underlying mechanism has not been determined. This article aimed to synthesize and consolidate the knowledge of the pathological mechanism of ALS induced by ANG mutation and provide a theoretical basis for ALS diagnosis and targeted therapy. This article further delves into the mechanisms underlying the current understanding of the structure and function of the ANG gene, the association between ANG and ALS, and its pathogenesis. Mutations in ANG may lead to the development of ALS through the loss of neuroprotective function, induction of oxidative stress, or inhibition of rRNA synthesis. ANG mutations and genetic and environmental factors may cause disease heterogeneity and more severe disease than in ALS patients with the wild-type gene. Exploring this mechanism is expected to provide a new approach for ALS treatment through increasing ANG expression or angiogenin activity. However, the related study is still in its infancy; therefore, this article also highlights the need for further exploration of the application of ANG gene mutations in clinical trials and animal experiments is needed to achieve improved early diagnosis and treatment of ALS.}, } @article {pmid38427252, year = {2024}, author = {Rajaratnam, S and Pradhan, SS and Naik, AA and Sivaramakrishnan, V}, title = {Integrated Multi-Omics Analysis and Validation in Yeast Model of Amyotrophic Lateral Sclerosis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2761}, number = {}, pages = {397-419}, pmid = {38427252}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Multiomics ; Software ; Gene Expression Profiling ; }, abstract = {Transcriptomics is a complex process that involves raw data extraction, normalization, differential gene expression, and analysis. The Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) is a repository of experimental datasets. Amyotrophic lateral sclerosis (ALS) datasets are deposited by various scientists and research investigators to expand the horizon of scientific knowledge. R-statistical tools are the most common ways for conducting these kinds of studies. The first step is the identification of appropriate datasets. Since the raw data is available in a variety of formats, a large array of software is used for extraction and analysis. Normalization is conducted for the datasets using NetworkAnalyst. Differential analysis is further conducted on the normalized data to identify significantly enriched genes. The significant genes are then grouped into pathways. The results were validated using yeast model of ALS in which the yeast is transformed with ALS plasmids encoding genes associated with ALS. The resulting GFP-tagged protein aggregates are imaged using fluorescence microscopy and subsequently validated using filter retardation assay and quantified using ImageJ software. Functional role of different genes is studied using metabolite treatment and knockout studies.}, } @article {pmid38427990, year = {2024}, author = {El-Hajj, VG and Daller, C and Fletcher-Sandersjöö, A and Gharios, M and Bydon, M and Söderman, M and Jabbour, P and Edström, E and Elmi-Terander, A and Arnberg, F}, title = {The negative impact of treatment delays on the long-term neurological outcomes of spinal dural arteriovenous fistulas: a longitudinal cohort study.}, journal = {Neurosurgical focus}, volume = {56}, number = {3}, pages = {E14}, doi = {10.3171/2023.12.FOCUS23703}, pmid = {38427990}, issn = {1092-0684}, mesh = {Humans ; Male ; Aged ; Female ; Cohort Studies ; Longitudinal Studies ; Retrospective Studies ; *Treatment Delay ; *Central Nervous System Vascular Malformations/complications/surgery ; }, abstract = {OBJECTIVE: Dural arteriovenous fistulas are rare vascular malformations that affect the brain and spinal cord. Spinal dural arteriovenous fistulas (sdAVFs) are the most frequently encountered vascular malformation affecting the spinal cord. The object of this study was to evaluate the impact of treatment delays on the long-term neurological outcomes of either open surgical or interventional treatment of sdAVFs.

METHODS: In this retrospective, population-based cohort study, the authors examined consecutive patients with diagnosed sdAVFs at a tertiary care center between 2005 and 2020. Patients were assessed using the Aminoff-Logue disability scale (ALS) at various time points including symptom onset, primary care visit, first specialist outpatient visit, as well as both short and long-term follow-ups. The postoperative long-term ALS gait and bladder grades constituted the primary outcomes of the study.

RESULTS: Among the 34 patients included in the study, the median age was 65 years, and there was a male predominance (71%). Most lesions were in the lumbar region (47%). Significant worsening in ALS gait and bladder grades was observed preoperatively, followed by postoperative improvements (p < 0.05). There was no difference in outcomes between surgical and endovascular treatments. Older age (OR 1.10, 95% CI 1.03-1.17, p = 0.007), worse preoperative ALS gait grades (OR 5.12, 95% CI 2.18-12.4, p < 0.001), and longer time from first specialist outpatient visit to first treatment (OR 1.00, 95% CI 1.00-1.01, p = 0.040) were independently associated with worse long-term gait outcomes. Only the preoperative ALS bladder score was a predictor of worse long-term bladder function (OR 92.7, 95% CI 28.0-306.7, p < 0.001).

CONCLUSIONS: Both surgical and endovascular treatments for sdAVFs led to significant neurological improvements. However, treatment delays were associated with less favorable long-term outcomes. Prompt diagnosis and early intervention prior to symptom progression may enhance recovery and help to preserve neurological function.}, } @article {pmid38428126, year = {2024}, author = {Wahbeh, F and Restifo, D and Laws, S and Pawar, A and Parikh, NS}, title = {Impact of tobacco smoking on disease-specific outcomes in common neurological disorders: A scoping review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {10-18}, pmid = {38428126}, issn = {1532-2653}, support = {K23 AG073524/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation ; Smoking/adverse effects/epidemiology ; Tobacco Smoking ; *Stroke/epidemiology/etiology/therapy ; *Multiple Sclerosis ; }, abstract = {Although the association of smoking with the risk of incident neurological disorders is well established, less is known about the impact of smoking and smoking cessation on outcomes of these conditions. The objective of this scoping review was to synthesize what is known about the impact of smoking and smoking cessation on disease-specific outcomes for seven common neurological disorders. We included 67 studies on the association of smoking and smoking cessation on disease-specific outcomes. For multiple sclerosis, smoking was associated with greater clinical and radiological disease progression, relapses, risk for disease-related death, cognitive decline, and mood symptoms, in addition to reduced treatment effectiveness. For stroke and transient ischemic attack, smoking was associated with greater rates of stroke recurrence, post-stroke cardiovascular outcomes, post-stroke mortality, post-stroke cognitive impairment, and functional impairment. In patients with cognitive impairment and dementia, smoking was associated with faster cognitive decline, and smoking was also associated with greater cognitive decline in Parkinson's disease, but not motor symptom worsening. Patients with amyotrophic lateral sclerosis who smoked faced increased mortality. Last, in patients with cluster headache, smoking was associated with more frequent and longer cluster attack periods. Conversely, for multiple sclerosis and stroke, smoking cessation was associated with improved disease-specific outcomes. In summary, whereas smoking is detrimentally associated with disease-specific outcomes in common neurological conditions, there is growing evidence that smoking cessation may improve outcomes. Effective smoking cessation interventions should be leveraged in the management of common neurological disorders to improve patient outcomes.}, } @article {pmid38428228, year = {2024}, author = {Masroor, A and Zaidi, N and Nabi, F and Malik, S and Zehra, S and Arjmand, F and Naseem, N and Khan, RH}, title = {Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4][+][glycinate][-] chemotherapeutic drug candidate against human lysozyme aggregation.}, journal = {Biophysical chemistry}, volume = {308}, number = {}, pages = {107214}, doi = {10.1016/j.bpc.2024.107214}, pmid = {38428228}, issn = {1873-4200}, mesh = {Humans ; *Amyloid/chemistry ; Muramidase/chemistry ; Molecular Docking Simulation ; *Amyloidosis/drug therapy/metabolism ; Dynamic Light Scattering ; Protein Aggregates ; }, abstract = {In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4][+][glycinate][-] is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 10[4] M[-1]), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis.}, } @article {pmid38428880, year = {2024}, author = {Hu, CJ and Chen, PC and Padmanabhan, N and Zahn, A and Ho, CM and Wang, K and Yen, Y}, title = {A new potential therapeutic approach for ALS: A case report with NGS analysis.}, journal = {Medicine}, volume = {103}, number = {9}, pages = {e37401}, pmid = {38428880}, issn = {1536-5964}, mesh = {Humans ; Male ; Aged ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics ; Artificial Intelligence ; Treatment Outcome ; *Hypotension/drug therapy ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS.

PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis.

DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria.

INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy.

OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being.

LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.}, } @article {pmid38429929, year = {2024}, author = {Schuster, KH and Zalon, AJ and DiFranco, DM and Putka, AF and Stec, NR and Jarrah, SI and Naeem, A and Haque, Z and Zhang, H and Guan, Y and McLoughlin, HS}, title = {ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {5}, pages = {1359-1372}, pmid = {38429929}, issn = {1525-0024}, support = {R01 NS122751/NS/NINDS NIH HHS/United States ; R35 GM133346/GM/NIGMS NIH HHS/United States ; U01 NS106670/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Oligodendroglia/metabolism ; Mice ; *Machado-Joseph Disease/genetics/therapy/pathology/metabolism ; *Oligonucleotides, Antisense ; *Disease Models, Animal ; *Ataxin-3/genetics/metabolism ; Humans ; Repressor Proteins/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.}, } @article {pmid38431829, year = {2024}, author = {Yuan, W and Lin, J and Wang, J and Wang, C and Shan, Y and Jing, W and Fei, Z and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 2: Modulation of hypoxia, redox status, and mitochondrial protection in a neuroblastoma cell line, SH-SY5Y.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {162-168}, doi = {10.5414/CP204505}, pmid = {38431829}, issn = {0946-1965}, mesh = {Humans ; *Medicine, Chinese Traditional ; Kaempferols/pharmacology ; Cell Line, Tumor ; Network Pharmacology ; *Neuroblastoma/drug therapy/metabolism ; Oxidation-Reduction ; Hypoxia/drug therapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis.

MATERIALS AND METHODS: Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity.

RESULTS: Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells.

DISCUSSION: Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity.

CONCLUSION: Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.}, } @article {pmid38431830, year = {2024}, author = {Li, R and Han, X and Wang, Q and Wang, C and Jing, W and Zhang, H and Wang, J and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 3: Alleviation of hypoxia, muscle-wasting, and modulation of redox functions in amyotrophic lateral sclerosis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {169-177}, doi = {10.5414/CP204520}, pmid = {38431830}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Medicine, Chinese Traditional ; Network Pharmacology ; Treatment Outcome ; Hypoxia ; Cholecalciferol ; Muscles ; Disease Progression ; }, abstract = {OBJECTIVE: The aim of this clinical study is to obtain evidence for the clinical efficacy of Bu-Shen-Jian-Pi formula (BSJP), a traditional Chinese medicine, used for the treatment of amyotrophic lateral sclerosis, a relatively rare, progressive and usually fatal disease possibly associated with alterations in tissue redox status, hypoxia, and muscular injury.

BACKGROUND: The active agents in BSJP formula[†] causing apoptosis, modulation of redox changes, and alterations in the immune status have been studied previously by us using cell cultures. The findings from these investigations have been incorporated into pharmacology databases employed in our analysis of BSJP using network pharmacology analysis/artifical intelligence. This information has been used here in the design of the investigation and to optimize evaluation of the clinical efficacy and usefulness of this herbal medicine, as far as possible using evidence-based medicine criteria.

MATERIALS AND METHODS: The design of the study was a randomized multi-center, controlled clinical trial in 127 patients with confirmed diagnoses of amyotrophic lateral sclerosis. Patients and investigator were double-blinded. Clinical efficacy was determined using the Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R), together with tests of limb muscle strength using the manual muscle test (MMT), forced vital capacity (FVC), and clinical chemistry laboratory tests over a 20-week observation period.

RESULTS: The scores of ALS-SSIT in the BSJP group increased significantly (22%) after treatment. The ALSFRS-R score in the BSJP group decreased significantly after treatment (19%). The rate of decrease in muscle function (MMT score) in most BSJP patients was lower than that in the control group, where the differences in the scores for the trapezius and triceps brachii were statistically significant compared to the control group. The fall in FVC in the BJSP group was significantly slower than in the control group. There were no marked differences observed in the frequency of side effects. Serum vitamin D3 levels in the BSJP group showed greater increases compared to the control group.

CONCLUSION: BSJP treatment reduced the rate of progression of amyotrophic lateral sclerosis according to the ALS-SSITS and ALSFRS scores and significantly reduced the rate of deterioration in muscle function in the limbs of amyotrophic lateral sclerosis patients. The modes of action of BSJP in treating amyotrophic lateral sclerosis are probably diverse and multi targeted, some of which may involve regulation of serum vitamin D3 and alleviation of the impairments in liver and kidney function.}, } @article {pmid38431841, year = {2024}, author = {Gao, C and Shi, Q and Pan, X and Chen, J and Zhang, Y and Lang, J and Wen, S and Liu, X and Cheng, TL and Lei, K}, title = {Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {3}, pages = {113892}, doi = {10.1016/j.celrep.2024.113892}, pmid = {38431841}, issn = {2211-1247}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Proteins/genetics ; Dipeptides/pharmacology/metabolism ; DNA Repeat Expansion ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.}, } @article {pmid38435120, year = {2024}, author = {Duan, C and Kang, M and Pan, X and Gan, Z and Huang, V and Li, G and Place, RF and Li, LC}, title = {Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1[G93A] ALS mouse model.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {1}, pages = {102147}, pmid = {38435120}, issn = {2162-2531}, abstract = {Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing in which short interfering RNAs (siRNAs) effectively degrade complementary transcripts. However, delivery to extrahepatic tissues like the CNS has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enable activity in CNS tissues. Local delivery via intracerebroventricular or intrathecal injection into SOD1[G93A] mice delayed disease progression and extended animal survival with superior efficacy compared with an ASO resembling tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function, including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (i.e., siRNA-ACO) represents a novel modality for delivery of duplex RNA (e.g., siRNA) to the CNS that is currently being tested in the clinic for treatment of ALS.}, } @article {pmid38443977, year = {2024}, author = {Duan, QQ and Wang, H and Su, WM and Gu, XJ and Shen, XF and Jiang, Z and Ren, YL and Cao, B and Li, GB and Wang, Y and Chen, YP}, title = {TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {96}, pmid = {38443977}, issn = {1741-7015}, support = {2022YFC2703101//the National Key Research and Development Program of China/ ; 2021YFS0051//Sichuan Province Science and Technology Support Program/ ; 2023YFS0269//Sichuan Province Science and Technology Support Program/ ; 81971188//the National Natural Science Fund of China/ ; 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Drug Repositioning ; Mendelian Randomization Analysis ; Protein Serine-Threonine Kinases/genetics ; *Aminopyridines ; }, abstract = {BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.

METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.

RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.

CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.}, } @article {pmid38445369, year = {2024}, author = {Nishimura, K and Sanchez-Molano, J and Kerr, N and Pressman, Y and Silvera, R and Khan, A and Gajavelli, S and Bramlett, HM and Dietrich, WD}, title = {Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury.}, journal = {Journal of neurotrauma}, volume = {41}, number = {21-22}, pages = {2395-2412}, pmid = {38445369}, issn = {1557-9042}, support = {R37 NS133195/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Rats, Sprague-Dawley ; Male ; Rats ; *Exosomes/metabolism/transplantation ; Humans ; *Schwann Cells/metabolism ; *Head Injuries, Penetrating ; }, abstract = {There is a growing body of evidence that the delivery of cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord injury and improve outcomes. Exosomes are nanometer-sized vesicles that are released by Schwann cells and may have neuroprotective effects by reducing post-traumatic inflammatory processes as well as promoting tissue healing and functional recovery. The purpose of this study was to evaluate the beneficial effects of human Schwann-cell exosomes (hSC-Exos) in a severe model of penetrating ballistic-like brain injury (PBBI) in rats and investigate effects on multiple outcomes. Human Schwann cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction and purification steps approved by the Food and Drug Administration for an expanded access single ALS patient Investigational New Drug. Anesthetized male Sprague-Dawley rats (280-350g) underwent PBBI surgery or Sham procedures and, starting 30 min after injury, received either a dose of hSC-Exos or phosphate-buffered saline through the jugular vein. At 48h after PBBI, flow cytometry analysis of cortical tissue revealed that hSC-Exos administration reduced the number of activated microglia and levels of caspase-1, a marker of inflammasome activation. Neuropathological analysis at 21 days showed that hSC-Exos treatment after PBBI significantly reduced overall contusion volume and decreased the frequency of Iba-1 positive activated and amoeboid microglia by immunocytochemical analysis. This study revealed that the systemic administration of hSC-Exos is neuroprotective in a model of severe TBI and reduces secondary inflammatory injury mechanisms and histopathological damage. The administration of hSC-Exos represents a clinically relevant cell-based therapy to limit the detrimental effects of neurotrauma or other progressive neurological injuries by impacting multiple pathophysiological events and promoting neurological recovery.}, } @article {pmid38447450, year = {2024}, author = {Malacarne, C and Giagnorio, E and Chirizzi, C and Cattaneo, M and Saraceno, F and Cavalcante, P and Bonanno, S and Mantegazza, R and Moreno-Manzano, V and Lauria, G and Metrangolo, P and Bombelli, FB and Marcuzzo, S}, title = {FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {173}, number = {}, pages = {116380}, doi = {10.1016/j.biopha.2024.116380}, pmid = {38447450}, issn = {1950-6007}, mesh = {Mice ; Animals ; Superoxide Dismutase-1/metabolism ; Reactive Oxygen Species/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/pathology ; Myoblasts/metabolism ; *Nanoparticles ; Atrophy/pathology ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase/metabolism ; *Benzamides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.}, } @article {pmid38452377, year = {2024}, author = {Rajabi, D and Khanmohammadi, S and Rezaei, N}, title = {The role of long noncoding RNAs in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {5}, pages = {533-547}, pmid = {38452377}, issn = {2191-0200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *RNA, Long Noncoding/genetics/metabolism ; Animals ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis leading to death. The diagnosis and treatment of ALS are inherently challenging due to its complex pathomechanism. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides involved in different cellular processes, incisively gene expression. In recent years, more studies have been conducted on lncRNA classes and interference in different disease pathologies, showing their promising contribution to diagnosing and treating neurodegenerative diseases. In this review, we discussed the role of lncRNAs like NEAT1 and C9orf72-as in ALS pathogenesis mechanisms caused by mutations in different genes, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), superoxide dismutase type 1 (SOD1). NEAT1 is a well-established lncRNA in ALS pathogenesis; hence, we elaborate on its involvement in forming paraspeckles, stress response, inflammatory response, and apoptosis. Furthermore, antisense lncRNAs (as-lncRNAs), a key group of transcripts from the opposite strand of genes, including ZEB1-AS1 and ATXN2-AS, are discussed as newly identified components in the pathology of ALS. Ultimately, we review the current standing of using lncRNAs as biomarkers and therapeutic agents and the future vision of further studies on lncRNA applications.}, } @article {pmid38455726, year = {2024}, author = {Liu, L and Wu, L and Li, Z and Fang, Y and Ju, B and Zhang, S and Bai, L and Pan, L}, title = {The Pro-197-Thr mutation in the ALS gene confers novel resistance patterns to ALS-inhibiting herbicides in Bromus japonicus in China.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1348815}, pmid = {38455726}, issn = {1664-462X}, abstract = {INTRODUCTION: Bromus japonicus is one of the most notorious agricultural weeds in China. The long-term use of ALS-inhibiting herbicides has led to rapid evolution of herbicide resistance in B. japonicus. B. japonicus population (BJ-R) surviving mesosulfuron-methyl treatment was collected from wheatland. Here, we aimed to confirm the resistance mechanisms in this putative resistant population.

METHODS: The dose-reponse tests were used to test the resistance level of the B. japonicus to ALS-inhibiting herbicides. Pretreatment with P450 and GST inhibitors and GST activity assays were used to determine whether P450 or GST was involved in the resistance of the BJ-R population. Sanger sequencing was used to analyse the ALS mutation of the BJ-R population. RT-qPCR was used to confirm the the expression levels of the ALS gene in mesosulfuron-methyl -resistant (BJ-R) and-susceptible (BJ-S) B. japonicus. An in vitro ALS activity assay was used to determine the ALS activity of the BJ-R and BJ-S populations. Homology modelling and docking were used to determine the binding energy of the BJ-R and BJ-S populations with ALS-inhibiting herbicides.

RESULTS: B. japonicus population (BJ-R) was confirmed to be 454- and 2.7-fold resistant to the SU herbicides mesosulfuron-methyl and nicosulfuron, and 7.3-, 2.3-, 1.1- and 10.8-fold resistant to the IMI herbicide imazamox, the TP herbicide penoxsulam, the PTB herbicide pyribenzoxim and the SCT herbicide flucarbazone-sodium, respectively, compared with its susceptible counterpart (BJ-S). Neither a P450 inhibitor nor a GST inhibitor could reverse the level of resistance to mesosulfuron-methyl in BJ-R. In addition, no significant differences in GST activity were found between the BJ-R and BJ-S. ALS gene sequencing revealed a Pro-197-Thr mutation in BJ-R, and the gene expression had no significant differences between the BJ-R and BJ-S. The ALS activity of BJ-R was 106-fold more tolerant to mesosulfuron-methyl than that of BJ-S. Molecular docking showed that the binding energy of the ALS active site and mesosulfuron-methyl was changed from -6.67 to -4.57 kcal mol[-1] due to the mutation at position 197.

DISCUSSION: These results suggested that the Pro-197-Thr mutation was the main reason for the high resistance level of BJ-R to mesosulfuron-methyl. Unlike previous reports of the cross-resistance pattern conferred by this mutation, we firstly documented that the Pro-197-Thr mutation confers broad cross-resistance spectrums to ALS-inhibiting herbicides in B. japonicus.}, } @article {pmid38466738, year = {2024}, author = {Pelletier, C and Shaw, S and Alsayegh, S and Brown, AJP and Lorenz, A}, title = {Candida auris undergoes adhesin-dependent and -independent cellular aggregation.}, journal = {PLoS pathogens}, volume = {20}, number = {3}, pages = {e1012076}, pmid = {38466738}, issn = {1553-7374}, support = {MR/M026663/1/MRC_/Medical Research Council/United Kingdom ; MR/M026663/2/MRC_/Medical Research Council/United Kingdom ; MR/V033417/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Antifungal Agents/therapeutic use ; *Candida/genetics ; Candida auris ; Virulence ; Drug Resistance, Fungal ; Adhesins, Bacterial/metabolism ; Microbial Sensitivity Tests ; }, abstract = {Candida auris is a fungal pathogen of humans responsible for nosocomial infections with high mortality rates. High levels of resistance to antifungal drugs and environmental persistence mean these infections are difficult to treat and eradicate from a healthcare setting. Understanding the life cycle and the genetics of this fungus underpinning clinically relevant traits, such as antifungal resistance and virulence, is of the utmost importance to develop novel treatments and therapies. Epidemiological and genomic studies have identified five geographical clades (I-V), which display phenotypic and genomic differences. Aggregation of cells, a phenotype primarily of clade III strains, has been linked to reduced virulence in some infection models. The aggregation phenotype has thus been associated with conferring an advantage for (skin) colonisation rather than for systemic infection. However, strains with different clade affiliations were compared to infer the effects of different morphologies on virulence. This makes it difficult to distinguish morphology-dependent causes from clade-specific or even strain-specific genetic factors. Here, we identify two different types of aggregation: one induced by antifungal treatment which is a result of a cell separation defect; and a second which is controlled by growth conditions and only occurs in strains with the ability to aggregate. The latter aggregation type depends on an ALS-family adhesin which is differentially expressed during aggregation in an aggregative C. auris strain. Finally, we demonstrate that macrophages cannot clear aggregates, suggesting that aggregation might after all provide a benefit during systemic infection and could facilitate long-term persistence in the host.}, } @article {pmid38467696, year = {2024}, author = {Hilton, JBW and Kysenius, K and Liddell, JR and Mercer, SW and Paul, B and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Hare, DJ and Roberts, BR and Crouch, PJ}, title = {Evidence for disrupted copper availability in human spinal cord supports Cu[II](atsm) as a treatment option for sporadic cases of ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5929}, pmid = {38467696}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; Copper/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Ceruloplasmin/metabolism ; Disease Models, Animal ; *Thiosemicarbazones ; *Coordination Complexes ; }, abstract = {The copper compound Cu[II](atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu[II](atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for Cu[II](atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu[II](atsm) involving copper availability may also be pertinent to sporadic cases of ALS.}, } @article {pmid38470068, year = {2024}, author = {Van Damme, P and Al-Chalabi, A and Andersen, PM and Chiò, A and Couratier, P and De Carvalho, M and Hardiman, O and Kuźma-Kozakiewicz, M and Ludolph, A and McDermott, CJ and Mora, JS and Petri, S and Probyn, K and Reviers, E and Salachas, F and Silani, V and Tysnes, OB and van den Berg, LH and Villanueva, G and Weber, M}, title = {European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16264}, pmid = {38470068}, issn = {1468-1331}, support = {//ERN Euro-NMD/ ; //European Academy of Neurology/ ; //ALS Liga Belgium/ ; //EUpALS/ ; //ENCALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Europe ; Neurology/standards/methods ; Neuromuscular Diseases/therapy ; }, abstract = {BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS).

METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available.

RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management.

CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.}, } @article {pmid38471489, year = {2024}, author = {D'Souza, A and Zink, K and Langhorst, J and Wildner, M and Stupp, C and Keil, T}, title = {How Effective Is Drinking Natural Mineral Water against Heartburn from Functional Dyspepsia, Gastroesophageal Reflux Disease, or Other Causes? A Systematic Review of Clinical Intervention Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {253-265}, pmid = {38471489}, issn = {2504-2106}, mesh = {Humans ; *Mineral Waters/therapeutic use ; *Gastroesophageal Reflux/therapy/drug therapy ; *Heartburn/drug therapy ; *Dyspepsia/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: For centuries, spring and other natural waters have been recommended as external or internal remedies for numerous diseases. For studies that examined the effects of drinking mineral waters against heartburn, gastroesophageal reflux disease (GERD), or functional dyspepsia, a systematic review is lacking.

OBJECTIVES: The main aim of this systematic review was to examine the effects of drinking natural mineral waters on heartburn from various causes by identifying all published intervention studies and critically appraising their methods as well as summarizing their results.

METHODS: We systematically searched the largest medical literature database MEDLINE, further relevant web sources, and gray literature for randomized and nonrandomized trials, with or without control groups, up to September 2021 and no language restrictions. Further inclusion criteria were adult patients with heartburn, drinking cure with natural mineral water as the intervention, compared to no or other interventions (care-as-usual, waiting list). We defined the reduction of heartburn symptoms and duration of disease episodes as primary and quality of life as secondary outcomes. Two reviewers independently carried out the study quality assessments (risk of bias) using the National Institutes of Health-Study Quality Assessment Tools.

RESULTS: Nine trials comprising 393 patients from Italy, Russia, Ukraine, and Germany fulfilled all inclusion criteria. We identified three randomized controlled trials (all with poor methodological quality), plus six before-after (pre/post) intervention studies without a control group. The intervention groups of the three comparative trials seemed to show a stronger reduction of self-reported heartburn symptoms, and duration of heartburn episodes than the respective control groups; however, they all had poor methodological quality.

CONCLUSION: Based on the best available evidence of clinical studies, we cannot recommend or advise against drinking natural mineral waters as a treatment for heartburn. The potential benefits of natural mineral waters that were reported in some studies with a lower evidence level (e.g., lacking a control group) should be verified by good quality randomized clinical trials with adequate comparison groups and longer follow-up periods.

UNLABELLED: HintergrundSeit Jahrhunderten werden Quell- und andere natürliche Wässer als äußerliche oder innerliche Heilmittel für zahlreiche Krankheiten empfohlen. Für Studien, die die Wirkung des Trinkens von Mineralwasser gegen Sodbrennen, gastroösophageale Refluxkrankheit (GERD) oder funktionelle Dyspepsie untersuchten, fehlt eine systematische Übersicht.ZielsetzungDas Hauptziel dieser systematischen Übersichtsarbeit war es, die Auswirkungen von Trinkkuren mit natürlichen Mineralwässern auf Sodbrennen verschiedener Ursachen zu untersuchen, indem alle veröffentlichten Interventionsstudien identifiziert und ihre Methoden kritisch bewertet sowie ihre Ergebnisse zusammengefasst wurden.MethodenWir durchsuchten systematisch die größte medizinische Literaturdatenbank MEDLINE, weitere relevante Internetquellen und graue Literatur nach randomisierten und nicht-randomisierten Studien, mit oder ohne Kontrollgruppen, bis September 2021 und ohne sprachliche Einschränkungen. Weitere Einschlusskriterien waren erwachsene Patienten mit Sodbrennen, Trinkkur mit natürlichem Mineralwasser als Intervention, im Vergleich zu keiner oder anderen Interventionen (care-as-usual, Warteliste). Wir definierten die Abnahme der Symptome des Sodbrennens und die Dauer der Krankheitsepisoden als primäre und die Lebensqualität als sekundäre Endpunkte. Zwei Gutachter bewerteten unabhängig voneinander die Qualität der Studien (Verzerrungsrisiko) anhand der National Institutes of Health-Study Quality Assessment Tools.ErgebnisseNeun Studien mit 393 Patienten aus Italien, Russland, der Ukraine und Deutschland erfüllten alle Einschlusskriterien. Wir identifizierten drei randomisierte kontrollierte Studien (alle mit schlechter methodischer Qualität) sowie sechs Vorher-Nachher-Studien (Prä-/Post-Studien) ohne Kontrollgruppe. Die Interventionsgruppen der drei randomisierten Vergleichsstudien schienen eine stärkere Verringerung der selbstberichteten Symptome und der Dauer der Episoden des Sodbrennens zu zeigen als die jeweiligen Kontrollgruppen, allerdings waren sie alle von schlechter methodischer Qualität.SchlussfolgerungAuf der Grundlage der besten verfügbaren Belege aus klinischen Studien können wir das Trinken natürlicher Mineralwässer zur Behandlung von Sodbrennen weder empfehlen noch davon abraten. Die potenziellen Vorteile natürlicher Mineralwässer, die in einigen Studien mit geringerer Evidenz (z. B. ohne Kontrollgruppe) berichtet wurden, sollten durch qualitativ hochwertige randomisierte klinische Studien mit angemessenen Vergleichsgruppen und längeren Nachbeobachtungszeiträumen überprüft werden.}, } @article {pmid38473944, year = {2024}, author = {Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Bordoni, M and Pansarasa, O}, title = {New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38473944}, issn = {1422-0067}, support = {Ricerca Corrente 2022-2024//Ministero della Salute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; Antioxidants/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Inflammation/drug therapy ; }, abstract = {Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.}, } @article {pmid38474416, year = {2024}, author = {Tzeplaeff, L and Jürs, AV and Wohnrade, C and Demleitner, AF}, title = {Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474416}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Treatment Outcome ; Clinical Trials as Topic ; }, abstract = {Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.}, } @article {pmid38474719, year = {2024}, author = {Noor Eddin, A and Alfuwais, M and Noor Eddin, R and Alkattan, K and Yaqinuddin, A}, title = {Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Nutrients}, volume = {16}, number = {5}, pages = {}, pmid = {38474719}, issn = {2072-6643}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; *Microbiota ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a highly fatal neurodegenerative disorder characterized by the progressive wasting and paralysis of voluntary muscle. Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited. However, recent evidence implicates gut dysbiosis and gut-brain axis (GBA) dysfunction in ALS pathogenesis. Alterations to the composition and diversity of microbial communities within the gut flora have been consistently observed in ALS patients. These changes are often correlated with disease progression and patient outcome, suggesting that GBA modulation may have therapeutic potential. Indeed, targeting the gut microbiota has been shown to be neuroprotective in several animal models, alleviating motor symptoms and mitigating disease progression. However, the translation of these findings to human patients is challenging due to the complexity of ALS pathology and the varying diversity of gut microbiota. This review comprehensively summarizes the current literature on ALS-related gut dysbiosis, focusing on the implications of GBA dysfunction. It delineates three main mechanisms by which dysbiosis contributes to ALS pathology: compromised intestinal barrier integrity, metabolic dysfunction, and immune dysregulation. It also examines preclinical evidence on the therapeutic potential of gut-microbiota-modulating agents (categorized as prebiotics, probiotics, and postbiotics) in ALS.}, } @article {pmid38477419, year = {2024}, author = {de Fátima Dos Santos Sampaio, M and de Paiva, YB and Sampaio, TB and Pereira, MG and Coimbra, NC}, title = {Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {134}, number = {5}, pages = {574-601}, doi = {10.1111/bcpt.13997}, pmid = {38477419}, issn = {1742-7843}, support = {2014/11869-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2020/15050-7//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; PDJ grant 155489/2018-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; Research Grant (NAP-USP-NuPNE; process IaPq2012-15//Universidade de São Paulo/ ; 374/2022//Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo/ ; 302605/2021-5//CNPq/ ; 301341/2015-0//CNPq/ ; 301905/2010-0//CNPq/ ; 155489/2018-6//CNPq/ ; }, mesh = {Humans ; *Cannabidiol/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; *Multiple Sclerosis/drug therapy ; Receptor, Serotonin, 5-HT1A/therapeutic use ; *Cannabinoids/pharmacology/therapeutic use ; *Epilepsy/drug therapy ; *Mental Disorders/drug therapy ; Comorbidity ; }, abstract = {Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.}, } @article {pmid38481899, year = {2024}, author = {El-Ghanem, M and Abdulrazeq, H and Brasiliense, L and Abbad, H and Aguilar-Salinas, P and Al-Mufti, F and Dumont, T}, title = {Outcomes of Mechanical Thrombectomy in Patients With Neurological Disorders: A National Inpatient Sample Database Analysis.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54063}, pmid = {38481899}, issn = {2168-8184}, abstract = {INTRODUCTION: Mechanical thrombectomy (MT) has changed the standard of care for patients presenting with acute ischemic stroke (AIS). The window of treatment has significantly increased the number of patients who would benefit from intervention and operators may be confronted with patients harboring preexistent neurological disorders. Still, the epidemiology of patients with AIS and neurological disorders has not been established.

METHODS: This is a retrospective study, which utilizes data from the National Inpatient Sample (NIS) between 2012 and 2016. Patients with the major neurological comorbidities in the study were included: Alzheimer's dementia (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and myasthenia gravis (MG). These patients were divided into groups and analyzed based on discharged home status, length of hospital stay (LOS), and inpatient mortality. These outcomes were also compared between patients who underwent MT versus those who did not.

RESULTS: In this study, 460,070 patients with AIS were identified and included. MT was performed less often when the patient had a neurological diagnosis compared to those without a neurological disease (p<0.0001). However, patients with AIS who have underlying neurological disorders such as AD, PD, and MS have shown similar outcomes after MT to those who do not have these disorders.

CONCLUSION: Patients with preexisting neurological disorders were less likely to undergo MT. Further studies are required to elucidate the implications of having a neurological disorder in the setting of an AIS.}, } @article {pmid38483107, year = {2024}, author = {Adari, MD and Pandian, BA and Gaines, TA and Prasad, PV and Jugulam, M}, title = {Confirmation and characterization of the first case of acetolactate synthase (ALS)-inhibitor resistance in Japanese brome (Bromus japonicus) in the US.}, journal = {Pest management science}, volume = {80}, number = {8}, pages = {3717-3725}, doi = {10.1002/ps.8074}, pmid = {38483107}, issn = {1526-4998}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Bromus/enzymology/drug effects/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Kansas ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Plant Weeds/drug effects/genetics/enzymology ; }, abstract = {BACKGROUND: Japanese brome (Bromus japonicus Thumb.) is one of the problematic annual weeds in winter wheat (Triticum aestivum L.) and is generally controlled by acetolactate synthase (ALS) inhibitors. Repeated use of the ALS inhibitor propoxycarbazone-Na resulted in the evolution of resistance to this herbicide in three B. japonicus populations, i.e., R1, R2, and R3 in Kansas (KS). However, the level of resistance and mechanism conferring resistance in these populations is unknown. The objectives of this research were to (i) evaluate the level of resistance to propoxycarbazone-Na in R1, R2, and R3 in comparison with a known susceptible population (S1), (ii) investigate the mechanism of resistance involved in conferring ALS-inhibitor resistance, and (iii) investigate the cross-resistance to other ALS inhibitors.

RESULTS: Dose-response (0 to 16x; x = 44 g ai ha[-1] of propoxycarbazone-Na) assay indicated 167, 125, and 667-fold resistance in R1, R2 and R3 populations, respectively, compared to S1 population. ALS gene sequencing confirmed the mutations resulting in amino acid substitutions, i.e., Pro-197-Thr (R3, R1)/Ser (R2, R1) bestowing resistance to these ALS inhibitors. Such amino acid substitutions also showed differential cross-resistance to sulfosulfuron, mesosulfuron-methyl, pyroxsulam, and imazamox among resistant populations. Pretreatment with malathion (a cytochrome P450 enzyme-inhibitor) followed by imazamox treatment suggested cross-resistance to this herbicide possibly via metabolism only in R3 population.

CONCLUSION: Overall, these results confirm the first case of target-site based resistance to ALS inhibitors in B. japonicus in the US, highlighting the need for exploring herbicides with alternative modes of action to enhance weed control in winter wheat. © 2024 Society of Chemical Industry.}, } @article {pmid38487369, year = {2024}, author = {Fagnani, E and Bonì, F and Seneci, P and Gornati, D and Muzio, L and Mastrangelo, E and Milani, M}, title = {Stabilization of the retromer complex: Analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface.}, journal = {Computational and structural biotechnology journal}, volume = {23}, number = {}, pages = {1088-1093}, pmid = {38487369}, issn = {2001-0370}, abstract = {The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.}, } @article {pmid38487578, year = {2024}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Association between CNS-active drugs and risk of Alzheimer's and age-related neurodegenerative diseases.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1358568}, pmid = {38487578}, issn = {1664-0640}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer's Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated.

RESEARCH DESIGN AND METHODS: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals.

RESULTS: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction.

CONCLUSION: Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.}, } @article {pmid38489867, year = {2024}, author = {Tausendfreund, O and Bidlingmaier, M and Martini, S and Müller, K and Rippl, M and Schilbach, K and Schmidmaier, R and Drey, M}, title = {Growth hormone treatment in aged patients with comorbidities: A systematic review.}, journal = {Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {75}, number = {}, pages = {101584}, doi = {10.1016/j.ghir.2024.101584}, pmid = {38489867}, issn = {1532-2238}, mesh = {Aged ; Humans ; Comorbidity ; Growth Hormone ; *Human Growth Hormone/adverse effects/therapeutic use ; Insulin-Like Growth Factor I ; Quality of Life ; Randomized Controlled Trials as Topic ; *Aging/pathology ; }, abstract = {OBJECTIVE: Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects.

DESIGN: A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library.

INCLUSION CRITERIA: participants aged over 65 years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis.

RESULTS: The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3×/week), doses (0.41 mg-2.6 mg; mean 1.3 mg per 60 kg patient) and duration (1-12 months; mean 7 months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life.

CONCLUSION: Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.}, } @article {pmid38493058, year = {2024}, author = {Milani, M and Della Valle, I and Rossi, S and Fabbrizio, P and Margotta, C and Nardo, G and Cozzolino, M and D'Ambrosi, N and Apolloni, S}, title = {Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {3}, pages = {e00346}, pmid = {38493058}, issn = {1878-7479}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Disease Models, Animal ; *Disease Progression ; Inflammation/drug therapy ; Mice, Transgenic ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Niclosamide/pharmacology/therapeutic use ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (e.g., STAT3, mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. We administered niclosamide intraperitoneally to two transgenic murine models, SOD1-G93A and FUS mice, mimicking key pathological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed disease progression by neurological scores, rotarod and wire tests, and monitored survival. Furthermore, we investigated cellular and molecular mechanisms affected by niclosamide in the spinal cord and muscle of ALS mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterised by reduced gliosis, motor neuron loss, muscle atrophy, and inflammatory pathways. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.}, } @article {pmid38498721, year = {2024}, author = {Kertesz, A and Finger, E and Munoz, DG}, title = {Progress in Primary Progressive Aphasia: A Review.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {37}, number = {1}, pages = {3-12}, pmid = {38498721}, issn = {1543-3641}, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/genetics ; *Supranuclear Palsy, Progressive/genetics/pathology ; Syndrome ; *Aphasia, Primary Progressive ; }, abstract = {We present a review of the definition, classification, and epidemiology of primary progressive aphasia (PPA); an update of the taxonomy of the clinical syndrome of PPA; and recent advances in the neuroanatomy, pathology, and genetics of PPA, as well as the search for biomarkers and treatment. PPA studies that have contributed to concepts of language organization and disease propagation in neurodegeneration are also reviewed. In addition, the issues of heterogeneity versus the relationships of the clinical phenotypes and their relationship to biological, pathological, and genetic advances are discussed, as is PPA's relationship to other conditions such as frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, and amyotrophic lateral sclerosis. Arguments are presented in favor of considering these conditions as one entity versus many.}, } @article {pmid38499161, year = {2024}, author = {Bashir, S and Aiman, A and Shahid, M and Chaudhary, AA and Sami, N and Basir, SF and Hassan, I and Islam, A}, title = {Amyloid-induced neurodegeneration: A comprehensive review through aggregomics perception of proteins in health and pathology.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102276}, doi = {10.1016/j.arr.2024.102276}, pmid = {38499161}, issn = {1872-9649}, mesh = {Humans ; Amyloid/metabolism ; *Amyloidosis/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; Perception ; }, abstract = {Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.}, } @article {pmid38504285, year = {2024}, author = {Papaiz, F and Dourado, MET and de Medeiros Valentim, RA and Pinto, R and de Morais, AHF and Arrais, JP}, title = {Ensemble-imbalance-based classification for amyotrophic lateral sclerosis prognostic prediction: identifying short-survival patients at diagnosis.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {80}, pmid = {38504285}, issn = {1472-6947}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Prognosis ; Machine Learning ; }, abstract = {Prognosticating Amyotrophic Lateral Sclerosis (ALS) presents a formidable challenge due to patients exhibiting different onset sites, progression rates, and survival times. In this study, we have developed and evaluated Machine Learning (ML) algorithms that integrate Ensemble and Imbalance Learning techniques to classify patients into Short and Non-Short survival groups based on data collected during diagnosis. We aimed to identify individuals at high risk of mortality within 24 months of symptom onset through analysis of patient data commonly encountered in daily clinical practice. Our Ensemble-Imbalance approach underwent evaluation employing six ML algorithms as base classifiers. Remarkably, our results outperformed those of individual algorithms, achieving a Balanced Accuracy of 88% and a Sensitivity of 96%. Additionally, we used the Shapley Additive Explanations framework to elucidate the decision-making process of the top-performing model, pinpointing the most important features and their correlations with the target prediction. Furthermore, we presented helpful tools to visualize and compare patient similarities, offering valuable insights. Confirming the obtained results, our approach could aid physicians in devising personalized treatment plans at the time of diagnosis or serve as an inclusion/exclusion criterion in clinical trials.}, } @article {pmid38504592, year = {2024}, author = {Hamilton, HL and Akther, M and Anis, S and Colwell, CB and Vargas, MR and Pehar, M}, title = {Nicotinamide Adenine Dinucleotide Precursor Supplementation Modulates Neurite Complexity and Survival in Motor Neurons from Amyotrophic Lateral Sclerosis Models.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {7-9}, pages = {573-589}, pmid = {38504592}, issn = {1557-7716}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Motor Neurons/metabolism/pathology/drug effects ; Mice ; Humans ; *Disease Models, Animal ; *NAD/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurites/metabolism/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Nicotinamide Mononucleotide/pharmacology/metabolism ; Neuroprotective Agents/pharmacology ; DNA-Binding Proteins/metabolism/genetics ; Cell Survival/drug effects ; Dietary Supplements ; }, abstract = {Aims: Increasing nicotinamide adenine dinucleotide (NAD[+]) availability has been proposed as a therapeutic approach to prevent neurodegeneration in amyotrophic lateral sclerosis (ALS). Accordingly, NAD[+] precursor supplementation appears to exert neuroprotective effects in ALS patients and mouse models. The mechanisms mediating neuroprotection remain uncertain but could involve changes in multiple cell types. We investigated a potential direct effect of the NAD[+] precursor nicotinamide mononucleotide (NMN) on the health of cultured induced pluripotent stem cell (iPSC)-derived human motor neurons and in motor neurons isolated from two ALS mouse models, that is, mice overexpressing wild-type transactive response DNA binding protein-43 (TDP-43) or the ALS-linked human superoxide dismutase 1 with the G93A mutation (hSOD1[G93A]). Results: NMN treatment increased the complexity of neuronal processes in motor neurons isolated from both mouse models and in iPSC-derived human motor neurons. In addition, NMN prevented neuronal death induced by trophic factor deprivation. In mouse and human motor neurons expressing ALS-linked mutant superoxide dismutase 1, NMN induced an increase in glutathione levels, but this effect was not observed in nontransgenic or TDP-43 overexpressing motor neurons. In contrast, NMN treatment normalized the TDP-43 cytoplasmic mislocalization induced by its overexpression. Innovation: NMN can directly act on motor neurons to increase the growth and complexity of neuronal processes and prevent the death induced by trophic factor deprivation. Conclusion: Our results support a direct beneficial effect of NAD[+] precursor supplementation on the maintenance of the neuritic arbor in motor neurons. Importantly, this was observed in motor neurons isolated from two different ALS models, with and without involvement of TDP-43 pathology, supporting its therapeutic potential in sporadic and familial ALS. Antioxid. Redox Signal. 41, 573-589.}, } @article {pmid38508480, year = {2024}, author = {Bager, P and Hvas, CL and Dahlerup, JF}, title = {Severe Fatigue in Inflammatory Bowel Disease: Dopaminergic Therapy With Modafinil or Vitamin Therapy With Thiamine.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {22}, number = {11}, pages = {2348-2349}, doi = {10.1016/j.cgh.2024.03.002}, pmid = {38508480}, issn = {1542-7714}, mesh = {Humans ; *Modafinil/therapeutic use ; *Fatigue/drug therapy ; *Inflammatory Bowel Diseases/drug therapy/complications ; *Thiamine/therapeutic use ; Treatment Outcome ; Male ; Female ; Middle Aged ; }, abstract = {We found Moulton et al's[1] illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly interesting. [1] Among the patients, 8 previously had undergone treatment with multiple psychotropic medications, and 2 had active IBD as indicated by increased fecal calprotectin levels. Remarkably, all 10 patients responded positively to open-label treatment with modafinil, a central nervous system stimulant that blocks dopamine reuptake transport, which resulted in an impressive improvement in their fatigue symptoms. At baseline, the self-reported mean fatigue score was 16, measured on the IBD Fatigue Assessment Scale (IBD-FAS), which ranges up to 20, and with levels higher than 11 indicating severe fatigue. After 6 months of modafinil treatment, the mean fatigue score was 6.7.[1].}, } @article {pmid38510000, year = {2024}, author = {Ditan, ID and Turalde, CWR}, title = {Treatment gaps in the care of amyotrophic lateral sclerosis in the Philippines: A scoping review.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27944}, pmid = {38510000}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting both the upper and lower motor neurons. Much of the management of ALS is supportive with the goal of maximizing patient quality of life. While the Philippines was participative in the "Ice Bucket Challenge" in 2014, it is up for investigation whether substantial changes occurred to improve healthcare for ALS patients. This study aims to evaluate the treatment gaps in the management of ALS in the Philippines through a scoping review. Data on epidemiology, health systems, and pharmacotherapy available regarding ALS in the local setting were synthesized. Nine articles were included. As of July 2023, there were only four indexed studies on ALS from the Philippines. Five of the included articles investigated ALS in Filipino populations but were not authored by Filipinos nor affiliated with Philippine institutions. The available literature showed a distinct lack of local ALS epidemiologic data, as well as limited availability in diagnostic centers, medications, health financing options, and digestible information for Filipinos. The limitations in managing ALS in the country are multifactorial - from political, medical, and social. It is imperative to establish a national database, financing systems, support groups, and accessible diagnostic centers for ALS patients.}, } @article {pmid38511059, year = {2024}, author = {Casado Gama, H and Amorós, MA and Andrade de Araújo, M and Sha, CM and Vieira, MPS and Torres, RGD and Souza, GF and Junkes, JA and Dokholyan, NV and Leite Góes Gitaí, D and Duzzioni, M}, title = {Systematic review and meta-analysis of dysregulated microRNAs derived from liquid biopsies as biomarkers for amyotrophic lateral sclerosis.}, journal = {Non-coding RNA research}, volume = {9}, number = {2}, pages = {523-535}, pmid = {38511059}, issn = {2468-0540}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; }, abstract = {The discovery of disease-specific biomarkers, such as microRNAs (miRNAs), holds the potential to transform the landscape of Amyotrophic Lateral Sclerosis (ALS) by facilitating timely diagnosis, monitoring treatment response, and accelerating drug discovery. Such advancement could ultimately improve the quality of life and survival rates for ALS patients. Despite more than a decade of research, no miRNA biomarker candidate has been translated into clinical practice. We conducted a systematic review and meta-analysis to quantitatively synthesize data from original studies that analyzed miRNA expression from liquid biopsies via PCR and compared them to healthy controls. Our analysis encompasses 807 miRNA observations from 31 studies, stratified according to their source tissue. We identified consistently dysregulated miRNAs in serum (hsa-miR-3665, -4530, -4745-5p, -206); blood (hsa-miR-338-3p, -183-5p); cerebrospinal fluid (hsa-miR-34a-3p); plasma (hsa-miR-206); and neural-enriched extracellular vesicles from plasma (hsa-miR-146a-5p, -151a-5p, -10b-5p, -29b-3p, and -4454). The meta-analyses provided further support for the upregulation of hsa-miR-206, hsa-miR-338-3p, hsa-miR-146a-5p and hsa-miR-151a-5p, and downregulation of hsa-miR-183-5p, hsa-miR-10b-5p, hsa-miR-29b-3p, and hsa-miR-4454 as consistent indicators of ALS across independent studies. Our findings provide valuable insights into the current understanding of miRNAs' dysregulated expression in ALS patients and on the researchers' choices of methodology. This work contributes to the ongoing efforts towards discovering disease-specific biomarkers.}, } @article {pmid38511649, year = {2024}, author = {Craig, RA and De Vicente, J and Estrada, AA and Feng, JA and Lexa, KW and Canet, MJ and Dowdle, WE and Erickson, RI and Flores, BN and Haddick, PCG and Kane, LA and Lewcock, JW and Moerke, NJ and Poda, SB and Sweeney, Z and Takahashi, RH and Tong, V and Wang, J and Yulyaningsih, E and Solanoy, H and Scearce-Levie, K and Sanchez, PE and Tang, L and Xu, M and Zhang, R and Osipov, M}, title = {Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {7}, pages = {5758-5782}, doi = {10.1021/acs.jmedchem.3c02422}, pmid = {38511649}, issn = {1520-4804}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mutation ; Eukaryotic Initiation Factor-2B/genetics/metabolism ; Brain/metabolism ; *Leukoencephalopathies/metabolism ; }, abstract = {Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.}, } @article {pmid38515326, year = {2024}, author = {Lee, DY and Kwon, YN and Lee, K and Kim, SJ and Sung, JJ}, title = {Dual effects of TGF-β inhibitor in ALS - inhibit contracture and neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2495-2514}, doi = {10.1111/jnc.16102}, pmid = {38515326}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea (NRF) Grant/ ; 2019M3C7A1031867//National Research Foundation of Korea (NRF) Grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Mice ; *Transforming Growth Factor beta/metabolism/antagonists & inhibitors ; *Contracture/drug therapy/prevention & control ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Piperidines/pharmacology/therapeutic use ; Humans ; }, abstract = {As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.}, } @article {pmid38515787, year = {2024}, author = {Wang, L and Fang, X and Ling, B and Wang, F and Xia, Y and Zhang, W and Zhong, T and Wang, X}, title = {Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1359453}, pmid = {38515787}, issn = {1662-5102}, abstract = {Globally, millions of individuals are impacted by neurodegenerative disorders including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Although a great deal of energy and financial resources have been invested in disease-related research, breakthroughs in therapeutic approaches remain elusive. The breakdown of cells usually happens together with the onset of neurodegenerative diseases. However, the mechanism that triggers neuronal loss is unknown. Lipid peroxidation, which is iron-dependent, causes a specific type of cell death called ferroptosis, and there is evidence its involvement in the pathogenic cascade of neurodegenerative diseases. However, the specific mechanisms are still not well known. The present article highlights the basic processes that underlie ferroptosis and the corresponding signaling networks. Furthermore, it provides an overview and discussion of current research on the role of ferroptosis across a variety of neurodegenerative conditions.}, } @article {pmid38516735, year = {2024}, author = {Li, X and Bedlack, R}, title = {Evaluating emerging drugs in phase II & III for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {29}, number = {2}, pages = {93-102}, doi = {10.1080/14728214.2024.2333420}, pmid = {38516735}, issn = {1744-7623}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; *Drug Development ; *Drugs, Investigational/pharmacology ; Animals ; *Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Drug Design ; Molecular Targeted Therapy ; Research Design ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis is a rapidly progressive motor neuron disorder causing severe disability and premature death. Owing to the advances in uncovering ALS pathophysiology, efficient clinical trial design and research advocacy program, several disease-modifying drugs have been approved for treating ALS. Despite this progress, ALS remains a rapidly disabling and life shortening condition. There is a critical need for more effective therapies.

AREAS COVERED: Here, we reviewed the emerging ALS therapeutics undergoing phase II & III clinical trials. To identify the investigational drugs, we searched ALS and phase II/III trials that are active and recruiting or not yet recruiting on clinicaltrials.gov and Pharmaprojects database.

EXPERT OPINION: The current pipeline is larger and more diverse than ever, with drugs targeting potential genetic and retroviral causes of ALS and drugs targeting a wide array of downstream pathways, including RNA metabolism, protein aggregation, integrated stress response and neuroinflammation.We remain most excited about those that target direct causes of ALS, e.g. antisense oligonucleotides targeting causative genes. Drugs that eliminate abnormal protein aggregates are also up-and-coming. Eventually, because of the heterogeneity of ALS pathophysiology, biomarkers that determine which biological events are most important for an individual ALS patient are needed.}, } @article {pmid38524401, year = {2024}, author = {Pota, V and Sansone, P and De Sarno, S and Aurilio, C and Coppolino, F and Barbarisi, M and Barbato, F and Fiore, M and Cosenza, G and Passavanti, MB and Pace, MC}, title = {Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.}, journal = {Behavioural neurology}, volume = {2024}, number = {}, pages = {1228194}, pmid = {38524401}, issn = {1875-8584}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Pain Measurement ; Quality of Life ; *Neurodegenerative Diseases/complications ; Pain/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.}, } @article {pmid38526287, year = {2024}, author = {Chen, W and Jiang, S and Li, S and Li, C and Xu, R}, title = {OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {11}, pages = {2513-2521}, pmid = {38526287}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202419110-00031/figure1/v/2024-03-08T184507Z/r/image-tiff Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.}, } @article {pmid38531340, year = {2024}, author = {Lee, KH and Kim, MH and Kim, J and Nam, HJ}, title = {Acupuncture for Tinnitus: A Scoping Review of Clinical Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {292-301}, pmid = {38531340}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Tinnitus/therapy ; Randomized Controlled Trials as Topic ; Acupuncture Points ; }, abstract = {BACKGROUND: Acupuncture treatment for tinnitus has received attention owing to its potential as an alternative to conventional treatment modalities. We conducted a scoping review to identify detailed information on acupuncture treatment methods used in clinical studies and to provide useful information for practitioners, patients, and researchers.

METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA), and the China National Knowledge Infrastructure (CNKI) were searched from their inception to December 2023. This review included single-arm trials, open-label randomized controlled trials (RCTs), and double-blind RCTs using needle-type acupuncture to treat tinnitus in English, Chinese, and Korean. We investigated basic and detailed information on the acupuncture treatment methods, assessment methods, and study outcomes. Network analysis was also conducted to evaluate the centrality between acupoints in the double-blind RCTs.

RESULTS: We included 106 articles. There were 11 single-arm trials, 90 open-label RCTs, and 5 double-blind RCTs. Most (89.6%) of these studies were conducted in China. Manual acupuncture was the most common type of acupuncture in treatment group. A total of 119 acupuncture points were used 1,138 times. The most frequently used acupoints were local points around the ear (TE17, GB2, SI19, and TE21). Both local and distant acupoints were used simultaneously in these studies. The treatment duration of 20-39 days, 10 to 19 sessions of treatment, the mean acupuncture duration of 30 min, needle diameter of 0.30 mm × 40 mm, and needling depth over 30 mm and less than 50 mm were confirmed as the most common.

CONCLUSION: These study outcomes will enable future acupuncture studies on tinnitus to perform more effective and standardized acupuncture treatments in selecting acupoints and procedures. Furthermore, the study has implications for informing clinicians and students about more impactful acupuncture strategies for addressing tinnitus.

UNLABELLED: HintergrundDie Anwendung von Akupunktur bei Tinnitus erhält seit einiger Zeit Aufmerksamkeit als potenzielle Alternative zu konventionellen Behandlungsmodalitäten. Wir führten einen Scoping-Review durch, um detaillierte Informationen zu den in klinischen Studien angewandten Akupunktur-Behandlungsmethoden zu sammeln und nützliche Informationen für Praktiker, Patienten und Forscher bereitzustellen.MethodenMEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA) und die China National Knowledge Infrastructure (CNKI) wurden von ihrem jeweiligen Beginn bis Dezember 2023 durchsucht. In diese Übersichtsarbeit wurden einarmige Studien, offene, randomisierte, kontrollierte Studien (RCTs) sowie doppelt verblindete RCTs zu Nadel-Akupunktur zur Behandlung von Tinnitus in englischer, chinesischer und koreanischer Sprache einbezogen. Wir untersuchten grundlegende und detaillierte Informationen zu den Akupunktur-Behandlungsmethoden, Untersuchungsmethoden und Studienergebnissen. Außerdem wurden Netzwerkanalysen zur Beurteilung der Zentralität zwischen Akupunkten in den doppelt verblindeten RCTs durchgeführt.Ergebnisse106 Artikel wurden eingeschlossen. Sie behandelten 11 einarmige Studien, 90 offene RCTs und 5 doppelt verblindete RCTs. Die meisten (89,6%) dieser Studien waren in China durchgeführt worden. Manuelle Akupunktur war die häufigste Form der Akupunktur in den Behandlungsgruppen. 119 Akupunkturpunkte wurden insgesamt 1’138 Mal verwendet. Die am häufigsten verwendeten Akupunkte waren lokale Punkte im Bereich des Ohrs (TE17, GB2, SI19 und TE21). Jedoch wurden in den Studien lokale und entfernte Akupunkte gleichzeitig angewendet. Außerdem wurde festgestellt, dass die Behandlungsdauer am häufigsten 20 bis 39 Tage betrug, die Zahl der Sitzungen 10 bis 19, die mittlere Akupunkturdauer 30 Minuten, die Nadelgröße 0.30 mm × 40 mm und die Einstichtiefe zwischen 30 mm und weniger als 50 mm.SchlussfolgerungDiese Studienergebnisse bieten eine Grundlage für künftige Studien zu Akupunktur bei Tinnitus, um durch die Auswahl der Akupunkte und Verfahren wirksamere und standardisierte Akupunkturbehandlungen durchzuführen. Darüber hinaus hat die Studie Implikationen für die Aufklärung von Praktikern und Schülern über wirkungsvollere Akupunkturstrategien zur Behandlung von Tinnitus.}, } @article {pmid38533300, year = {2024}, author = {Moskvin, SV}, title = {A brief literature review of low-level laser therapy for treating amyotrophic lateral sclerosis and confirmation of its effectiveness.}, journal = {BioMedicine}, volume = {14}, number = {1}, pages = {1-9}, pmid = {38533300}, issn = {2211-8020}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a steadily progressive course due to the death of central and peripheral motor neurons responsible for voluntary movements. Low-level laser therapy (LLLT) is a treatment method unique in its universality and efficacy, particularly for neurodegenerative diseases.

METHODS: In this review, we discuss the effect and application of LLLT in the treatment of ALS. A literature search for English and Russian publications for the keywords "Amyotrophic Lateral Sclerosis", "Low-Level Laser Therapy" was performed using PubMed, Scopus, Google Scholar, Web of Science and Russian Science Citation Index (RSCI) databases.

RESULTS: The article provided a brief literature review, substantiated the potential use of low-level laser therapy for ALS. The particular techniques of LLLT were developed.

CONCLUSION: Based on the results of several studies and many years of successful experience with low-level laser therapy in Russia we conclude that a LLLT technique, including intravenous laser blood illumination (ILBI), noninvasive laser blood illumination (NLBI), and local exposure, is a promising treatment method for ALS.}, } @article {pmid38533934, year = {2024}, author = {Deutsch, AJ}, title = {PICking out progressive PIC alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {131}, number = {5}, pages = {822-824}, pmid = {38533934}, issn = {1522-1598}, support = {NS091836//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS131816/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; AG067758//HHS | NIH | National Institute on Aging (NIA)/ ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS131816//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/physiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron death. Alterations to motoneuron excitability in ALS are suspected to contribute to motoneuron degeneration. Therefore, mechanisms underlying changes in motoneuron excitability are being thoroughly investigated. A recent publication from Trajano et al. (Trajano GS, Orssatto LB, McCombe PA, Rivlin W, Tang L, Henderson RD. J Physiol 601: 4723-4735, 2023) examined temporal changes to persistent inward currents (PICs) in ALS patients. They show that delta frequency (ΔF, an estimate of PICs) has opposite temporal trends in stronger and weaker muscles of ALS patients. This study is very important to aid in the understanding of disease mechanisms. This Neuro Forum article explores some important considerations for interpreting the results of this study, including treatment effects, potential sex differences, and a lack of comparison to healthy individuals.}, } @article {pmid38538275, year = {2024}, author = {Ceccarelli, L and Verriello, L and Pauletto, G and Valente, M and Spadea, L and Salati, C and Zeppieri, M and Ius, T}, title = {The Role of Human Pluripotent Stem Cells in Amyotrophic Lateral Sclerosis: From Biological Mechanism to Practical Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {3}, pages = {114}, doi = {10.31083/j.fbl2903114}, pmid = {38538275}, issn = {2768-6698}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism ; *Pluripotent Stem Cells/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3-5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.}, } @article {pmid38542223, year = {2024}, author = {Salvatori, I and Nesci, V and Spalloni, A and Marabitti, V and Muzzi, M and Zenuni, H and Scaricamazza, S and Rosina, M and Fenili, G and Goglia, M and Boffa, L and Massa, R and Moreno, S and Mercuri, NB and Nazio, F and Longone, P and Ferri, A and Valle, C}, title = {Trimetazidine Improves Mitochondrial Dysfunction in SOD1[G93A] Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542223}, issn = {1422-0067}, support = {CNR IFT DBA.AD005.225 -NUTRAGE- FOE2021//National Research Council/ ; RF-2019-12369105//Ministero della Salute/ ; HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 'Unraveling the protective effects of NOS1AP in the rescue of TDP-43 loss of function pathological mechanisms//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Ref. 27019//Italian Association for Cancer Research/ ; Prot. GeCoWEB n. A0375-2020- 36668//Regione Lazio/ ; The Grant of Excellence Departments 2023-2027//Ministero dell'Università e Ricerca Italy/ ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Trimetazidine/pharmacology/therapeutic use ; Mice, Transgenic ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase/metabolism ; Autophagy ; *Mitochondrial Diseases ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1[G93A]-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1[G93A], with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.}, } @article {pmid38542497, year = {2024}, author = {Nemeth, C and Banik, NL and Haque, A}, title = {Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542497}, issn = {1422-0067}, support = {R21 NS118393/NS/NINDS NIH HHS/United States ; I01 BX001262/BX/BLRD VA/United States ; 1R21NS118393-01/NH/NIH HHS/United States ; I01 BX004269/BX/BLRD VA/United States ; I01 BX006101/BX/BLRD VA/United States ; IK6 BX005964/BX/BLRD VA/United States ; }, mesh = {Humans ; Neuromuscular Junction/metabolism ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/metabolism ; Spinal Cord/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Spinal Cord Injuries/metabolism ; }, abstract = {The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.}, } @article {pmid38551974, year = {2024}, author = {Jiménez-García, AM and Bonnel, G and Álvarez-Mota, A and Arias, N}, title = {Current perspectives on neuromodulation in ALS patients: A systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0300671}, pmid = {38551974}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Quality of Life ; *Neurodegenerative Diseases ; Exercise Therapy/methods ; Muscle Spasticity ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, paralysis, and eventually patient mortality. In recent years, neuromodulation techniques have emerged as promising potential therapeutic approaches to slow disease progression and improve the quality of life of ALS patients. A systematic review was conducted until August 8, 2023, to evaluate the neuromodulation methods used and their potential in the treatment of ALS. The search strategy was applied in the Cochrane Central database, incorporating results from other databases such as PubMed, Embase, CTgov, CINAHL, and ICTRP. Following the exclusion of papers that did not fulfil the inclusion criteria, a total of 2090 records were found, leaving a total of 10 studies. R software was used to conduct meta-analyses based on the effect sizes between the experimental and control groups. This revealed differences in muscle stretch measures with manual muscle testing (p = 0.012) and resting motor threshold (p = 0.0457), but not with voluntary isometric contraction (p = 0.1883). The functionality of ALS was also different (p = 0.007), but not the quality of life. Although intracortical facilitation was not seen in motor cortex 1 (M1) (p = 0.1338), short-interval intracortical inhibition of M1 was significant (p = 0.0001). BDNF showed no differences that were statistically significant (p = 0.2297). Neuromodulation-based treatments are proposed as a promising therapeutic approach for ALS that can produce effects on muscle function, spasticity, and intracortical connections through electrical, magnetic, and photonic stimulation. Photobiomodulation stands out as an innovative approach that uses specific wavelengths to influence mitochondria, with the aim of improving mitochondrial function and reducing excitotoxicity. The lack of reliable placebo controls and the variation in stimulation frequency are some of the drawbacks of neuromodulation.}, } @article {pmid38559706, year = {2024}, author = {Bhor, S and Tonny, SH and Dinesh, S and Sharma, S}, title = {Computational screening of damaging nsSNPs in human SOD1 genes associated with amyotrophic lateral sclerosis identifies destabilising effects of G38R and G42D mutations through in silico evaluation.}, journal = {In silico pharmacology}, volume = {12}, number = {1}, pages = {20}, pmid = {38559706}, issn = {2193-9616}, abstract = {Amyotrophic lateral sclerosis (ALS), a complicated neurodegenerative disorder affected by hereditary and environmental variables, is a condition. In this study, the genetic makeup of ALS is investigated, with a focus on the SOD1 gene's single-nucleotide polymorphisms (SNPs) and their ability to affect disease risk. Eleven high-risk missense variations that may impair the functionality of the SOD1 protein were discovered after a thorough examination of SNPs in the SOD1 gene. These mutations were chosen using a variety of prediction approaches, highlighting their importance in the aetiology of ALS. Notably, it was discovered that the stability of the SOD1 wild-type protein structure was compromised by the G38R and G42D SOD1 variants. Additionally, Edaravone, a possible ALS medication, showed a greater affinity for binding mutant SOD1 structures, pointing to potential personalised treatment possibilities. The high-risk SNPs discovered in this investigation seem to have functional effects, especially on the stability of proteins and their interactions with other molecules. This study clarifies the complex genetics of ALS and offers insights into how these genetic variations may affect the effectiveness of therapeutic interventions, particularly in the context of edaravone. In this study advances our knowledge of the genetic mechanisms causing ALS vulnerability and prospective therapeutic strategies. Future studies are necessary to confirm these results and close the gap between individualised clinical applications and improved ALS care.}, } @article {pmid38560897, year = {2024}, author = {Minatoguchi, S and Fujita, Y and Niizuma, K and Tominaga, T and Yamashita, T and Abe, K and Dezawa, M}, title = {Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.}, journal = {Stem cells translational medicine}, volume = {13}, number = {6}, pages = {532-545}, pmid = {38560897}, issn = {2157-6580}, support = {//New Energy and Industrial Technology Development Organization/ ; //Japan Agency for Medical Research and Development/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; //Japan Society for the Promotion of Science/ ; //SENSHIN Medical Research Foundation/ ; //Life Science Institute Inc/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Mesenchymal Stem Cell Transplantation/methods ; Immunosuppressive Agents/pharmacology/therapeutic use ; HLA Antigens/metabolism ; Cell Differentiation ; Animals ; Histocompatibility Testing/methods ; }, abstract = {The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.}, } @article {pmid38560980, year = {2024}, author = {Xiang, SR and Ma, Q and Dong, J and Ren, YF and Lin, JZ and Zheng, C and Xiao, P and You, FM}, title = {Contrasting Effects of Music Therapy and Aromatherapy on Perioperative Anxiety: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {278-291}, doi = {10.1159/000538425}, pmid = {38560980}, issn = {2504-2106}, mesh = {*Aromatherapy ; *Music Therapy ; Humans ; *Anxiety/therapy ; Heart Rate ; }, abstract = {INTRODUCTION: Music therapy and aromatherapy have been demonstrated effective for perioperative anxiety. However, the available studies have indicated discordant results about which adjunct treatment is better for perioperative anxiety. Therefore, we conducted this meta-analysis to explore the contrasting effects between them.

METHODS: Six electronic databases were searched for clinical trials evaluating the efficacy of music therapy compared with aromatherapy in alleviating perioperative anxiety. The primary outcome was the postintervention anxiety level. Secondary outcomes included differences in blood pressure and heart rate before and after the intervention as well as pain scores at intraoperative and postoperative time points. The study protocol was registered on PROSPERO (CRD42021249737).

RESULTS: Twelve studies (894 patients) were included. The anxiety level showed no statistically significant difference (SMD, 0.28; 95% CI: -0.12, 0.68; p = 0.17). The analysis of blood pressure and heart rate also did not identify statistically significant differences. Notably, the pain scores at the intraoperative time point suggested that aromatherapy was superior to music therapy (WMD, 0.29 cm; 95% CI: 0.05, 0.52; p = 0.02), while those at 4 h after surgery indicated the opposite results (WMD, -0.48 cm; 95% CI: -0.60, -0.36; p < 0.001).

CONCLUSION: Low-to-moderate quality evidence suggests that music therapy and aromatherapy have similar potential to relieve perioperative anxiety. The potential data indicate that the two therapies have different benefits in intervention duration and age distribution. More direct high-quality comparisons are encouraged in the future to verify this point.

UNLABELLED: EinleitungMusik- und Aromatherapie haben sich bei perioperativen Angstzuständen als wirksam erwiesen. Die verfügbaren Studien zeigten jedoch widersprüchliche Ergebnisse zur Frage, welche adjuvante Therapie bei perioperativen Angstzuständen besser ist. Daher führten wir die vorliegende Metaanalyse durch, um die unterschiedlichen Effekte der beiden Therapien zu untersuchen.MethodenSechs (6) elektronische Datenbanken wurden nach klinischen Studien zur Wirksamkeit von Musiktherapie im Vergleich zur Aromatherapie bei der Linderung perioperativer Angstzustände durchsucht. Primäres Zielkriterium war das Angstniveau nach der Intervention. Die sekundären Zielkriterien umfassten die Unterschiede bei Blutdruck und Herzfrequenz vor und nach der Intervention sowie die Schmerz-Scores zu intra- und postoperativen Zeitpunkten. Das Studienprotokoll wurde auf PROSPERO (CRD42021249737) registriert.ErgebnisseZwölf (12) Studien (894 Patienten) wurden eingeschlossen. Das Angstniveau zeigte keinen statistisch signifikanten Unterschied (SMD, 0,28; 95%-KI: −0,12, 0,68, p = 0,17) und auch die Analyse von Blutdruck und Herzfrequenz ergab keine statistisch signifikanten Unterschiede. Insbesondere die Schmerz-Scores zum intraoperativen Zeitpunkt sprachen dafür, dass die Aromatherapie gegenüber der Musiktherapie überlegen war (WMD, 0,29 cm; 95%-KI: 0,05, 0,52; p = 0,02), während die Werte 4 Stunden nach der Operation gegenteilige Ergebnisse zeigten (WMD, −0,48 cm; 95%-KI: −0,60, −0,36, p < 0,001).SchlussfolgerungEvidenzen von geringer bis mässiger Qualität deuten darauf hin, dass Musik- und Aromatherapie ein vergleichbares Potenzial bei der Linderung perioperativer Ängste besitzen. Die potenziellen Daten zeigen, dass die beiden Therapien unterschiedliche Vorteile hinsichtlich Interventionsdauer und Altersverteilung haben. Künftig sollten mehr direkte und qualitativ hochwertige Vergleiche durchgeführt werden, um diesen Aspekt zu überprüfen.}, } @article {pmid38561605, year = {2024}, author = {Singh, K and Gupta, JK and Kumar, S and Soni, U}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides.}, journal = {Current protein & peptide science}, volume = {25}, number = {7}, pages = {507-526}, pmid = {38561605}, issn = {1875-5550}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Peptides/therapeutic use/chemistry/pharmacology ; Animals ; Alzheimer Disease/drug therapy/metabolism/pathology ; Parkinson Disease/drug therapy/metabolism/pathology ; Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Oxidative Stress/drug effects ; Huntington Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry ; }, abstract = {Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.}, } @article {pmid38563056, year = {2024}, author = {Umar, TP and Jain, N and Papageorgakopoulou, M and Shaheen, RS and Alsamhori, JF and Muzzamil, M and Kostiks, A}, title = {Artificial intelligence for screening and diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {425-436}, doi = {10.1080/21678421.2024.2334836}, pmid = {38563056}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Humans ; *Artificial Intelligence ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurological disease that leads to progressive motor function degeneration. Diagnosing ALS is challenging due to the absence of a specific detection test. The use of artificial intelligence (AI) can assist in the investigation and treatment of ALS.

METHODS: We searched seven databases for literature on the application of AI in the early diagnosis and screening of ALS in humans. The findings were summarized using random-effects summary receiver operating characteristic curve. The risk of bias (RoB) analysis was carried out using QUADAS-2 or QUADAS-C tools.

RESULTS: In the 34 analyzed studies, a meta-prevalence of 47% for ALS was noted. For ALS detection, the pooled sensitivity of AI models was 94.3% (95% CI - 63.2% to 99.4%) with a pooled specificity of 98.9% (95% CI - 92.4% to 99.9%). For ALS classification, the pooled sensitivity of AI models was 90.9% (95% CI - 86.5% to 93.9%) with a pooled specificity of 92.3% (95% CI - 84.8% to 96.3%). Based on type of input for classification, the pooled sensitivity of AI models for gait, electromyography, and magnetic resonance signals was 91.2%, 92.6%, and 82.2%, respectively. The pooled specificity for gait, electromyography, and magnetic resonance signals was 94.1%, 96.5%, and 77.3%, respectively.

CONCLUSIONS: Although AI can play a significant role in the screening and diagnosis of ALS due to its high sensitivities and specificities, concerns remain regarding quality of evidence reported in the literature.}, } @article {pmid38563162, year = {2024}, author = {Pastora, LE and Namburu, NS and Arora, K and Christov, PP and Wilson, JT}, title = {STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases.}, journal = {ACS applied bio materials}, volume = {7}, number = {8}, pages = {4867-4878}, pmid = {38563162}, issn = {2576-6422}, support = {T32 DK101003/DK/NIDDK NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; }, mesh = {*Membrane Proteins/metabolism/antagonists & inhibitors ; *Nanoparticles/chemistry ; Animals ; Mice ; Inflammation/drug therapy ; Humans ; Biocompatible Materials/chemistry/pharmacology ; Particle Size ; Materials Testing ; Nucleotidyltransferases/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; STING Protein ; }, abstract = {Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151-as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.}, } @article {pmid38564446, year = {2024}, author = {Kinnear, EE and Beales, D and Paton, A and Challice, S}, title = {Making a difference: neurological support in the community.}, journal = {British journal of community nursing}, volume = {29}, number = {4}, pages = {190-194}, doi = {10.12968/bjcn.2024.29.4.190}, pmid = {38564446}, issn = {1462-4753}, mesh = {Humans ; Quality of Life ; *Nervous System Diseases/therapy ; *Parkinson Disease/therapy ; *Multiple Sclerosis/therapy ; *Stroke ; }, abstract = {Nearly 3 million people in the UK have a neurological condition; stroke, traumatic brain injury, Parkinson's disease, multiple sclerosis, brain tumour, motor neurone disease, among others - all affecting the person for the rest of their life. The NHS provides treatment at the onset of a condition but after that, there is a huge need for ongoing support. Research shows that those who are supported and know more about their condition are less likely to have to call on further in-hospital and GP care. There is enormous scope for improving the quality of life for those with neurological conditions. The right support-therapeutic and social-makes all the difference. The book, which this article is based on, shows how those with neurological conditions benefit from integrated ongoing support provided in the local community and self-help, and how lives can be improved. It explains good practice and encouraging methods in the support and treatment of those with life changing conditions.}, } @article {pmid38565200, year = {2024}, author = {Stierwalt, J and Stierwalt, JAG and Clark, H and Burda, A and Benavidez Kiley, H and Collins, E and Kortemeyer, M and Miller, E and Peckenschneider, G and Schieltz, E and Shah, Y and Simon, K}, title = {Factors Affecting Performance on a Screening Tool in Persons with Amyotrophic Lateral Sclerosis.}, journal = {Seminars in speech and language}, volume = {45}, number = {3}, pages = {228-241}, doi = {10.1055/s-0044-1785447}, pmid = {38565200}, issn = {1098-9056}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Frontotemporal Dementia/diagnosis/psychology ; Adult ; Aged, 80 and over ; }, abstract = {Persons with amyotrophic lateral sclerosis (PALS) are at risk of developing cognitive impairments and frontotemporal dementia (FTD). This study examined the relationship between performance of the ALS-Cognitive Behavioral Screen (ALS-CBS) and the demographic parameters of sex, education, time post-ALS diagnosis, and severity of symptoms. Data were collected retrospectively from 69 participants seen at the Mayo Clinic. Correlations were conducted on the ALS-CBS total scores and subsection scores and the above listed parameters; t-tests were conducted between participant subgroups. No statistically significant relationships or differences occurred between the ALS-CBS or its subsections and the variables measured with exception of age and the attention subsection. Older participants had lower ALS-CBS attention subsection scores. Based on the ALS-CBS scores, most participants had some degree of cognitive impairments: 43 had suspected cognitive impairment, 8 had suspected FTD; 18 fell within the normal range of cognitive function. Overall, the variables of sex, education, time post-diagnosis, and severity of symptoms do not appear to influence ALS-CBS scores. It is recommended cognitive screenings be completed for all PALS due to the high risk for developing cognitive impairments and FTD. Such knowledge can help clinicians develop assessment and treatment plans.}, } @article {pmid38567799, year = {2024}, author = {Wang, XJ and Cornell, PY and Belanger, E and Thomas, KS}, title = {Do end-of-life outcomes differ by assisted living memory-care designation?.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {8}, pages = {2491-2499}, pmid = {38567799}, issn = {1532-5415}, support = {R01 AG057746/AG/NIA NIH HHS/United States ; R01 AG066902/AG/NIA NIH HHS/United States ; R01AG066902/AG/NIA NIH HHS/United States ; R01AG057746/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Assisted Living Facilities/statistics & numerical data ; Aged, 80 and over ; United States ; *Terminal Care/statistics & numerical data ; Aged ; *Medicare/statistics & numerical data ; Prospective Studies ; *Hospice Care/statistics & numerical data ; Alzheimer Disease/mortality/therapy ; Dementia/mortality/therapy ; }, abstract = {BACKGROUND: Residential care/assisted living (RC/AL) is an increasingly common place of end-of-life care for persons with Alzheimer's disease and related dementia (ADRD), who have unique care needs as their health declines. Approximately 22% of RC/ALs provide specialized memory care (memory-care RC/AL). Understanding how end-of-life outcomes differ by memory care among residents with ADRD could facilitate aging/dying in place for this population. The objective of this paper is to examine if end-of-life outcomes (i.e., mortality, hospice use, and number of days receiving hospice in the last month of life) differ between residents with ADRD who moved to memory-care RC/AL, compared with residents with ADRD who moved to RC/AL without memory care (general RC/AL).

METHODS: Prospective cohort of 15,152 fee-for-service Medicare beneficiaries with ADRD who moved to large RC/AL (> = 25 beds) between 2016 and 2018. We used inverse probability treatment weighting to account for observable differences between memory-care and general RC/AL residents. Two-part models estimated the difference by memory care in the number of days receiving hospice care in the last months of life among RC/AL decedents.

RESULTS: The unadjusted mortality rates were 13.4% in general RC/AL and 15.8% in memory-care RC/AL with an adjusted difference of 1.3 percentage points higher mortality among memory-care RC/AL residents (p = 0.04). Hospice use was 8% and 10.6% among general and memory-care RC/AL residents, respectively, with an adjusted difference of 1.4 percentage points (p = 0.01) higher in memory care. Two-part models showed that decedents in memory-care RC/AL spent about 1.4 more days receiving hospice care in the last month of life (p = 0.02).

CONCLUSION: We find a higher mortality rate and higher rate of hospice use among memory-care RC/AL residents. These findings suggest that memory care may attract residents closer to the end of life and/or promote hospice use at the end of life.}, } @article {pmid38568044, year = {2024}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Grassano, M and Daviddi, M and De Mattei, F and Matteoni, E and Gallone, S and Brunetti, M and Sbaiz, L and Cabras, S and Peotta, L and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A}, title = {High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {150-158}, doi = {10.1002/ana.26928}, pmid = {38568044}, issn = {1531-8249}, support = {RF-2016-02362405//Ministero della Salute/ ; 101017598//HORIZON EUROPE Health/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 259867//FP7 Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Aged ; Middle Aged ; *Cognitive Dysfunction/genetics/psychology ; Adult ; }, abstract = {OBJECTIVE: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls.

METHODS: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included.

RESULTS: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse.

INTERPRETATION: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.}, } @article {pmid38570095, year = {2024}, author = {Wiblin, L}, title = {An introduction to neuropalliative care: A growing need.}, journal = {Clinical medicine (London, England)}, volume = {24}, number = {2}, pages = {100038}, pmid = {38570095}, issn = {1473-4893}, mesh = {Humans ; *Palliative Care/methods ; *Quality of Life ; Motor Neuron Disease/therapy/psychology ; }, abstract = {Palliative care (PC) defined as 'an approach improving the quality of life of patients and their families facing problems associated with life-limiting illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual' aims to enhance the improve the remaining time that patients have, emphasising choice for patients and families.[1] Patients with neurological disease such as Parkinson's (PD) and motor neurone disease (MND) benefit from PC earlier in disease with increasing emphasis over time. Understanding and communicating uncertain trajectories, honest prognostic communication when patients are ready and careful symptom control has been shown to enhance quality of life in patients and caregivers, giving greater autonomy to these patients when supported in decision-making by a palliative approach. Although obstacles to palliative care are frequent, there are strategies which can help overcome them.}, } @article {pmid38582030, year = {2024}, author = {van Unnik, JWJ and Meyjes, M and Janse van Mantgem, MR and van den Berg, LH and van Eijk, RPA}, title = {Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study.}, journal = {EBioMedicine}, volume = {103}, number = {}, pages = {105104}, pmid = {38582030}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; *Disease Progression ; *Wearable Electronic Devices ; Middle Aged ; Prospective Studies ; Aged ; Accelerometry/instrumentation ; Prognosis ; Remote Sensing Technology/instrumentation/methods ; Adult ; }, abstract = {BACKGROUND: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS.

METHODS: Patients with ALS wore an accelerometer on the hip for 3-7 days, every 2-3 months during a multi-year observation period. An accelerometer-derived outcome, the Vertical Movement Index (VMI), was calculated, together with predicted disease progression rates, and jointly analysed with overall survival. The clinical utility of VMI was evaluated using comparisons to patient-reported functionality, while the impact of various monitoring schemes on empirical power was explored through simulations.

FINDINGS: In total, 97 patients (70.1% male) wore the accelerometer for 1995 days, for a total of 27,701 h. The VMI was highly discriminatory for predicted disease progression rates, revealing faster rates of decline in patients with a worse predicted prognosis compared to those with a better predicted prognosis (p < 0.0001). The VMI was strongly associated with the hazard for death (HR 0.20, 95% CI: 0.09-0.44, p < 0.0001), where a decrease of 0.19-0.41 unit was associated with reduced ambulatory status. Recommendations for future studies using accelerometery are provided.

INTERPRETATION: The results serve as motivation to incorporate accelerometer-derived outcomes in clinical trials, which is essential for further validation of these markers to meaningful endpoints.

FUNDING: Stichting ALS Nederland (TRICALS-Reactive-II).}, } @article {pmid38585517, year = {2023}, author = {Firstenfeld, AJ and Listorti, J and Jalaff, N and Loaiza Orozco, CP and Navarrete Gosdenovich, F and Schurr, T}, title = {Add-on treatment with Cerebrolysin improves clinical symptoms in patients with ALS: results from a prospective, single-center, placebo-controlled, randomized, double-blind, phase II study.}, journal = {Journal of medicine and life}, volume = {16}, number = {12}, pages = {1750-1755}, pmid = {38585517}, issn = {1844-3117}, mesh = {Humans ; *Amino Acids ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; *Neuroprotective Agents/therapeutic use ; Prospective Studies ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and progressive neurodegenerative disease with limited treatment options available. Cerebrolysin is a drug candidate for the treatment of ALS because of its neuroprotective and neuroregenerative effects. We initiated a pilot clinical study of a combination of Cerebrolysin and riluzole to assess the therapeutic benefit of Cerebrolysin as an add-on treatment on clinical signs and symptoms in outpatients with ALS. Twenty patients with a clinically definitive diagnosis of ALS were enrolled and randomly assigned in a 1:1 ratio to receive Cerebrolysin or placebo. All patients received 50 mg of riluzole PO twice daily as a standard treatment. Patients in the Cerebrolysin group received intravenous injections of 10 mL of Cerebrolysin once daily, five days a week for the first month and three days a week for the next two months. Analysis of the ALS Functional Rating Scale - revised at Month 1 (primary outcome measure), showed a significant treatment effect in favor of Cerebrolysin with a 2.3-point improvement from baseline to Month 1 compared to a 0.9-point decrease in patients on placebo (P=0.005). The effect was maintained over the three-month study period, and the beneficial effect of Cerebrolysin over placebo was also evident in the secondary outcome measures. The safety analysis showed that the combination of riluzole and Cerebrolyisn was well tolerated. Our results demonstrate for the first time a significant clinical effect of Cerebrolysin in improving functional outcomes in patients with ALS and suggest that Cerebrolysin has potential as a novel therapeutic option for ALS.}, } @article {pmid38585774, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585774}, issn = {2692-8205}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, } @article {pmid38593477, year = {2024}, author = {Lindborg, SR and Goyal, NA and Katz, J and Burford, M and Li, J and Kaspi, H and Abramov, N and Boulanger, B and Berry, JD and Nicholson, K and Mozaffar, T and Miller, R and Jenkins, L and Baloh, RH and Lewis, R and Staff, NP and Owegi, MA and Dagher, B and Blondheim-Shraga, NR and Gothelf, Y and Levy, YS and Kern, R and Aricha, R and Windebank, AJ and Bowser, R and Brown, RH and Cudkowicz, ME}, title = {Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.}, journal = {Muscle & nerve}, volume = {69}, number = {6}, pages = {719-729}, doi = {10.1002/mus.28093}, pmid = {38593477}, issn = {1097-4598}, support = {//California Institute for Regenerative Medicine/ ; //I AM ALS/ ; //ALS Association/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Biomarkers/cerebrospinal fluid ; Double-Blind Method ; *Neurofilament Proteins/cerebrospinal fluid ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint.

METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R.

RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFβ1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037).

DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.}, } @article {pmid38596406, year = {2024}, author = {Tanaka, Y and Kozuma, L and Hino, H and Takeya, K and Eto, M}, title = {Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.}, journal = {Biochemistry and biophysics reports}, volume = {38}, number = {}, pages = {101705}, pmid = {38596406}, issn = {2405-5808}, abstract = {(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.}, } @article {pmid38596495, year = {2024}, author = {Dirjayanto, VJ and Audrey, J and Simadibrata, DM}, title = {Vonoprazan-amoxicillin dual regimen with Saccharomyces boulardii as a rescue therapy for Helicobacter pylori: Current perspectives and implications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {10}, pages = {1280-1286}, pmid = {38596495}, issn = {2219-2840}, mesh = {Humans ; Amoxicillin/therapeutic use ; Anti-Bacterial Agents/adverse effects ; *Helicobacter pylori ; *Saccharomyces boulardii ; *Helicobacter Infections/drug therapy ; Clarithromycin/therapeutic use ; Drug Therapy, Combination ; Proton Pump Inhibitors/adverse effects ; H(+)-K(+)-Exchanging ATPase ; Ions/pharmacology/therapeutic use ; Treatment Outcome ; *Pyrroles ; *Sulfonamides ; }, abstract = {Yu et al's study in the World Journal of Gastroenterology (2023) introduced a novel regimen of Vonoprazan-amoxicillin dual therapy combined with Saccharomyces boulardii (S. boulardii) for the rescue therapy against Helicobacter pylori (H. pylori), a pathogen responsible for peptic ulcers and gastric cancer. Vonoprazan is a potassium-competitive acid blocker renowned for its rapid and long-lasting acid suppression, which is minimally affected by mealtime. Compared to proton pump inhibitors, which bind irreversibly to cysteine residues in the H[+]/K[+]-ATPase pump, Vonoprazan competes with the K[+] ions, prevents the ions from binding to the pump and blocks acid secretion. Concerns with increasing antibiotic resistance, effects on the gut microbiota, patient compliance, and side effects have led to the advent of a dual regimen for H. pylori. Previous studies suggested that S. boulardii plays a role in stabilizing the gut barrier which improves H. pylori eradication rate. With an acceptable safety profile, the dual-adjunct regimen was effective regardless of prior treatment failure and antibiotic resistance profile, thereby strengthening the applicability in clinical settings. Nonetheless, S. boulardii comes in various formulations and dosages, warranting further exploration into the optimal dosage for supplementation in rescue therapy. Additionally, larger, randomized, double-blinded controlled trials are warranted to confirm these promising results.}, } @article {pmid38600555, year = {2024}, author = {Liu, Y and Yan, D and Yang, L and Chen, X and Hu, C and Chen, M}, title = {Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {20}, pmid = {38600555}, issn = {2047-9158}, support = {2023A1515010477//Guangdong Basic and Applied Basic Research Foundation/ ; 32000690//National Natural Science Foundation of China/ ; 2019B030335001//The Key-Area Research and Development Program of Guangdong Province,China/ ; 2023-Z04-103//The Key Medical and Health Projects of Panyu District Science and Technology Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; DNA-Binding Proteins/genetics ; *Stathmin/antagonists & inhibitors ; *TDP-43 Proteinopathies/drug therapy ; }, } @article {pmid38600725, year = {2024}, author = {Madhubala, D and Patra, A and Khan, MR and Mukherjee, AK}, title = {Phytomedicine for neurodegenerative diseases: The road ahead.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {6}, pages = {2993-3019}, doi = {10.1002/ptr.8192}, pmid = {38600725}, issn = {1099-1573}, support = {//IASST/ ; EMR/2017/001829//Science and Engineering Research Board/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Catechin/analogs & derivatives/therapeutic use/pharmacology ; *Phytotherapy ; Curcumin/therapeutic use/pharmacology ; Quercetin/pharmacology/therapeutic use ; Animals ; Cannabinoids/therapeutic use/pharmacology ; Apigenin/pharmacology/therapeutic use ; Blood-Brain Barrier/drug effects ; Phytochemicals/pharmacology/therapeutic use ; Plant Extracts/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.}, } @article {pmid38601118, year = {2024}, author = {Patel, GD and Liu, L and Li, A and Yang, YH and Shen, CC and Brand-Saberi, B and Yang, X}, title = {Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1361723}, pmid = {38601118}, issn = {2296-858X}, abstract = {BACKGROUND: Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above.

METHODS: PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review.

RESULTS: In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient.

CONCLUSION: Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.}, } @article {pmid38603949, year = {2024}, author = {Shin-Yi Lin, C and Howells, J and Rutkove, S and Nandedkar, S and Neuwirth, C and Noto, YI and Shahrizaila, N and Whittaker, RG and Bostock, H and Burke, D and Tankisi, H}, title = {Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {162}, number = {}, pages = {91-120}, doi = {10.1016/j.clinph.2024.03.015}, pmid = {38603949}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Motor Neurons/physiology ; *Motor Neuron Disease/physiopathology/diagnostic imaging/diagnosis ; *Biomarkers ; *Electromyography/methods ; *Neural Conduction/physiology ; }, abstract = {This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.}, } @article {pmid38606777, year = {2024}, author = {Babu, S and Nicholson, KA and Rothstein, JD and Swenson, A and Sampognaro, PJ and Pant, P and Macklin, EA and Spruill, S and Paganoni, S and Gendron, TF and Prudencio, M and Petrucelli, L and Nix, D and Landrette, S and Nkrumah, E and Fandrick, K and Edwards, J and Young, PR}, title = {Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {9}, pages = {2998-3008}, doi = {10.1093/brain/awae109}, pmid = {38606777}, issn = {1460-2156}, support = {//OrphAI Therapeutics/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; Adult ; Aged ; *C9orf72 Protein/genetics ; Pyrazoles/therapeutic use/pharmacokinetics ; Treatment Outcome ; Biomarkers/blood ; Hydrazones ; Morpholines ; Pyrimidines ; }, abstract = {Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.}, } @article {pmid38609644, year = {2024}, author = {Khalil, M and Teunissen, CE and Lehmann, S and Otto, M and Piehl, F and Ziemssen, T and Bittner, S and Sormani, MP and Gattringer, T and Abu-Rumeileh, S and Thebault, S and Abdelhak, A and Green, A and Benkert, P and Kappos, L and Comabella, M and Tumani, H and Freedman, MS and Petzold, A and Blennow, K and Zetterberg, H and Leppert, D and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders - towards clinical application.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {5}, pages = {269-287}, pmid = {38609644}, issn = {1759-4766}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Intermediate Filaments/metabolism ; *Nervous System Diseases/diagnosis/metabolism/blood ; *Neurofilament Proteins/blood/metabolism ; }, abstract = {Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.}, } @article {pmid38610012, year = {2024}, author = {Liu, X and Shen, L and Wan, M and Xie, H and Wang, Z}, title = {Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {170}, pmid = {38610012}, issn = {1477-3155}, support = {82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&D Program of China/ ; }, mesh = {Humans ; Prospective Studies ; *Extracellular Vesicles ; *Exosomes ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.}, } @article {pmid38610192, year = {2024}, author = {Papadopoulou, M and Papapostolou, A and Dimakopoulos, R and Salakou, S and Koropouli, E and Fanouraki, S and Bakola, E and Moschovos, C and Tsivgoulis, G}, title = {Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {38610192}, issn = {2227-9032}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS.

AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials.

MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients.

CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.}, } @article {pmid38612804, year = {2024}, author = {Giri, PM and Banerjee, A and Ghosal, A and Layek, B}, title = {Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612804}, issn = {1422-0067}, support = {P20 GM109024/GM/NIGMS NIH HHS/United States ; 2P20M109024/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Neuroinflammatory Diseases ; Inflammation/therapy ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; }, abstract = {Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.}, } @article {pmid38614367, year = {2024}, author = {Roghani, AK and Garcia, RI and Roghani, A and Reddy, A and Khemka, S and Reddy, RP and Pattoor, V and Jacob, M and Reddy, PH and Sehar, U}, title = {Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.}, journal = {Ageing research reviews}, volume = {97}, number = {}, pages = {102291}, doi = {10.1016/j.arr.2024.102291}, pmid = {38614367}, issn = {1872-9649}, support = {R01 AG069333/AG/NIA NIH HHS/United States ; RF1 AG079264/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Delivery Systems/methods ; Animals ; *Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/administration & dosage ; Nanoparticle Drug Delivery System ; }, abstract = {The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.}, } @article {pmid38621743, year = {2024}, author = {Rezvykh, A and Shteinberg, D and Bronovitsky, E and Ustyugov, A and Funikov, S}, title = {Animal Models of FUS-Proteinopathy: A Systematic Review.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S34-S56}, doi = {10.1134/S0006297924140037}, pmid = {38621743}, issn = {1608-3040}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Mutation ; Disease Models, Animal ; }, abstract = {Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.}, } @article {pmid38623278, year = {2024}, author = {Inci, OK and Basırlı, H and Can, M and Yanbul, S and Seyrantepe, V}, title = {Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Journal of lipids}, volume = {2024}, number = {}, pages = {4530255}, pmid = {38623278}, issn = {2090-3030}, abstract = {Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.}, } @article {pmid38630299, year = {2024}, author = {Wolff, A and Demleitner, AF and Feneberg, E and Lingor, P}, title = {[Smell the smoke before one sees the fire-The oligosymptomatic prodromal phase of neurodegenerative diseases].}, journal = {Der Nervenarzt}, volume = {95}, number = {8}, pages = {689-696}, pmid = {38630299}, issn = {1433-0407}, mesh = {*Neurodegenerative Diseases/diagnosis ; *Prodromal Symptoms ; Humans ; *Early Diagnosis ; *Biomarkers/blood ; Disease Progression ; }, abstract = {BACKGROUND: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing.

OBJECTIVE: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences.

MATERIAL AND METHODS: Selective literature search, discussion of basic research and expert recommendations.

RESULTS: Many neurodegenerative diseases have a prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose.

DISCUSSION: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a neurodegenerative disease can be referred to centers for clinical trials and observational studies.}, } @article {pmid38644578, year = {2024}, author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F}, title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14721}, pmid = {38644578}, issn = {1755-5949}, support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; *Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.

AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.

METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.

RESULTS: Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).

DISCUSSION: The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).

CONCLUSION: The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.}, } @article {pmid38646691, year = {2024}, author = {Flynn, MB and Flynn, JF and Palacios, AM}, title = {Capitalizing on Hope: Questionable Marketing Approval and Pricing of a New ALS Drug.}, journal = {International journal of social determinants of health and health services}, volume = {54}, number = {4}, pages = {405-411}, doi = {10.1177/27551938241247778}, pmid = {38646691}, issn = {2755-1946}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Approval ; United States ; United States Food and Drug Administration ; Cost-Benefit Analysis ; }, abstract = {Regulatory agencies must balance patient demands to access new treatments for fatal diseases with limited treatment options while ensuring drug safety and efficacy. However, questionable U.S. regulatory actions resulted in the early approval of AMX0035 to treat amyotrophic lateral sclerosis (ALS) by reconvening advisory commissions to obtain positive decisions and designating the drug as a new molecular entity. Data from one randomized clinical trial suggests minimal delays in disease progression and longer survivability, but debate remains about the lack of confirmatory evidence of effectiveness owing to study limitations. A patient's decision-making process details the experience of using the drug, including perspectives on access, cost, effectiveness, and adverse effects. In line with the "nichebuster" business model, the drugmaker, Amylyx Pharmaceuticals, is charging US$158,000/year/patient and thus forecast to turn a profit on a drug with debatable clinical effectiveness prior to completing a Phase 3 trial. Early marketing approval, despite community demands, is unnecessary and may have reduced access because of the end of a compassionate use program, and the high price tag results in restricted coverage and high out-of-pocket costs. Also, the drug's key ingredients are available as a generic and a supplement.}, } @article {pmid38647433, year = {2024}, author = {Mousavi, H and Rimaz, M and Zeynizadeh, B}, title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {9}, pages = {1828-1881}, doi = {10.1021/acschemneuro.4c00055}, pmid = {38647433}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Molecular Docking Simulation/methods ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Heterocyclic Compounds, 2-Ring/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; }, abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.}, } @article {pmid38655443, year = {2024}, author = {Zubair, AS and Saab, L and Scharer, K and Khokhar, B}, title = {Patients' experiences with methylcobalamin injections in amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {10}, number = {1}, pages = {60-66}, pmid = {38655443}, issn = {2455-4626}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no definitive treatment. Vitamin B12 is not a Food and Drug Administration-approved treatment in the United States, although it has been prescribed off-label as ultra-high-dose methylcobalamin, which has been shown to be safe and effective in slowing functional decline in patients with ALS. This study evaluates the impact of Vitamin B12 injections on the quality of life of five patients.

METHODS: Semi-structured interviews were conducted with the patients and caregivers. The data was carefully read, coded, and organized into themes and sub-themes by two independent researchers.

RESULTS: The study found four themes and 11 subthemes from the data, including initial circumstances, administration of the injection, subjective experience with Vitamin B12, and outcomes and expectations. All participants recognized some benefits from Vitamin B12 injections, specifically increased energy, reduced fatigue, and improved balance. However, some patients had difficulty monitoring its specific effect due to the progressive nature of the disease.

DISCUSSION: The flexibility offered by this intervention is beneficial for patients with declining mobility and strength who wish to adapt their treatment to their schedule. This work is a modest call to fill the existing gap in the literature and push for more randomized controlled trials investigating and clarifying the effects of Vitamin B12 injections on disease progression, muscle function, and quality of life in a small but diverse pool of patients with ALS.}, } @article {pmid38661532, year = {2024}, author = {Li, A and Yi, J and Li, X and Dong, L and Ostrow, LW and Ma, J and Zhou, J}, title = {Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38661532}, issn = {2050-084X}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 AG071676/AG/NIA NIH HHS/United States ; R01NS105621/NH/NIH HHS/United States ; R01AG071676/NH/NIH HHS/United States ; R01NS129219/NH/NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mice ; *Satellite Cells, Skeletal Muscle/metabolism ; *Disease Models, Animal ; *Transcriptome ; Mice, Transgenic ; Oculomotor Muscles/innervation/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7[+]satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.}, } @article {pmid38662766, year = {2024}, author = {Stikvoort García, DJL and Goedee, HS and van Eijk, RPA and van Schelven, LJ and van den Berg, LH and Sleutjes, BTHM}, title = {Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {8}, pages = {2842-2853}, pmid = {38662766}, issn = {1460-2156}, support = {AV20180012//Dutch ALS Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Motor Neurons/physiology ; Adult ; Action Potentials/physiology ; Principal Component Analysis ; Axons/physiology ; Membrane Potentials/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.}, } @article {pmid38663103, year = {2024}, author = {Nozal, V and Fernández-Gómez, P and García-Rubia, A and Martínez-González, L and Cuevas, EP and Carro, E and Palomo, V and Martínez, A}, title = {Designing multitarget ligands for neurodegenerative diseases with improved permeability trough PLGA nanoencapsulation.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116626}, doi = {10.1016/j.biopha.2024.116626}, pmid = {38663103}, issn = {1950-6007}, mesh = {*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Ligands ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Permeability ; Nanoparticles/chemistry ; Drug Design ; Drug Compounding ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; }, abstract = {Multitarget ligands (MTLs) have emerged as an interesting alternative for addressing complex multifactorial pathologies such as neurodegenerative diseases. However, a common challenge associated with these compounds is often their high molecular weight and low solubility, which becomes a hurdle when trying to permeate over the blood-brain barrier (BBB). In this study, we have designed two new MTLs that modulate three pharmacological targets simultaneously (tau, beta-amyloid and TAR DNA-binding protein 43). To enhance their brain penetration, we have formulated organic polymeric nanoparticles using poly(lactic-co-glycolic acid). The characterization of the formulations, evaluation of their permeability through an in vitro BBB model, and assessment of their activity on disease-representative cellular models, such as Alzheimer's disease and amyotrophic lateral sclerosis, have been conducted. The results demonstrate the potential of the new MTLs and their nanoparticle encapsulation for the treatment of neurodegenerative diseases.}, } @article {pmid38666601, year = {2024}, author = {Officer, L and Armon, C and Barkhaus, P and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Carbunar, OM and Carter, GT and Crayle, J and Denson, K and Feldman, E and Fullam, T and Heiman-Patterson, T and Jackson, C and Jhooty, S and Levinson, D and Li, X and Linares, A and Mallon, E and Mascias Cadavid, J and Mcdermott, C and Mushannen, T and Ostrow, L and Patel, R and Pattee, G and Ratner, D and Sun, Y and Sladky, J and Wicks, P and Bedlack, R}, title = {ALSUntangled #75: Portable neuromodulation stimulator therapy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {648-652}, doi = {10.1080/21678421.2024.2346825}, pmid = {38666601}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Electric Stimulation Therapy/methods/instrumentation ; }, abstract = {Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.}, } @article {pmid38666665, year = {2024}, author = {Forsberg, K and Karlsborg, M and Salvesen, L and Svenstrup, K and Winroth, I and Berntsson, H and M Andersen, P}, title = {[SOD1 gene therapy delays ALS disease progression].}, journal = {Lakartidningen}, volume = {121}, number = {}, pages = {}, pmid = {38666665}, issn = {1652-7518}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *Superoxide Dismutase-1/genetics ; *Genetic Therapy ; *Disease Progression ; Male ; Middle Aged ; Mutation ; Oligonucleotides, Antisense/therapeutic use/administration & dosage ; Oligonucleotides/therapeutic use/administration & dosage ; }, abstract = {We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.}, } @article {pmid38674921, year = {2024}, author = {Wang, W and Pan, D and Liu, Q and Chen, X and Wang, S}, title = {L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review.}, journal = {Nutrients}, volume = {16}, number = {8}, pages = {}, pmid = {38674921}, issn = {2072-6643}, mesh = {Humans ; *Carnitine/therapeutic use ; Dietary Supplements ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; }, abstract = {OBJECTIVE: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research.

METHODS: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search.

RESULTS: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud's syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation.

CONCLUSION: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer's disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.}, } @article {pmid38676303, year = {2024}, author = {Zhao, W and Wang, R and Chen, M}, title = {Clinical analysis of air-leak syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients.}, journal = {Pediatric blood & cancer}, volume = {71}, number = {7}, pages = {e31008}, doi = {10.1002/pbc.31008}, pmid = {38676303}, issn = {1545-5017}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; Retrospective Studies ; Child ; Child, Preschool ; Adolescent ; Infant ; Prognosis ; Survival Rate ; Follow-Up Studies ; Transplantation, Homologous ; Bronchiolitis Obliterans/etiology/mortality/therapy ; Pneumonia/etiology/mortality ; }, abstract = {BACKGROUND: Air-leak syndrome (ALS) is considered as an independent risk factor for poor prognosis in adult patients who had received hematopoietic stem cell transplantation (HSCT), and the 5-year overall survival (OS) of ALS is less than 30%. However, the clinical features of ALS among post-transplant pediatric patients have rarely been explored.

PROCEDURES: We retrospectively reviewed 2206 pediatric patients who had received an allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital, and analyzed the role of ALS in prognosis following HSCT.

RESULTS: In our research, ALS was divided into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS). Following treatment of the ALS, 18 patients survived (18/28, 64.3%), and 10 patients died of respiratory failure or infection (10/28, 35.7%).

CONCLUSIONS: The OS of ALS in Hebei Yanda Lu Daopei Hospital is significantly higher than others, and they were cited to be related to early diagnosis and timely FAM treatment in previous reports.}, } @article {pmid38676672, year = {2024}, author = {Kutlubaev, MA}, title = {[Promising approaches to the pathogenetic therapy of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4}, pages = {13-21}, doi = {10.17116/jnevro202412404113}, pmid = {38676672}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Neuroprotective Agents/therapeutic use ; Genetic Therapy ; Antioxidants/therapeutic use ; Stem Cell Transplantation ; Gastrointestinal Microbiome ; Immunologic Factors/therapeutic use ; Immunomodulating Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis is a severe incurable disease of the nervous system. Currently only methods of palliative care for the patients with this disease are available. Few medications for the pathogenetic therapy are registered in some countries, i.e. riluzole, edaravon, sodium phenylbutyrate/taurursodiol as well as tofersen (conditionally). Their efficacy is relatively low. The main directions in the development of pathogenetic therapy of ALS include gene therapy, use of stem cells, immunomodulators, agents affecting gut microbiota. A search is also underway for low-molecular compounds with neuroprotective and antioxidant properties. Perspective direction is prevention of ALS. This will be possible when biomarkers for identification of patients in pre-manifest/prodromal stage are detected.}, } @article {pmid38677733, year = {2024}, author = {Keul, J and Sperling, S and Rohde, V and Mielke, D and Ninkovic, M}, title = {Riluzole Reverses a Number of Undesirable Effects of Dexamethasone in Glioblastoma Cells.}, journal = {Anticancer research}, volume = {44}, number = {5}, pages = {1829-1835}, doi = {10.21873/anticanres.16984}, pmid = {38677733}, issn = {1791-7530}, mesh = {*Riluzole/pharmacology ; Humans ; *Glioblastoma/drug therapy/pathology/metabolism ; *Dexamethasone/pharmacology ; *Cell Movement/drug effects ; Cell Line, Tumor ; Brain Neoplasms/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; }, abstract = {BACKGROUND/AIM: Glioblastoma multiforme (GBM)-induced oedema is a major cause of morbidity and mortality among patients with GBM. Dexamethasone (Dex) is the most common corticosteroid used pre-operatively to control cerebral oedema in patients with GBM. Dex is associated with many side effects, and shorter overall survival and progression-free survival of patients with GBM. These negative effects of Dex highlight the need for combinational therapy. Riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), is thought to have potential as a treatment for various cancers, with clinical trials underway. Here, we investigated whether Ril could reverse some of the undesirable effects of Dex.

MATERIALS AND METHODS: The effect of Dex, Ril, and Ril-Dex treatment on cell migration was monitored using the xCELLigence system. Cell viability assays were performed using 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT). The expression of genes involved in migration, glucose metabolism, and stemness was examined using real-time polymerase chain reaction (PCR).

RESULTS: Pre-treating GBM cells with Ril reduced Dex-induced cell migration and altered Dex-induced effects on cell invasion, stem cell, and glucose metabolism markers. Furthermore, Ril remained effective in killing GBM cells in combination with Dex.

CONCLUSION: Ril, which acts as an anti-tumorigenic drug, mediates some of the negative effects of Dex; therefore, it could be a potential drug to manage the side effects of Dex therapy in GBM.}, } @article {pmid38678262, year = {2024}, author = {Xu, C and Mei, Y and Yang, R and Luo, Q and Zhang, J and Kou, X and Hu, J and Wang, Y and Li, Y and Chen, R and Zhang, Z and Yao, Y and Sima, J}, title = {Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer's disease by inhibiting neuroinflammation and neuronal necroptosis.}, journal = {Cell & bioscience}, volume = {14}, number = {1}, pages = {55}, pmid = {38678262}, issn = {2045-3701}, support = {82173804//National Natural Science Foundation of China/ ; 82001144//National Natural Science Foundation of China/ ; 3150120042//High-Level Talents Start-up Funding of China Pharmaceutical University/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.

RESULTS: We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD[+] depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.

CONCLUSIONS: Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.}, } @article {pmid38681726, year = {2024}, author = {Grzanka, M and Joniec, A and Rogulski, J and Sobiech, Ł and Idziak, R and Loryś, B}, title = {Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220868}, pmid = {38681726}, issn = {2391-5412}, abstract = {Delayed sowing of winter cereals or unfavorable weather conditions in autumn may make it impossible to carry out herbicide treatment in autumn. In such cases, weed control should be started in the spring. During this time, the plantation should be protected as effectively as possible because the weeds are at an advanced stage of growth. Therefore, they are less sensitive to applied herbicides. In the treatment, it is worth using a mixture of different mechanisms of action. Studies were conducted to evaluate the effectiveness of a band of tribenuron-methyl, and MCPA applied as soluble granules in spring control of dicotyledonous in winter cereals. The biological efficacy of herbicides was estimated in the 25 field experiments on winter cereals in Poland. Postemergence, a spring application of tribenuron-methyl + MCPA, effectively controls the majority of weed species present in spring: Anthemis arvensis, Brassica napus, Capsella bursa-pastoris, Centaurea cyanus, Lamium purpureum, Matricaria chamomilla, Tripleurospermum inodorum, Stellaria media and Thlaspi arvense. Satisfactory control was confirmed for Veronica persica, Viola arvensis, and Galium aparine. Tribenuron-methyl with MCPA is recommended for application to winter cereals in spring. To prevent the development of resistance in weeds, it is advantageous to combine two active substances.}, } @article {pmid38685454, year = {2024}, author = {Gadri, Y and Avneri, A and Peleg, Z}, title = {Induced mutation in the SiALS gene offers new weed management opportunities for sesame crop.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {345}, number = {}, pages = {112104}, doi = {10.1016/j.plantsci.2024.112104}, pmid = {38685454}, issn = {1873-2259}, mesh = {*Weed Control/methods ; *Herbicide Resistance/genetics ; *Sesamum/genetics/growth & development ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics ; Plant Weeds/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Mutation ; Crops, Agricultural/genetics/growth & development ; }, abstract = {Weeds are the primary biotic constraint affecting sesame growth and production. Here, we applied EMS mutagenesis to an elite sesame cultivar and discovered a novel point mutation in the sesame SiALS gene conferring resistance to imidazolinone, a group of acetolactate-synthase (ALS)-inhibitors. The mutant line exhibited high resistance to imazamox, an ALS-inhibitor, with hybrid plants displaying an intermediate response. Field-based validation confirmed the mutant line's substantial resistance, leading to a significantly higher yield under imazamox treatment. Under pre-emergence application of imazapic, the mutant plants sustained growth, whereas wild-type and weed were effectively controlled. Field trials using s-metolachlor and imazapic combined resulted in weed-free plots compared to untreated controls. Consequently, this treatment showed a significantly greater yield (2280 vs. 880 Kg ha[-1]) than the commercial practice (s-metolachlor). Overall, our study unveils the potential of utilizing this point mutation in sesame breeding programs, offering new opportunities for integrated weed management strategies for sesame cultivation. Developing herbicide-resistant crop plants holds promise for supporting sustainable production and addressing the challenges of weed infestations in sesame farming.}, } @article {pmid38691665, year = {2024}, author = {Singh, P and Belliveau, P and Towle, J and Neculau, AE and Dima, L}, title = {Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.}, journal = {American journal of therapeutics}, volume = {31}, number = {3}, pages = {e258-e267}, doi = {10.1097/MJT.0000000000001742}, pmid = {38691665}, issn = {1536-3686}, mesh = {*Edaravone/administration & dosage/pharmacology/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects ; Administration, Oral ; Suspensions ; Biological Availability ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.

MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.

PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.

CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.

THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.}, } @article {pmid38694387, year = {2024}, author = {Arora, H and Javed, B and Kutikuppala, LVS and Chaurasia, M and Khullar, K and Kannan, S and Golla, V}, title = {ST2 levels and neurodegenerative diseases: is this a significant relation?.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {2812-2817}, pmid = {38694387}, issn = {2049-0801}, abstract = {Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.}, } @article {pmid38697285, year = {2024}, author = {Tuerxun, K and Tang, RH and Abudoumijiti, A and Yusupu, Z and Aikebaier, A and Mijiti, S and Ibrahim, I and Cao, YL and Yasheng, A and Wu, YQ}, title = {Comparative proteomics analysis of samples from hepatic cystic echinococcosis patients using data-independent acquisition approach.}, journal = {Journal of proteomics}, volume = {301}, number = {}, pages = {105191}, doi = {10.1016/j.jprot.2024.105191}, pmid = {38697285}, issn = {1876-7737}, mesh = {*Proteomics/methods ; Humans ; *Echinococcus granulosus/metabolism ; Animals ; Helminth Proteins/metabolism/analysis ; Echinococcosis, Hepatic/metabolism/parasitology ; Proteome/analysis/metabolism ; }, abstract = {Cystic echinococcosis is a zoonotic disease resulting from infection caused by the larval stage of Echinococcus granulosus. This study aimed to assess the specific proteins that are potential candidates for the development of a vaccine against E. granulosus. The data-independent acquisition approach was employed to identify differentially expressed proteins (DEPs) in E. granulosus samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify several noteworthy proteins. Results: The DEPs in E. granulosus samples were identified (245 pericystic wall vs. parasite-free yellowish granuloma (PYG, 1725 PY vs. PYG, 2274 PN vs. PYG). Further examination of these distinct proteins revealed their predominant enrichment in metabolic pathways, amyotrophic lateral sclerosis, and neurodegeneration-associated pathways. Notably, among these DEPs, SH3BGRL, MST1, TAGLN2, FABP5, UBE2V2, and RARRES2 exhibited significantly higher expression levels in the PYG group compared with the PY group (P < 0.05). The findings may contribute to the understanding of the pathological mechanisms underlying echinococcosis, providing valuable insights into the development of more effective diagnostic tools, treatment modalities, and preventive strategies. SIGNIFICANCE: CE is a major public health hazard in the western regions of China, Central Asia, South America, the Mediterranean countries, and eastern Africa. Echinococcus granulosus is responsible for zoonotic disease through infection Our analysis focuses on the proteins in various samples by data-dependent acquisition (DIA) for proteomic analysis. The importance of this research is to develop new strategies and targets to protect against E. granulosus infections in humans.}, } @article {pmid38698397, year = {2024}, author = {Wilson, E and Palmer, J and Armstrong, A and Messer, B and Presswood, E and Faull, C}, title = {End of life decision making when home mechanical ventilation is used to sustain breathing in Motor Neurone Disease: patient and family perspectives.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {115}, pmid = {38698397}, issn = {1472-684X}, support = {Anne McLaren Research Fellowship//University of Nottingham/ ; }, mesh = {Humans ; *Motor Neuron Disease/psychology/therapy/complications ; *Decision Making ; Male ; Female ; Middle Aged ; *Qualitative Research ; *Respiration, Artificial/methods/psychology ; Aged ; *Terminal Care/methods/psychology ; *Family/psychology ; United Kingdom ; Adult ; Aged, 80 and over ; Home Care Services/standards ; }, abstract = {BACKGROUND: Motor Neurone Disease (MND) leads to muscle weakening, affecting movement, speech, and breathing. Home mechanical ventilation, particularly non-invasive ventilation (NIV), is used to alleviate symptoms and support breathing in people living with MND. While home mechanical ventilation can alleviate symptoms and improve survival, it does not slow the progression of MND. This study addresses gaps in understanding end-of-life decision-making in those dependent on home mechanical ventilation, considering the perspectives of patients, family members, and bereaved families.

METHODS: A UK-wide qualitative study using flexible interviews to explore the experiences of people living with MND (n = 16), their family members (n = 10), and bereaved family members (n = 36) about the use of home mechanical ventilation at the end of life.

RESULTS: Some participants expressed a reluctance to discuss end-of-life decisions, often framed as a desire to "live for the day" due to the considerable uncertainty faced by those with MND. Participants who avoided end-of-life discussions often engaged in 'selective decision-making' related to personal planning, involving practical and emotional preparations. Many faced challenges in hypothesising about future decisions given the unpredictability of the disease, opting to make 'timely decisions' as and when needed. For those who became dependent on ventilation and did not want to discuss end of life, decisions were often 'defaulted' to others, especially once capacity was lost. 'Proactive decisions', including advance care planning and withdrawal of treatment, were found to empower some patients, providing a sense of control over the timing of their death. A significant proportion lacked a clear understanding of the dying process and available options.

CONCLUSIONS: The study highlights the complexity and evolution of decision-making, often influenced by the dynamic and uncertain nature of MND. The study emphasises the need for a nuanced understanding of decision-making in the context of MND.}, } @article {pmid38703766, year = {2024}, author = {Alfahel, L and Gschwendtberger, T and Kozareva, V and Dumas, L and Gibbs, R and Kertser, A and Baruch, K and Zaccai, S and Kahn, J and Thau-Habermann, N and Eggenschwiler, R and Sterneckert, J and Hermann, A and Sundararaman, N and Vaibhav, V and Van Eyk, JE and Rafuse, VF and Fraenkel, E and Cantz, T and Petri, S and Israelson, A}, title = {Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {5}, pages = {101546}, pmid = {38703766}, issn = {2666-3791}, mesh = {*Macrophage Migration-Inhibitory Factors/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; Animals ; Humans ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Induced Pluripotent Stem Cells/metabolism ; Intramolecular Oxidoreductases/metabolism/genetics ; Mice, Transgenic ; Dependovirus/genetics ; Disease Models, Animal ; Male ; Mutation/genetics ; Female ; Protein Folding ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1[G37R] mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.}, } @article {pmid38711616, year = {2024}, author = {Chen, L and Chen, G and Zhang, M and Zhang, X}, title = {Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUS[R503fs] mutation.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1364164}, pmid = {38711616}, issn = {1662-5102}, abstract = {INTRODUCTION: Fused in sarcoma (FUS) mutations represent the most common genetic etiology of juvenile amyotrophic lateral sclerosis (JALS), for which effective treatments are lacking. In a prior report, we identified a novel FUS mutation, c.1509dupA: p. R503fs (FUSR503fs), in a sporadic JALS patient.

METHODS: The physicochemical properties and structure of FUSR503fs protein were analyzed by software: Multi-electrode array (MEA) assay, calcium activity imaging assay and transcriptome analysis were used to explore the pathophysiological mechanism of iPSC derived motor neurons.

RESULTS: Structural analysis and predictions regarding physical and chemical properties of this mutation suggest that the reduction of phosphorylation and glycosylation sites, along with alterations in the amino acid sequence, may contribute to abnormal FUS accumulation within the cytoplasm and nucleus of induced pluripotent stem cell- derived motor neurons (MNs). Multi-electrode array and calcium activity imaging indicate diminished spontaneous electrical and calcium activity signals in MNs harboring the FUS[R503fs] mutation. Transcriptomic analysis reveals upregulation of genes associated with viral infection and downregulation of genes involved in neural function maintenance, such as the ATP6V1C2 gene. Treatment with ropinirole marginally mitigates the electrophysiological decline in FUS[R503fs] MNs, suggesting the utility of this cell model for mechanistic exploration and drug screening.

DISCUSSION: iPSCs-derived motor neurons from JALS patients are promising tools for drug screening. The pathological changes in motor neurons of FUS[R503fs] may occur earlier than in other known mutation types that have been reported.}, } @article {pmid38712849, year = {2024}, author = {Ludolph, AC and Corcia, P and Desnuelle, C and Heiman-Patterson, T and Mora, JS and Mansfield, CD and Couratier, P}, title = {Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {36-41}, doi = {10.1002/mus.28101}, pmid = {38712849}, issn = {1097-4598}, support = {//AB Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Clinical Trials as Topic/methods ; Disease Progression ; Outcome Assessment, Health Care/standards ; *Research Design ; Severity of Illness Index ; }, abstract = {The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.}, } @article {pmid38718295, year = {2024}, author = {Huang, J and Fu, Y and Wang, A and Shi, K and Peng, Y and Yi, Y and Yu, R and Gao, J and Feng, J and Jiang, G and Song, Q and Jiang, J and Chen, H and Gao, X}, title = {Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {31}, pages = {e2405323}, doi = {10.1002/adma.202405323}, pmid = {38718295}, issn = {1521-4095}, support = {2022YFC2502800//National Key Research and Development Program of China/ ; 2023ZKZD21//Innovation Program of Shanghai Municipal Education Commission/ ; 81973272//National Natural Science Foundation of China/ ; 92068111//National Natural Science Foundation of China/ ; 81801212//National Natural Science Foundation of China/ ; 23S41900100//Shanghai Science and Technology Development Foundation/ ; 22QA1405000//Shanghai Science and Technology Development Foundation/ ; 21XD1422200//Shanghai Science and Technology Development Foundation/ ; SHSMU-ZDCX20211201//Innovative Research Team of High-Level Local Universities in Shanghai/ ; }, mesh = {Animals ; Mice ; *Biomimetic Materials/chemistry ; *Drug Carriers/chemistry ; *Blood-Brain Barrier/metabolism ; *Hyaluronic Acid/chemistry ; *Catalase/metabolism/chemistry ; *Brain/metabolism ; Nanoparticles/chemistry ; Protamines/chemistry ; Amyotrophic Lateral Sclerosis/drug therapy ; Disease Models, Animal ; Humans ; Brain Injuries/drug therapy/metabolism ; Biomimetics/methods ; }, abstract = {Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.}, } @article {pmid38719860, year = {2024}, author = {Cusaro, CM and Capelli, E and Picco, AM and Brusoni, M}, title = {Incidence of resistance to ALS and ACCase inhibitors in Echinochloa species and soil microbial composition in Northern Italy.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {10544}, pmid = {38719860}, issn = {2045-2322}, support = {ECS00000036//MUR - M4C2 1.5 of PNRR funded by the European Union - NextGenerationEU/ ; }, mesh = {*Soil Microbiology ; Italy/epidemiology ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Echinochloa/drug effects ; *Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors ; Plant Weeds/drug effects ; Microbiota/drug effects ; Biodiversity ; Bacteria/drug effects/genetics/isolation & purification/classification ; Soil/chemistry ; Fungi/drug effects/isolation & purification/genetics ; }, abstract = {The increasing amount of weeds surviving herbicide represents a very serious problem for crop management. The interaction between microbial community of soil and herbicide resistance, along with the potential evolutive consequences, are still poorly known and need to be investigated to better understand the impact on agricultural management. In our study, we analyzed the microbial composition of soils in 32 farms, located in the Northern Italy rice-growing area (Lombardy) with the aim to evaluate the relationship between the microbial composition and the incidence of resistance to acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides in Echinochloa species. We observed that the coverage of weeds survived herbicide treatment was higher than 60% in paddy fields with a low microbial biodiversity and less than 5% in those with a high microbial biodiversity. Fungal communities showed a greater reduction in richness than Bacteria. In soils with a reduced microbial diversity, a significant increase of some bacterial and fungal orders (i.e. Lactobacillales, Malasseziales and Diaporthales) was observed. Interestingly, we identified two different microbial profiles linked to the two conditions: high incidence of herbicide resistance (H-HeR) and low incidence of herbicide resistance (L-HeR). Overall, the results we obtained allow us to make hypotheses on the greater or lesser probability of herbicide resistance occurrence based on the composition of the soil microbiome and especially on the degree of biodiversity of the microbial communities.}, } @article {pmid38720896, year = {2024}, author = {Zong, J and Yang, Y and Wang, H and Zhang, H and Yang, X and Yang, X}, title = {The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1325908}, pmid = {38720896}, issn = {1664-3224}, mesh = {Humans ; *Inflammatory Bowel Diseases/complications ; *Neurodegenerative Diseases/epidemiology/etiology ; Longitudinal Studies ; Risk Factors ; Prospective Studies ; }, abstract = {OBJECTIVE: Previous studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.

METHODS: We accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.

RESULTS: The final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer's disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03-1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13-1.36, P<0.001), multiple sclerosis (HR =2.07, 95% CI:1.42-3.02, P<0.001) and Parkinson's disease (HR =1.23, 95% CI:1.10-1.38, P<0.001). Two articles reported an increased incidence of amyotrophic lateral sclerosis or multiple system atrophy in IBD patients. Three studies investigated the prospective association between multiple sclerosis and IBD, revealing an elevated risk of the latter in patients with the former. (HR=1.87, 95% CI:1.66-2.10, P<0.001).

INTERPRETATION: These findings verified the two-directional relationship between the brain-gut axis, specifically demonstrating a heightened risk of various neurodegenerative diseases among IBD patients. It may be profitable to prepare screening strategies for IBD patients to find neurodegenerative diseases during the long-term course of treatment for IBD with a view to potential earlier diagnosis and treatment of neurodegenerative diseases, reducing public health and social burden.

PROSPERO (CRD42023437553).}, } @article {pmid38721118, year = {2024}, author = {Lu, L and Deng, Y and Xu, R}, title = {Current potential therapeutics of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1402962}, pmid = {38721118}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current literature about clinical and experimental ALS treatments. Based on them, this review primarily focused on summarizing the current potential clinical usage and trialing therapeutics of ALS. Currently, the clinical ALS treatments have focused primarily on relieving symptoms to improve the quality of life yet. There are a number of therapeutic approaches such as medicine, gene therapy, neuron protectants, combination therapy and stem cells. Among them, Stem cells including embryonic stem cells, mesenchymal stem cells, neural stem cells, and many other types of stem cells have been used in ALS treatment, and although the short-term efficacy is good, it is worth exploring whether this improved efficacy leads to prolonged patient survival. In addition, the supportive treatments also exert an important effect on improving the quality of life and prolong the survival of ALS patients in absence of effectively care for stopping or reversing the progression of ALS.}, } @article {pmid38731036, year = {2024}, author = {Ueha, R and Miura, C and Matsumoto, N and Sato, T and Goto, T and Kondo, K}, title = {Vocal Fold Motion Impairment in Neurodegenerative Diseases.}, journal = {Journal of clinical medicine}, volume = {13}, number = {9}, pages = {}, pmid = {38731036}, issn = {2077-0383}, abstract = {Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson's disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.}, } @article {pmid38732027, year = {2024}, author = {Cantara, S and Simoncelli, G and Ricci, C}, title = {Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732027}, issn = {1422-0067}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Motor Neuron Disease/genetics/therapy ; Animals ; Muscular Atrophy, Spinal/therapy/genetics ; Amyotrophic Lateral Sclerosis/genetics/therapy ; }, abstract = {Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.}, } @article {pmid38734896, year = {2024}, author = {Sun, S and Shen, Y and Zhang, X and Ding, N and Xu, Z and Zhang, Q and Li, L}, title = {The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {7}, pages = {2176-2189}, pmid = {38734896}, issn = {1525-0024}, mesh = {Animals ; *Neuromuscular Junction/metabolism/drug effects ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Disease Models, Animal ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; Longevity/drug effects ; Motor Neurons/metabolism/drug effects ; Agrin/metabolism/genetics ; Mice, Transgenic ; Antibodies/pharmacology ; Receptors, Cholinergic/metabolism/genetics ; LDL-Receptor Related Proteins/metabolism/genetics ; }, abstract = {The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PR[F/F] mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.}, } @article {pmid38735299, year = {2024}, author = {Gould, RL and McDermott, CJ and Thompson, BJ and Rawlinson, CV and Bursnall, M and Bradburn, M and Kumar, P and Turton, EJ and White, DA and Serfaty, MA and Graham, CD and McCracken, LM and Goldstein, LH and Al-Chalabi, A and Orrell, RW and Williams, T and Noad, R and Baker, I and Faull, C and Lambert, T and Chhetri, SK and Ealing, J and Hanratty, A and Radunovic, A and Gunawardana, N and Meadows, G and Gorrie, GH and Young, T and Lawrence, V and Cooper, C and Shaw, PJ and Howard, RJ and , }, title = {Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.}, journal = {Lancet (London, England)}, volume = {403}, number = {10442}, pages = {2381-2394}, doi = {10.1016/S0140-6736(24)00533-6}, pmid = {38735299}, issn = {1474-547X}, support = {NIHR202421//NIHR/ ; }, mesh = {Humans ; *Quality of Life ; *Acceptance and Commitment Therapy/methods ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/therapy/psychology ; United Kingdom ; Aged ; Treatment Outcome ; }, abstract = {BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease.

METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391).

FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention.

INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services.

FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.}, } @article {pmid38739991, year = {2024}, author = {Li, X and Liu, N and Wu, D and Li, SC and Wang, Q and Zhang, DW and Song, LL and Huang, M and Chen, X and Li, W}, title = {Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116746}, doi = {10.1016/j.biopha.2024.116746}, pmid = {38739991}, issn = {1950-6007}, mesh = {Animals ; *Pentylenetetrazole ; *Hippocampus/drug effects/metabolism/pathology ; *Apoptosis/drug effects ; *Anticonvulsants/pharmacology ; Male ; *Transcriptome/drug effects ; *Epilepsy/drug therapy/chemically induced/genetics ; *Gene Expression Profiling/methods ; Rats ; *Rats, Sprague-Dawley ; Disease Models, Animal ; Neurons/drug effects/metabolism/pathology ; Seizures/chemically induced/genetics/drug therapy ; }, abstract = {Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.}, } @article {pmid38741111, year = {2024}, author = {Maresova, P and Rezny, L and Bauer, P and Valko, M and Kuca, K}, title = {Nonpharmacological intervention therapies for dementia: potential break-even intervention price and savings for selected risk factors in the European healthcare system.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1293}, pmid = {38741111}, issn = {1471-2458}, support = {ERDF No. CZ.02.1.01/0.0/0.0/18_069/0010054-IT4Neuro(degeneration)//Ministry of Education Youth and Sports/ ; Excellence 2022//UHK FIM/ ; }, mesh = {Humans ; *Dementia/economics/epidemiology/prevention & control ; Risk Factors ; Europe/epidemiology ; Cost Savings ; Aged ; Health Care Costs/statistics & numerical data ; Models, Theoretical ; Male ; Female ; Prevalence ; Aged, 80 and over ; Middle Aged ; }, abstract = {BACKGROUND: New effective treatments for dementia are lacking, and early prevention focusing on risk factors of dementia is important. Non-pharmacological intervention therapies aimed at these factors may provide a valuable tool for reducing the incidence of dementia. This study focused on the development of a mathematical model to predict the number of individuals with neurodegenerative diseases, specifically Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. Scenarios for non-pharmacological intervention therapies based on risk factor reduction were also assessed. The estimated total costs and potential cost savings from societal were included.

METHODS: Based on demographic and financial data from the EU, a mathematical model was developed to predict the prevalence and resulting care costs of neurodegenerative diseases in the population. Each disease (Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis) used parameters that included prevalence, incidence, and death risk ratio, and the simulation is related to the age of the cohort and the disease stage.

RESULTS: A replicable simulation for predicting the prevalence and resulting cost of care for neurodegenerative diseases in the population exhibited an increase in treatment costs from 267 billion EUR in 2021 to 528 billion EUR by 2050 in the EU alone. Scenarios related to the reduction of the prevalence of dementia by up to 20% per decade led to total discounted treatment cost savings of up to 558 billion EUR.

CONCLUSION: The model indicates the magnitude of the financial burden placed on EU healthcare systems due to the growth in the population prevalence of neurodegenerative diseases in the coming decades. Lifestyle interventions based on reducing the most common risk factors could serve as a prevention strategy to reduce the incidence of dementia with substantial cost-savings potential. These findings could support the implementation of public health approaches throughout life to ultimately prevent premature mortality and promote a healthier and more active lifestyle in older individuals.}, } @article {pmid38741492, year = {2024}, author = {Kanda, S and Kanda, T}, title = {[Multifocal Motor Neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {5}, pages = {526-533}, doi = {10.11477/mf.1416202639}, pmid = {38741492}, issn = {1881-6096}, mesh = {Humans ; *Polyneuropathies/physiopathology/diagnosis ; Immunoglobulins, Intravenous/therapeutic use/administration & dosage ; }, abstract = {Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.}, } @article {pmid38743390, year = {2024}, author = {Vignolo, M and Zuccarino, R and Truffelli, R and Gemelli, C and Giove, E and Ferraro, PM and Manunza, D and Trinchero, C and Cipollina, I and Lungu, M and Lizio, A and Gragnano, G and Cabona, C and Pardini, M and Caponnetto, C and Rao, F}, title = {Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.}, journal = {European journal of physical and rehabilitation medicine}, volume = {60}, number = {3}, pages = {470-476}, pmid = {38743390}, issn = {1973-9095}, mesh = {Humans ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/rehabilitation ; Male ; Female ; Middle Aged ; *Animal Assisted Therapy/methods ; Aged ; *Physical Therapy Modalities ; Animals ; Dogs ; Treatment Outcome ; }, abstract = {BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated.

AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS.

DESIGN: This study was a randomized controlled pilot study.

SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa.

POPULATION: Sixty hospitalized ALS patients were enrolled.

METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale.

RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01).

CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS.

This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.}, } @article {pmid38747109, year = {2024}, author = {Bender, J and Kojeku, T and Preece, E}, title = {Grading lumbar foraminal stenosis - Interrater agreement of radiologists and radiology trainees before and after education of a standardised grading scale.}, journal = {Journal of medical imaging and radiation oncology}, volume = {68}, number = {5}, pages = {511-515}, doi = {10.1111/1754-9485.13669}, pmid = {38747109}, issn = {1754-9485}, mesh = {Humans ; *Spinal Stenosis/diagnostic imaging ; *Lumbar Vertebrae/diagnostic imaging ; *Observer Variation ; *Magnetic Resonance Imaging/methods ; *Radiologists ; Severity of Illness Index ; Radiology/education ; Reproducibility of Results ; Clinical Competence ; Male ; }, abstract = {INTRODUCTION: Lumbar foraminal stenosis is a key contributor to low back pain. Imaging, particularly MRI, is commonly used in the assessment of foraminal stenosis, contributing to treatment planning. The adoption of a standardised grading system to try and improve inter-rater agreement is thought to be of importance. Our study aims to assess the variability of grading lumbar foraminal stenosis amongst reporting doctors, determine whether education about a validated grading scale increases agreement, and determine if these changes persist over time.

METHODS: A single-site study involving MRI reporting registrars/radiologists was performed. Participants were shown select MRI images and asked to grade the degree of stenosis in each on a 4-point scale. Subsequently, they were educated about Lee et al's grading system and asked to re-grade the cases 1 and 6 weeks later. The level of agreement was calculated using Gwet's AC1 coefficient and Krippendorff's Alpha.

RESULTS: The baseline level of agreement was substantial (AC1 = 0.71). This decreased to a moderate level of agreement post-intervention (AC1 = 0.575 at 1-week, P-value 0.033 and AC1 = 0.598 at 6 weeks, P-value 0.012). A grading of severe stenosis was 21% more likely 6 weeks post-education.

CONCLUSION: The baseline agreement at our institution was substantial, thought to be due to the single-centre nature of the study. Moderate agreement was achieved after education regarding the Lee et al.'s scale, in-line with other studies, with changes maintained at 6 weeks, showing retention of the scale parameters. Grading of severe stenosis was more common post intervention.}, } @article {pmid38749729, year = {2025}, author = {Kunieda, K and Hayashi, Y and Fujishima, I and Shimohata, T}, title = {Weight and Muscle Mass Loss Associated with Acute Disease Can Be Reversed with Appropriate Nutrition Therapy and Exercise in a Patient with Amyotrophic Lateral Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {1}, pages = {133-136}, pmid = {38749729}, issn = {1349-7235}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation/therapy/diet therapy/physiopathology ; Aged, 80 and over ; *Exercise Therapy/methods ; *Weight Loss/physiology ; Nutrition Therapy/methods ; Acute Disease ; Deglutition Disorders/etiology/rehabilitation/therapy/physiopathology ; Muscle Strength/physiology ; Body Composition ; Treatment Outcome ; }, abstract = {Nutritional interventions targeting weight loss are useful for the treatment of amyotrophic lateral sclerosis (ALS). However, the changes in body composition after nutritional intervention remain unclear. We herein present a patient with ALS who experienced an increased weight and muscle mass owing to nutritional therapy and physical exercise. An 86-year-old man presented with dysphagia and dysarthria. The patient was diagnosed with bulbar-type ALS. As weight loss progressed, a gastrostomy was performed. After 21 months of disease onset, gastrointestinal bleeding due to a bumper ulcer led to further weight loss (from 40.2 kg to 36.8 kg). The patient experienced difficulty walking and ingesting food orally. Although the total daily energy expenditure (TDEE) was estimated to be 1,122 kcal/day, an intake of 1,500 kcal/day beyond the calculated TDEE was administered. The patient continued to perform daily voluntary exercises in addition to his usual rehabilitation. After 5 months, his weight increased from 36.8 kg to 40.4 kg. Muscle mass increased from 25.1 kg to 30.1 kg, as measured using a multifrequency bioelectrical impedance device. Muscle strength improved from 8.5/10.0 kg to 15.0/18.0 kg in grip strength and from 15.2 kPa to 20.4 kPa in tongue pressure. The patient's physical and swallowing functions also improved. In patients with ALS, a decreased body weight and muscle mass due to acute disease may be improved by appropriate nutritional therapy and physical exercise.}, } @article {pmid38751168, year = {2024}, author = {Raffaele, S and Nguyen, N and Milanese, M and Mannella, FC and Boccazzi, M and Frumento, G and Bonanno, G and Abbracchio, MP and Bonifacino, T and Fumagalli, M}, title = {Montelukast improves disease outcome in SOD1[G93A] female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity.}, journal = {British journal of pharmacology}, volume = {181}, number = {18}, pages = {3303-3326}, doi = {10.1111/bph.16408}, pmid = {38751168}, issn = {1476-5381}, support = {GPR17ALS-1//AriSLA ETS - Fondazione Italiana di ricerca per la SLA/ ; 2017NSXP8J//Italian Ministry of University and Research (MUR)/ ; PE0000006//#NEXTGENERATIONEU (NGEU) and the Italian Ministry of University and Research (MUR), NRRP - National Recovery and Resilience Plan/ ; //Foundation Bellandi Bernardoni/ ; }, mesh = {Animals ; Female ; *Cyclopropanes/pharmacology ; *Quinolines/pharmacology ; *Acetates/pharmacology/therapeutic use ; *Oligodendroglia/drug effects/metabolism/pathology ; *Sulfides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; *Mice, Transgenic ; Mice ; Male ; Receptors, Leukotriene/metabolism/genetics ; Receptors, G-Protein-Coupled/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism/pathology ; Nerve Tissue Proteins ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro-regenerative local milieu and re-establish proper oligodendrocyte functions may be beneficial.

EXPERIMENTAL APPROACH: Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein-coupled receptor 17 (GPR17) and of cysteinyl-leukotriene receptor 1 (CysLT1R) receptors on microglia and astrocytes, in the SOD1[G93A] ALS mouse model. We chronically treated SOD1[G93A] mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.

KEY RESULTS: Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1[G93A] mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1[G93A] mice, suggesting enhanced pro-regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex-based difference in the protective activity of MTK.

CONCLUSIONS AND IMPLICATIONS: Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti-asthmatic drug, may be a promising sex-specific strategy for personalized ALS treatment.}, } @article {pmid38756356, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Colorectal anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Frontiers in surgery}, volume = {11}, number = {}, pages = {1371567}, pmid = {38756356}, issn = {2296-875X}, abstract = {BACKGROUND: Anastomotic leaks (ALs) are a significant and feared postoperative complication, with incidence of up to 30% despite advances in surgical techniques. With implications such as additional interventions, prolonged hospital stays, and hospital readmission, ALs have important impacts at the level of individual patients and healthcare providers, as well as healthcare systems as a whole. Challenges in developing unified definitions and grading systems for leaks have proved problematic, despite acknowledgement that colorectal AL is a critical issue in intestinal surgery with serious consequences. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs, and consequences of this postoperative complication.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following keywords: anastomosis, anastomotic leak, colorectal, surgery, grading system, complications, risk factors, and consequences. Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

RESULTS: A universally accepted definition and grading system for ALs continues to be lacking, leading to variability in reported incidence in the literature. Additional factors add to variability in estimates, including differences in the anastomotic site and institutional/individual differences in operative technique. Various groups have worked to publish guidelines for defining and grading AL, with the International Study Group of Rectal Cancer (ISGRC/ISREC) definition the current most recommended universal definition for colorectal AL. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: Colorectal AL remains a significant challenge in intestinal surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid38758158, year = {2025}, author = {Zou, X and Shi, Y and Zhang, T and Huang, A and Cui, H and Wang, T}, title = {Electroacupuncture Combined with Chinese Herbal Medicine, Qidong Huoluo Granule, for Amyotrophic Lateral Sclerosis: An 8-Month Case Report.}, journal = {Alternative therapies in health and medicine}, volume = {31}, number = {4}, pages = {268-272}, pmid = {38758158}, issn = {1078-6791}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Male ; Middle Aged ; *Electroacupuncture/methods ; *Drugs, Chinese Herbal/therapeutic use ; Combined Modality Therapy ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder characterized by progressive muscle weakness and eventual paralysis, for which there is currently no curative treatment. Mainstream medical interventions primarily focus on providing supportive care. However, acupuncture offers promising avenues for alleviating symptoms and enhancing quality of life. Specific acupuncture points are targeted to address bulbar paralysis as well as paralysis affecting the upper and lower extremities.

OBJECTIVE: To investigate the efficacy of electroacupuncture combined with Chinese herbal medicine in delaying disease progression and alleviating symptoms of bulbar paralysis in patients with ALS.

CASE PRESENTATION: A 51-year-old male presented with a 4-year and 8-month history of weakness in his left arm and both legs, accompanied by muscle cramps and diminished coordination, which had rapidly worsened over the past year. ALS was diagnosed, and the patient was initiated on oral Riluzole (50 mg) and Qidong Huoluo granule, a Chinese herbal compound, administered twice daily. Concurrently, he underwent acupuncture treatment sessions twice weekly for over 8 months.

RESULTS: Following acupuncture therapy, the patient experienced gradual stabilization of symptoms, notably improvement in swallowing function. The combination of electroacupuncture and Qidong Huoluo granule resulted in sustained clinical enhancements post-treatment, including improvements in speech, coughing, articulation, and breathing.

CONCLUSION: Electroacupuncture therapy demonstrates the potential to slow disease progression and ameliorate symptoms of bulbar paralysis in ALS patients. However, further robust clinical research is imperative to explain the precise therapeutic role of electroacupuncture in managing this debilitating condition. Continued investigation into the efficacy and safety profile of electroacupuncture holds promise for advancing treatment modalities for ALS.}, } @article {pmid38758193, year = {2024}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {6}, pages = {549-553}, doi = {10.1080/14737175.2024.2355983}, pmid = {38758193}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.

AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.

EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.}, } @article {pmid38759454, year = {2024}, author = {Wei, Y and Zhong, S and Yang, H and Wang, X and Lv, B and Bian, Y and Pei, Y and Xu, C and Zhao, Q and Wu, Y and Luo, D and Wang, F and Sun, H and Chen, Y}, title = {Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.}, journal = {European journal of medicinal chemistry}, volume = {272}, number = {}, pages = {116496}, doi = {10.1016/j.ejmech.2024.116496}, pmid = {38759454}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.}, } @article {pmid38759931, year = {2024}, author = {Guo, X and Zhang, Z and Gu, J and Ke, P and Liu, J and Meng, Y and Zheng, W and Que, W and Fan, R and Luo, J and Xiao, F}, title = {FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.}, journal = {Neurobiology of disease}, volume = {197}, number = {}, pages = {106534}, doi = {10.1016/j.nbd.2024.106534}, pmid = {38759931}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Mitophagy/physiology ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; *Mitochondrial Proteins/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Humans ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1[G93A] or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1[G93A] mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1[G93A] mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1[G93A] mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.}, } @article {pmid38760174, year = {2024}, author = {Pal, A and Grossmann, D and Glaß, H and Zimyanin, V and Günther, R and Catinozzi, M and Boeckers, TM and Sterneckert, J and Storkebaum, E and Petri, S and Wegner, F and Grill, SW and Pan-Montojo, F and Hermann, A}, title = {Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.}, journal = {Life science alliance}, volume = {7}, number = {8}, pages = {}, pmid = {38760174}, issn = {2575-1077}, support = {/ERC_/European Research Council/International ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; *Glycolates/metabolism/pharmacology ; *Mitochondria/metabolism ; *Protein Deglycase DJ-1/metabolism/genetics ; *Lactic Acid/metabolism ; *Superoxide Dismutase-1/metabolism/genetics ; Membrane Potential, Mitochondrial ; Motor Neurons/metabolism ; Lysosomes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.}, } @article {pmid38761668, year = {2024}, author = {Silani, V}, title = {Continuity of treatment in ALS: Benefits and challenges of maintaining riluzole over the course of the disease.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123038}, doi = {10.1016/j.jns.2024.123038}, pmid = {38761668}, issn = {1878-5883}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/therapeutic use ; Male ; Female ; Middle Aged ; }, } @article {pmid38771698, year = {2024}, author = {Alarcan, H and Bruno, C and Emond, P and Raoul, C and Vourc'h, P and Corcia, P and Camu, W and Veyrune, JL and Garlanda, C and Locati, M and Juntas-Morales, R and Saker, S and Suehs, C and Masseguin, C and Kirby, J and Shaw, P and Malaspina, A and De Vos, J and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Blasco, H}, title = {Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1536}, number = {1}, pages = {82-91}, doi = {10.1111/nyas.15147}, pmid = {38771698}, issn = {1749-6632}, support = {//National Institute of Health and Medical Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Interleukin-2/administration & dosage/metabolism ; *Metabolomics/methods ; *T-Lymphocytes, Regulatory/metabolism/drug effects/immunology ; Male ; Middle Aged ; Female ; Kynurenine/metabolism ; Aged ; Metabolome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.}, } @article {pmid38772930, year = {2024}, author = {Kherbek, H and Itoh, CY and Daley, C and Eggers, SD and Hinson, S and Sarker, P and Staff, NP and Pittock, SJ and Dubey, D}, title = {Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4620-4627}, pmid = {38772930}, issn = {1432-1459}, support = {238183//State of Minnesota's David J. Tomassoni ALS Research Grant Program/ ; }, mesh = {Humans ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Female ; *Paraneoplastic Syndromes, Nervous System/immunology/diagnosis/blood ; Adult ; Autoantibodies/blood ; Brachial Plexus Neuropathies/etiology/diagnosis/physiopathology ; Carrier Proteins ; }, abstract = {BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited.

METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared.

RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement.

DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.}, } @article {pmid38774156, year = {2024}, author = {Canella, C and Braun, C and Witt, CM}, title = {Developing a digital mind body medicine supportive care intervention for people with amyotrophic lateral sclerosis using stakeholder engagement and design thinking.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241255928}, pmid = {38774156}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis disease (ALS) is also called the disease of a thousand farewells. Consequently, it is important to offer supportive care interventions that can be applied continuously during the whole course of the disease. People with ALS are interested in complementary and integrative medicine. Due to ALS' progressive nature, digital solutions might be most feasible and accessible for people with ALS in the long-term.

OBJECTIVES: In our study, we explored with stakeholders which digital complementary and integrative medicine interventions and formats are considered as supportive for people with ALS, and which settings are needed by the people with ALS to incorporate the interventions in everyday life.

METHODS: We used a participatory research approach and conducted a stakeholder engagement process, applying a design thinking process with qualitative research methods (interviews, workshops).

RESULTS: Due to the unpredictable course of the disease on their loss of abilities, people with ALS welcome online settings because they are accessible and easy to implement in their daily life. Stakeholders considered the following implementation factors for a complementary and integrative medicine intervention as essential: short-term realization of planned interventions, short duration of interventions, and user-friendliness in terms of accessibility and applicability. Concerning the complementary and integrative medicine interventions, the people with ALS preferred mind body medicine interventions, such as breathing, mindfulness and relaxation exercises.

CONCLUSIONS: Short-term treatment intervals and short online mind body medicine interventions align with the needs of people with ALS. The complementary and integrative medicine interventions as well as the digital infrastructure must meet the special accessibility and applicability needs of people with ALS.}, } @article {pmid38775303, year = {2024}, author = {Zhang, J and Yang, F and Li, M and Zhu, Y and Huang, X}, title = {Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {194-203}, doi = {10.1002/mus.28165}, pmid = {38775303}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; Electric Stimulation/methods ; Neuromuscular Junction/physiopathology ; Electromyography/methods ; }, abstract = {INTRODUCTION/AIMS: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice.

METHODS: A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building.

RESULTS: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset.

DISCUSSION: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.}, } @article {pmid38775852, year = {2024}, author = {Ebrahimi, P and Davoudi, E and Sadeghian, R and Zadeh, AZ and Razmi, E and Heidari, R and Morowvat, MH and Sadeghian, I}, title = {In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {10}, pages = {7501-7530}, pmid = {38775852}, issn = {1432-1912}, support = {29849//Shiraz University of Medical Sciences/ ; }, mesh = {Humans ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Gene Editing/methods ; }, abstract = {Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.}, } @article {pmid38778483, year = {2024}, author = {Yan, J and Chen, H and Zhang, Y and Peng, L and Wang, Z and Lan, X and Yu, S and Yang, Y}, title = {Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2353396}, pmid = {38778483}, issn = {1949-0984}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; Bacteroides ; Faecalibacterium prausnitzii ; *Fecal Microbiota Transplantation ; Feces/microbiology ; Gastrointestinal Microbiome ; Respiration, Artificial ; *Respiratory Insufficiency/therapy/microbiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.}, } @article {pmid38778595, year = {2025}, author = {Jayaprakash, B and Savira, M and Mahmood, AAR and Prasanna, M}, title = {The Role of Stem Cell Therapies in the Treatment of Neurodegenerative Diseases.}, journal = {Current stem cell research & therapy}, volume = {20}, number = {2}, pages = {146-165}, doi = {10.2174/011574888X313112240510160102}, pmid = {38778595}, issn = {2212-3946}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; Neural Stem Cells/transplantation ; Parkinson Disease/therapy ; }, abstract = {Cellular replacement therapy and genetic transfer in injured brains provide new pathways for treating human neurological illnesses. Current progress in the field focuses on the production of neurons and glial cells from many types of stem cells, such as embryonic, induced pluripotent, mesenchymal, and neural stem cells. This has led to a significant increase in research on brain transplantation treatments. Extended neurodegeneration results in the progressive decline of certain neuronal subtypes or whole neuronal cells. An analysis of the progress made in induced pluripotent and mesenchymal stem cells reveals their significant promise in disease modeling, regeneration, and medication screening. The requirement for stem cells in neurodegenerative disease studies has been crucial in recent years. Stem cells provide the potential for replacing impaired neurons, comprehending disease needs modeling, and creating efficient treatments, but they have many challenges in culturing and acceptability to the host immune cells. The need to use their potential in discovering novel therapies for diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis leads to promising therapy. This review examines the function of stem cells in the pathogenesis and treatment of Huntington's disease, Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review further examines hurdles such as immunological reactions and delivery systems intending to overcome these problems. This article offers a detailed viewpoint on the use of stem cell-based nanotherapies as revolutionary treatments for various neurological illnesses.}, } @article {pmid38782015, year = {2024}, author = {Benatar, M and Hansen, T and Rom, D and Geist, MA and Blaettler, T and Camu, W and Kuzma-Kozakiewicz, M and van den Berg, LH and Morales, RJ and Chio, A and Andersen, PM and Pradat, PF and Lange, D and Van Damme, P and Mora, G and Grudniak, M and Elliott, M and Petri, S and Olney, N and Ladha, S and Goyal, NA and Meyer, T and Hanna, MG and Quinn, C and Genge, A and Zinman, L and Jabari, D and Shoesmith, C and Ludolph, AC and Neuwirth, C and Nations, S and Shefner, JM and Turner, MR and Wuu, J and Bennett, R and Dang, H and Sundgreen, C and , }, title = {Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {687-699}, doi = {10.1016/S1474-4422(24)00134-0}, pmid = {38782015}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; *Neuroprotective Agents/therapeutic use/adverse effects ; Treatment Outcome ; Adult ; Hydroxylamines/therapeutic use/adverse effects/pharmacology ; Oxadiazoles/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.

METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.

FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).

INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.

FUNDING: Orphazyme.}, } @article {pmid38784093, year = {2024}, author = {Chen, W and Liu, X and Wan, P and Chen, Z and Chen, Y}, title = {Anti-artifacts techniques for neural recording front-ends in closed-loop brain-machine interface ICs.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1393206}, pmid = {38784093}, issn = {1662-4548}, abstract = {In recent years, thanks to the development of integrated circuits, clinical medicine has witnessed significant advancements, enabling more efficient and intelligent treatment approaches. Particularly in the field of neuromedical, the utilization of brain-machine interfaces (BMI) has revolutionized the treatment of neurological diseases such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. The BMI acquires neural signals via recording circuits and analyze them to regulate neural stimulator circuits for effective neurological treatment. However, traditional BMI designs, which are often isolated, have given way to closed-loop brain-machine interfaces (CL-BMI) as a contemporary development trend. CL-BMI offers increased integration and accelerated response speed, marking a significant leap forward in neuromedicine. Nonetheless, this advancement comes with its challenges, notably the stimulation artifacts (SA) problem inherent to the structural characteristics of CL-BMI, which poses significant challenges on the neural recording front-ends (NRFE) site. This paper aims to provide a comprehensive overview of technologies addressing artifacts in the NRFE site within CL-BMI. Topics covered will include: (1) understanding and assessing artifacts; (2) exploring the impact of artifacts on traditional neural recording front-ends; (3) reviewing recent technological advancements aimed at addressing artifact-related issues; (4) summarizing and classifying the aforementioned technologies, along with an analysis of future trends.}, } @article {pmid38785754, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Tavakol-Afshari, J}, title = {Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantations in ALS Patients by Investigating Patients' Specific Immunological and Biochemical Biomarkers.}, journal = {Diseases (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {38785754}, issn = {2079-9721}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors.

METHODS: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF).

RESULTS: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05.

CONCLUSIONS: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.}, } @article {pmid38790979, year = {2024}, author = {Mishra, PS and Phaneuf, D and Boutej, H and Picher-Martel, V and Dupre, N and Kriz, J and Julien, JP}, title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790979}, issn = {2227-9059}, support = {143275/CAPMC/CIHR/Canada ; 231575//Canada Research Chairs/ ; }, abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.}, } @article {pmid38791160, year = {2024}, author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R}, title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791160}, issn = {1422-0067}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs & derivatives ; }, abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.}, } @article {pmid38802174, year = {2024}, author = {Hobson, E and McDermott, C}, title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {119-169}, doi = {10.1016/bs.irn.2024.04.004}, pmid = {38802174}, issn = {2162-5514}, mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; }, abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.}, } @article {pmid38802175, year = {2024}, author = {Malaspina, A}, title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {171-207}, doi = {10.1016/bs.irn.2024.04.010}, pmid = {38802175}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; }, abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.}, } @article {pmid38805053, year = {2024}, author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S}, title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3953-3977}, pmid = {38805053}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.}, } @article {pmid38807021, year = {2024}, author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H}, title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1905-1925}, pmid = {38807021}, issn = {1573-6903}, mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Peripheral Nerve Injuries/therapy/metabolism ; Animals ; Nerve Regeneration/physiology ; }, abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.}, } @article {pmid38818523, year = {2024}, author = {Shen, J and Wang, X and Wang, M and Zhang, H}, title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1337442}, pmid = {38818523}, issn = {1664-042X}, abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.}, } @article {pmid38819491, year = {2024}, author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A}, title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {78}, number = {4}, pages = {e22301}, doi = {10.1002/syn.22301}, pmid = {38819491}, issn = {1098-2396}, support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; TEMS-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; }, mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.}, } @article {pmid38819717, year = {2024}, author = {Tappenden, P and Hardiman, O and Kwon, SH and Mon-Yee, M and Galvin, M and McDermott, C and , }, title = {A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.}, journal = {PharmacoEconomics}, volume = {42}, number = {9}, pages = {1003-1016}, pmid = {38819717}, issn = {1179-2027}, support = {NIHR301648//NIHR Sheffield BRC and an NIHR Research Professorship/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/drug therapy ; Humans ; *Cost-Benefit Analysis ; *Quality-Adjusted Life Years ; United Kingdom ; *Models, Economic ; Disease Progression ; Biomedical Technology/economics ; Technology Assessment, Biomedical ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon.

OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective.

METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness.

RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness.

CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.}, } @article {pmid38822985, year = {2024}, author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB}, title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1926-1944}, pmid = {38822985}, issn = {1573-6903}, mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use/pharmacology ; }, abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.}, } @article {pmid38823229, year = {2024}, author = {Roman-Pognuz, E and Rigutti, S and Colussi, G and Lena, E and Bonsano, M and Lucangelo, U}, title = {Acute esophageal necrosis following cardiac arrest: A rare and lethal syndrome with diagnostic challenges.}, journal = {International journal of surgery case reports}, volume = {120}, number = {}, pages = {109751}, pmid = {38823229}, issn = {2210-2612}, abstract = {Acute esophageal necrosis (AEN) is a condition characterized by the necrosis of the distal portion of the esophageal mucosa. Risk factors predisposing to this condition are associated to compromised vascular perfusion (e.g. diabetes mellitus, chronic kidney disease, advanced age, and hypertension, shock states). Complications of AEN can be severe including UGI stricture, perforation and overall increased mortality. The true incidence of AEN remains uncertain due to potential subclincal presentations and early resolution.

CASE PRESENTATION: The case outlined involves a 66-years-old obese male with history of alcoholism and lymph-edema of the left leg who presented to the emergency department with hematemesis, haemodynamic instability and impaired consciousness. Shortly after initial assessment, the patient went into cardiac arrest with pulse-less electrical activity (PEA). Return of spontaneous circulation (ROSC) was achieved following instigation of ALS protocol, fluid resuscitation and the administration of a total of 5 mg of adrenaline. Following stabilization, a CT scan was performed which reported a moderately enlarged esophagus with a thickened wall, liquid hypodense material within the esophagus and stomach, and liver cirrhosis. The emergent esophagogastroduodenoscopy (EGDS) revealed extensive mucosal findings indicative of diffuse necrosis with initial scarring, which was later diagnosed as AEN. The patient unfortunately deceased in ICU after developing progression of the AEN, post-cardiac arrest syndrome and liver failure.

CLINICAL DISCUSSION: The presented case highlights several crucial clinical issues and management problems related to AEN. To diagnose AEN, EGDS is still the gold-standard since it allows direct inspection of the esophageal mucosal layer. The management of AEN necessitates a multidisciplinary approach that includes aggressive resuscitation, treatment of underlying comorbidities, and supportive care (e.g. proton pump inhibitors). The mortality rate for AEN remains high despite improvements in diagnosis and treatment highlighting the need to recognize this condition early and intervene promptly in the patients affected. Moreover, long-term sequelae like stricture formation of the esophagus and impaired esophageal motility may contribute to morbidity requiring continuos monitoring. Therefore, to optimize outcomes while reducing complications among affected patients, prompt identification associated with appropriate medical measures are essential. More research needs to be done aiming to better understand the pathophysiology of AEN thereby identifying strategies for its prevention or cure.

CONCLUSIONS: AEN is a rare syndrome characterized by upper gastrointestinal bleeding and hypoxic damage of the esophageal mucosa, often associated with ischemia, gastric outlet obstruction, and compromised protective barriers. Treatment involves aggressive resuscitation, proton pump inhibitors, and monitoring for infection or perforation. However, despite intensive efforts, the mortality rate for AEN remains high at 32 %.}, } @article {pmid38825034, year = {2024}, author = {Fang, T and Pacut, P and Bose, A and Sun, Y and Gao, J and Sivakumar, S and Bloom, B and Nascimento Andrade, EI and Trombetta, B and Ghasemi, M}, title = {Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.}, journal = {Neurological research}, volume = {46}, number = {9}, pages = {859-867}, doi = {10.1080/01616412.2024.2362578}, pmid = {38825034}, issn = {1743-1328}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Genetic Testing/methods ; Adult ; Delayed Diagnosis ; Time Factors ; }, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS.

METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis.

RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12 months and remained unchanged from 2007 to 2021 (p = 0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p < 0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p < 0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p = 0.23), a positive genetic test (p = 0.16), different ALS genes (p = 0.25) and sporadic (p = 0.92) or familial (p = 0.85) ALS testing positive for ALS genes did not influence time to diagnosis.

DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.}, } @article {pmid38826246, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.24.595817}, pmid = {38826246}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 [G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid38826483, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38826483}, issn = {2693-5015}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.}, } @article {pmid38829431, year = {2024}, author = {Sabatelli, M and Cerri, F and Zuccarino, R and Patanella, AK and Bernardo, D and Bisogni, G and Tanel, R and Sansone, V and Filosto, M and Lattante, S and Martello, F and Doronzio, PN and Stano, S and Zanfini, BA and Coccia, M and Costantini, EM and Lizio, A and Lucioli, G and Padovani, A and Merlini, GP and Conte, A}, title = {Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5177-5186}, pmid = {38829431}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; Neurofilament Proteins/blood/cerebrospinal fluid ; Disease Progression ; Adult ; Retrospective Studies ; Treatment Outcome ; Cohort Studies ; }, abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.

METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.

RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.

CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.}, } @article {pmid38829511, year = {2025}, author = {Jiang, S and Xu, R}, title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {221-232}, pmid = {38829511}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/pathology/physiopathology ; Autophagy/physiology ; Dysbiosis/complications/microbiology/physiopathology ; Extracellular Vesicles/metabolism ; Gastrointestinal Microbiome/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.}, } @article {pmid38829866, year = {2024}, author = {Laurido-Soto, OJ and Faust, IM and Nielsen, SS and Racette, BA}, title = {Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304083}, pmid = {38829866}, issn = {1932-6203}, support = {K01 ES028295/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Medicare ; Male ; Female ; United States ; Aged ; Retrospective Studies ; Aged, 80 and over ; Guideline Adherence/statistics & numerical data ; Middle Aged ; Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.

METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist.

RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS.

CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.}, } @article {pmid38830181, year = {2024}, author = {Weemering, DN and Beelen, A and Kliest, T and van Leeuwen, LAG and van den Berg, LH and van Eijk, RPA}, title = {Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.}, journal = {Neurology}, volume = {103}, number = {1}, pages = {e209503}, pmid = {38830181}, issn = {1526-632X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Clinical Trials as Topic ; *Patient Participation ; Patient Selection ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.

METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models.

RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001).

DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.}, } @article {pmid38832321, year = {2024}, author = {Patel, JS and McCall, NS and Thomas, M and Zhou, J and Higgins, KA and Bradley, JD and Tian, S and McDonald, MW and Kesarwala, AH and Stokes, WA}, title = {Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.}, journal = {International journal of particle therapy}, volume = {12}, number = {}, pages = {100016}, pmid = {38832321}, issn = {2331-5180}, abstract = {PURPOSE: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution.

MATERIALS AND METHODS: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans.

RESULTS: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03).

CONCLUSION: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.}, } @article {pmid38833116, year = {2024}, author = {Mubeen, H and Masood, A and Zafar, A and Khan, ZQ and Khan, MQ and Nisa, AU}, title = {Insights into AlphaFold's breakthrough in neurodegenerative diseases.}, journal = {Irish journal of medical science}, volume = {193}, number = {5}, pages = {2577-2588}, pmid = {38833116}, issn = {1863-4362}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; Artificial Intelligence ; Deep Learning ; Parkinson Disease ; Alzheimer Disease ; Algorithms ; Frontotemporal Dementia/genetics ; }, abstract = {Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.}, } @article {pmid38835175, year = {2024}, author = {Barclay, G and Barbato, M and Yerbury, R and Harnish, L and Miranda, N}, title = {Bispectral Index monitoring of palliative sedation for home withdrawal of tracheostomy ventilation: A case report.}, journal = {Palliative medicine}, volume = {38}, number = {7}, pages = {755-758}, doi = {10.1177/02692163241257580}, pmid = {38835175}, issn = {1477-030X}, mesh = {Humans ; Male ; *Consciousness Monitors ; Deep Sedation ; *Hypnotics and Sedatives/administration & dosage/therapeutic use ; Motor Neuron Disease/therapy ; *Palliative Care ; *Respiration, Artificial ; Tracheostomy ; *Withholding Treatment ; }, abstract = {BACKGROUND: Tracheostomy ventilation in motor neurone disease is an uncommon life-sustaining treatment. Best practice is having a plan for ventilation withdrawal, but the literature to guide practice is limited. Case reports have documented standard doses of opioids and benzodiazepines used for sedation in such cases.

CASE: A 49-year-old man was diagnosed with motor neurone disease in 2016. He commenced tracheostomy ventilation in 2018. In 2022 and 2023, planning was undertaken, at the patient's request, for withdrawal of tracheostomy ventilation at home, when he was no longer able to communicate with technology.

CASE PLANNING: Planning included Bispectral Index monitoring prior to cessation of ventilation, ensuring this only occurred when deep sedation was achieved. After ventilation withdrawal in 2023, a retrospective review of medications given and his level of sedation on monitoring was undertaken, with family consent.

OUTCOME: Ventilation withdrawal was initiated after deep sedation was achieved, 6 h after commencing subcutaneous infusions of morphine, midazolam, clonazepam and phenobarbital.

LESSONS: Doses required to achieve acceptable sedation exceeded literature reports. Achieving deep sedation was a longer than expected process.

CONCLUSION: More research using an objective measure of sedation is required, as clinical assessment of sedation in this context is compromised.}, } @article {pmid38840222, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {32}, pmid = {38840222}, issn = {1756-6606}, support = {RF1 NS112719/NS/NINDS NIH HHS/United States ; RF1NS112719/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *MutL Protein Homolog 1/metabolism ; *DNA Damage ; *Protein Binding/drug effects ; Cell Line, Tumor ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism ; Middle Aged ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.}, } @article {pmid38848044, year = {2025}, author = {Samalia, P and Niederer, R}, title = {Letter to the Editor: Comment on Raad et al's "Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience".}, journal = {Ocular immunology and inflammation}, volume = {33}, number = {3}, pages = {377}, doi = {10.1080/09273948.2024.2362879}, pmid = {38848044}, issn = {1744-5078}, } @article {pmid38848664, year = {2024}, author = {Morioka, D and Sagisaka, R and Nakagawa, K and Takahashi, H and Tanaka, H}, title = {Effect of timing of advanced life support on out-of-hospital cardiac arrests at home.}, journal = {The American journal of emergency medicine}, volume = {82}, number = {}, pages = {94-100}, doi = {10.1016/j.ajem.2024.05.021}, pmid = {38848664}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Epinephrine/administration & dosage/therapeutic use ; Japan/epidemiology ; Middle Aged ; *Emergency Medical Services ; *Advanced Cardiac Life Support/methods ; Intubation, Intratracheal/statistics & numerical data ; Time-to-Treatment/statistics & numerical data ; Aged, 80 and over ; Registries ; Time Factors ; Return of Spontaneous Circulation ; Cardiopulmonary Resuscitation/methods ; }, abstract = {AIM: In cases of out-of-hospital cardiac arrests (OHCA) occurring at home, Japanese emergency medical services personnel decide whether to provide treatment on the scene or during transport based on their judgment. This study aimed to evaluate the association between the timing of advanced life support (ALS) (i.e., endotracheal intubation [ETI] or adrenaline administration) for OHCA at home and prognosis.

METHOD: This retrospective cohort study used data from the Japan Utstein Registry and emergency transport data collected from patients who underwent pre-hospital ETI (n = 6806) and received adrenaline (n = 22,636) between 2016 and 2019. The timing of ETI or adrenaline administration was determined as "on the scene" or "in the ambulance." Multiple logistic regression analysis was used to estimate the association among the timing of ALS implementation, pre-hospital return of spontaneous circulation (ROSC), and survival at 1 month.

RESULT: ETI on the scene was significantly positively associated with pre-hospital ROSC (adjusted odds ratio [AOR], 1.81; 95% confidence interval [CI], 1.57-2.09) and survival at 1 month (AOR, 1.81; 95% CI, 1.47-2.23). Adrenaline administration on the scene was significantly positively associated with pre-hospital ROSC (AOR, 2.51; 95% CI, 2.33-2.70) and survival at 1 month (AOR, 2.13; 95% CI, 1.89-2.40).

CONCLUSION: Our analysis suggests performing ALS on the scene was associated with pre-hospital ROSC and survival at 1 month. Further efforts are needed to increase the rate of ALS implementation on the scene by emergency life-saving technicians.}, } @article {pmid38850875, year = {2024}, author = {Coen, M and Benyamine, A and Delmont, E and Kaplanski, G and Bouabdallah, R and Xerri, L and Attarian, S and Serratrice, J}, title = {Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.}, journal = {Pathology, research and practice}, volume = {260}, number = {}, pages = {155377}, doi = {10.1016/j.prp.2024.155377}, pmid = {38850875}, issn = {1618-0631}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Lymphoma, B-Cell/pathology/immunology ; Aged ; Adult ; }, abstract = {INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas.

METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected.

RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease.

CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.}, } @article {pmid38852112, year = {2024}, author = {Leighton, DJ and Ansari, M and Newton, J and Cleary, E and Stephenson, L and Beswick, E and Carod Artal, J and Davenport, R and Duncan, C and Gorrie, GH and Morrison, I and Swingler, R and Deary, IJ and Porteous, M and Chandran, S and Pal, S and , }, title = {Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5256-5266}, pmid = {38852112}, issn = {1432-1459}, support = {CAF/MND/15/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; CAF/MND/15/01//MND Scotland/ ; CAF/MND/15/01/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Scotland/epidemiology ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Phenotype ; *C9orf72 Protein/genetics ; Genotype ; Adult ; DNA Repeat Expansion/genetics ; Cohort Studies ; Aged, 80 and over ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.

METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.

RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.

CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.}, } @article {pmid38853922, year = {2024}, 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, MA 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 = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853922}, 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 pathological 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 ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize 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 neurodegenerative disease patients.}, } @article {pmid38855716, year = {2024}, author = {Morganroth, J and Bardakjian, TM and Dratch, L and Quinn, CC and Elman, LB}, title = {Enhancing Clinical Infrastructure for the Delivery of Intrathecal and Genetic Therapies: A Qalsody (Tofersen) Model for Patients With SOD1-ALS.}, journal = {Neurology. Clinical practice}, volume = {14}, number = {4}, pages = {e200303}, pmid = {38855716}, issn = {2163-0402}, abstract = {BACKGROUND: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.

RECENT FINDINGS: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.

IMPLICATIONS FOR PRACTICE: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.}, } @article {pmid38856793, year = {2025}, author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R}, title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {386-411}, pmid = {38856793}, issn = {1559-1182}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; *Nerve Growth Factors/genetics ; Gene Transfer Techniques ; Genetic Vectors ; }, abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.}, } @article {pmid38856890, year = {2024}, author = {Tripathi, S and Bhawana, }, title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.}, journal = {Neurochemical research}, volume = {49}, number = {9}, pages = {2319-2335}, pmid = {38856890}, issn = {1573-6903}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.}, } @article {pmid38859699, year = {2024}, author = {Finsterer, J and Strobl, W}, title = {Gastrointestinal involvement in neuromuscular disorders.}, journal = {Journal of gastroenterology and hepatology}, volume = {39}, number = {10}, pages = {1982-1993}, doi = {10.1111/jgh.16650}, pmid = {38859699}, issn = {1440-1746}, mesh = {Humans ; *Neuromuscular Diseases/complications/etiology ; *Gastrointestinal Diseases/etiology/therapy/diagnosis ; Myotonic Dystrophy/complications/diagnosis/physiopathology ; Mitochondrial Diseases/complications ; }, abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.}, } @article {pmid38860943, year = {2024}, author = {Zhang, Y and Xia, Y and Sun, J}, title = {Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2363880}, pmid = {38860943}, issn = {1949-0984}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; *DNA-Binding Proteins/metabolism/genetics ; *Gastrointestinal Microbiome ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neuroglia/metabolism ; *Probiotics/administration & dosage/pharmacology ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.}, } @article {pmid38864944, year = {2024}, author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y}, title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Neurochemical research}, volume = {49}, number = {10}, pages = {2653-2667}, pmid = {38864944}, issn = {1573-6903}, mesh = {*Ferroptosis/drug effects/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; Animals ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; Antioxidants/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.}, } @article {pmid38867220, year = {2024}, author = {Jia, Q and Song, Y and Zhang, C and Li, M and Feng, L and Sugimoto, K and Zhang, X and Liu, J and Gao, Y}, title = {Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {231}, pmid = {38867220}, issn = {2662-7671}, support = {QN2021110001L//National Foreign Expert Project/ ; 2018, 12//Chinese Medicine Inheritance and Innovation Talent Project Leading Talent Support Program of National Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Medicine, Chinese Traditional/methods ; Female ; Male ; Middle Aged ; Surveys and Questionnaires ; Aged ; China ; Adult ; Quality of Life ; Qualitative Research ; }, abstract = {BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.

MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.

RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.

CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).}, } @article {pmid38869826, year = {2024}, author = {Wang, H and Zeng, R}, title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {4826-4851}, pmid = {38869826}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.}, } @article {pmid38872258, year = {2024}, author = {Xiong, B and Yang, C and Yang, X and Luo, S and Li, S and Chen, C and He, K and Nie, L and Li, P and Li, S and Huang, H and Liu, J and Zhang, Z and Xie, Y and Zou, L and Yang, X}, title = {Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1[G93A] transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14692}, pmid = {38872258}, issn = {1755-5949}, support = {SZSM201611090//Sanming Project of Medicine in Shenzhen/ ; 82171583//National Natural Science Foundation of China/ ; JCYJ20200109144418639//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; JCYJ20200109150717745//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Sirtuin 1/metabolism ; Mice ; *NF-kappa B/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Furans/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Interleukin-1beta/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Lignans/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Motor Neurons/drug effects/pathology/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.

METHODS: A-1 at 33.3 mg/kg was administrated in SOD1[G93A] transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.

RESULTS: A-1 administration in SOD1[G93A] mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.

CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.}, } @article {pmid38873369, year = {2024}, author = {Hong, J and Kim, GC and Cha, JG and Park, J and Park, B and Park, SY and Kim, SU}, title = {Transcholecystic Duodenal Drainage as an Alternative Decompression Method for Afferent Loop Syndrome: Two Case Reports.}, journal = {Journal of the Korean Society of Radiology}, volume = {85}, number = {3}, pages = {661-667}, pmid = {38873369}, issn = {2951-0805}, abstract = {Afferent loop syndrome (ALS) is a rare complication of gastrectomies and gastrointestinal reconstruction. This can predispose patients to fatal conditions, such as cholangitis, pancreatitis, and duodenal perforation with peritonitis. Therefore, emergency decompression is necessary to prevent these complications. Herein, we report two cases in which transcholecystic duodenal drainage, an alternative decompression treatment, was performed in ALS patients without bile duct dilatation. Two patients who underwent distal gastrectomy with Billroth II anastomosis sought consultation in an emergency department for epigastric pain and vomiting. On CT, ALS with acute pancreatitis was diagnosed. However, biliary access could not be achieved because of the absence of bile duct dilatation. To overcome this problem, a duodenal drainage catheter was placed to decompress the afferent loop after traversing the cystic duct via a transcholecystic approach. The patients were discharged without additional surgical treatment 2 weeks and 1 month after drainage.}, } @article {pmid38875517, year = {2024}, author = {Michielsen, A and van Veenhuijzen, K and Janse van Mantgem, MR and van Es, MA and Veldink, JH and van Eijk, RPA and van den Berg, LH and Westeneng, HJ}, title = {Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209603}, pmid = {38875517}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/metabolism/pathology ; *Magnetic Resonance Imaging ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Disease Progression ; Cognition/physiology ; Adult ; Energy Metabolism/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.

RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).

DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.}, } @article {pmid38878150, year = {2025}, author = {Wang, F and Wen, H and Liu, L and Aisa, HA and Xin, X}, title = {A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.}, journal = {Inflammation}, volume = {48}, number = {1}, pages = {361-371}, pmid = {38878150}, issn = {1573-2576}, support = {2020YFE0205600//the National Key Research and Development Program of China/ ; U1703235//the National Natural Science Foundation of China/ ; }, mesh = {*Lignans/pharmacology/chemistry ; *Cyclooxygenase 2/metabolism ; Animals ; *Nitric Oxide Synthase Type II/metabolism/antagonists & inhibitors ; Mice ; *NF-kappa B/metabolism ; *MAP Kinase Signaling System/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; *Anti-Inflammatory Agents/pharmacology ; Cell Line ; Lipopolysaccharides ; Microglia/drug effects ; }, abstract = {Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.}, } @article {pmid38878554, year = {2024}, author = {Mincic, AM and Antal, M and Filip, L and Miere, D}, title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {7}, pages = {1832-1849}, doi = {10.1016/j.clnu.2024.05.036}, pmid = {38878554}, issn = {1532-1983}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/therapy ; *Probiotics/administration & dosage/therapeutic use ; *Prebiotics/administration & dosage ; *Dysbiosis/therapy/microbiology ; Animals ; Fecal Microbiota Transplantation ; }, abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.

RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.

CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.}, } @article {pmid38878774, year = {2024}, author = {Kumbier, K and Roth, M and Li, Z and Lazzari-Dean, J and Waters, C and Hammerlindl, S and Rinaldi, C and Huang, P and Korben, VA and , and Phatnani, H and Shneider, N and Jacobson, MP and Wu, LF and Altschuler, SJ}, title = {Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.}, journal = {Developmental cell}, volume = {59}, number = {16}, pages = {2134-2142.e6}, doi = {10.1016/j.devcel.2024.05.011}, pmid = {38878774}, issn = {1878-1551}, support = {R01 NS106236/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; Mutation/genetics ; Male ; Female ; Skin/pathology/metabolism ; Machine Learning ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.}, } @article {pmid38885838, year = {2024}, author = {López Sanz, P and Azaña Defez, JM}, title = {Is ILVEN a misnomer? Proposal of MALID as an accurate nomenclature. Response to Polubothu et al's "ILVEN should be genotyped to direct treatment and genetic counselling".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e107-e108}, doi = {10.1016/j.jaad.2024.05.084}, pmid = {38885838}, issn = {1097-6787}, mesh = {Humans ; *Terminology as Topic ; *Genetic Counseling ; Genotype ; }, } @article {pmid38886938, year = {2025}, author = {Helmold, BR and Ahrens, A and Fitzgerald, Z and Ozdinler, PH}, title = {Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.}, journal = {Neural regeneration research}, volume = {20}, number = {3}, pages = {725-739}, pmid = {38886938}, issn = {1673-5374}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.}, } @article {pmid38887384, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Chen, Z and Huang, Y and Pei, X and Zhao, S and Liu, Z and Guo, T and Liang, F}, title = {Immediate Efficacy of Contralateral Acupuncture on SI3 Combined with Active Exercise for Acute Lumbar Sprains: Protocol for a Randomized Controlled Trial.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {2099-2110}, pmid = {38887384}, issn = {1178-7090}, abstract = {PURPOSE: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.

METHODS AND ANALYSIS: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the χ[2] test or Fisher's exact test.

DISCUSSION: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.}, } @article {pmid38889403, year = {2024}, author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X}, title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {855-875}, pmid = {38889403}, issn = {2191-0200}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Astrocytes/metabolism ; Animals ; Cell Communication/physiology ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.}, } @article {pmid38891002, year = {2024}, author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS}, title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891002}, issn = {2304-8158}, abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.}, } @article {pmid38891021, year = {2024}, author = {Nguyen, L}, title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891021}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.}, } @article {pmid38891059, year = {2024}, author = {Dashtmian, AR and Darvishi, FB and Arnold, WD}, title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891059}, issn = {2073-4409}, support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.}, } @article {pmid38891289, year = {2024}, author = {Idziak, R and Waligóra, H and Majchrzak, L and Szulc, P}, title = {Multifunctional Adjuvants Affect Sulfonylureas with Synthetic Auxin Mixture in Weed and Maize Grain Yield.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891289}, issn = {2223-7747}, abstract = {A field study in the years 2017-2019 was carried out to evaluate the impact of novel adjuvant formulations on the efficacy of sulfonylurea and synthetic auxin herbicides. Treatments included nicosulfuron + rimsulfuron + dicamba (N+R+D) at full and reduced rates with three multicomponent (TEST-1, TEST-2, TEST-3) as well as standard (MSO, S) adjuvants. In this greenhouse study, Echinochloa crus-galli seeds were planted and treated with N+R+D at 2-3 leaf stages. The water with the desired pH (4, 7, and 9) for the preparation of the spray liquid was prepared by incorporating citric acid or K3PO4 to either lower or raise the pH of the water. Adjuvant TEST-1 added to the spray liquid at pH 4 increased the effectiveness to 68%, TEST-2 to 81%, and TEST-3 to 80%, compared to 73% and 66% with the MSO and S. The efficacy of N+R+D at pH 7 with TEST-1 increased to 83%, TEST-2 to 82%, and TEST-3 to 77%, but with MSO, it increased to 81%, and 71% with S. Adjuvants TEST-1, TEST-2, and TEST-3 in the liquid at pH 9 increased efficacy to 76 and 80%, compared to 79 and 63% with MSO or S adjuvants. N+R+D applied with TEST-1, TEST-2, and TEST-3 provided greater weed control than herbicides with surfactant (S) and similar or even better than with standard methylated seed oil (MSO) adjuvants. Maize grain yield after herbicide-with-tested-adjuvant application was higher than from an untreated check, and comparable to yield from herbicide-with-MSO treatment, but higher than from S treatment.}, } @article {pmid38891791, year = {2024}, author = {Tokuda, E and Sakashita, Y and Tokoro, N and Date, A and Kosuge, Y and Miyasaka, T}, title = {MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891791}, issn = {1422-0067}, support = {2022-2025//The Takeda Science Foundation/ ; }, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Motor Neurons/metabolism/pathology ; Mice ; *Zinc/metabolism/deficiency ; *Protein Folding ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Mutation ; Mice, Transgenic ; Heterozygote ; Protein Conformation ; }, abstract = {Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term "misfolding" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1[G93A] mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.}, } @article {pmid38891895, year = {2024}, author = {Dabrowska, S and Turano, E and Scambi, I and Virla, F and Nodari, A and Pezzini, F and Galiè, M and Bonetti, B and Mariotti, R}, title = {A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891895}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Microglia/metabolism ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Cell Line ; Adipose Tissue/cytology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu[+]/Zn[+] superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.}, } @article {pmid38895204, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 [S59L].}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.04.597429}, pmid = {38895204}, issn = {2692-8205}, abstract = {Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H [S81L] , and human cell models expressing CHCHD10 [S59L] , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 [S59L] . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 [S59L] -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 [S59L] -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 [S59L] -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H [S81L] . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 [S59L] . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 [S59L] -induced ALS-FTD and possibly other related diseases.}, } @article {pmid38895485, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.06.597745}, pmid = {38895485}, issn = {2692-8205}, abstract = {UNLABELLED: Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

AUTHOR SUMMARY: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.}, } @article {pmid38895672, year = {2024}, author = {Deng, J and Sun, WT and Gong, K and Wang, LP and Li, FZ}, title = {Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis.}, journal = {International journal of ophthalmology}, volume = {17}, number = {6}, pages = {1079-1085}, pmid = {38895672}, issn = {2222-3959}, abstract = {AIM: To compare the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis (MF) in highly myopic eyes.

METHODS: This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths (ALs) ranging from 26-32 mm treated between January 2020 and January 2022. All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo. Based on the features on spectral-domain optical coherence tomography (SD-OCT), the eyes were divided into the MF-only group (Group A, n=15 eyes), MF with central foveal detachment group (Group B, n=20 eyes), and MF with lamellar macular hole group (Group C, n=13 eyes). According to AL, eyes were further divided into three groups: Group D (26.01-28.00 mm, n=12 eyes), Group E (28.01-30.00 mm, n=26 eyes), and Group F (30.01-32.00 mm, n=10 eyes). The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and complications were recorded.

RESULTS: The patients included 16 males and 24 females with the mean age of 56±9.82y. The BCVA and CFT improved in all groups after surgery (P<0.01), while there was no significant difference of the CFT in Group A, B, and C postoperatively (P>0.05). The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D, E, and F. Twenty eyes were injected with sterile air, and 28 eyes were injected with silicone oil for tamponade based on the AL. However, there was no statistically significant difference among Groups D, E, and F in terms of the results of sterile air or silicone oil tamponade. The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade, and the difference was not statistically significant.

CONCLUSION: PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs≤32 mm.}, } @article {pmid38896262, year = {2024}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5541-5548}, pmid = {38896262}, issn = {1432-1459}, support = {XDB39040100//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; 2022-PUMCH-B-017//High-level Hospital Construction Project of Guangdong Provincial People's Hospital/ ; 2022YFC2703904//Key Technologies Research and Development Program/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 81971293//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Middle Aged ; Female ; Adult ; Aged ; Young Adult ; Adolescent ; Aged, 80 and over ; China/epidemiology ; Retrospective Studies ; *C9orf72 Protein/genetics ; Age of Onset ; Mutation ; Phenotype ; Exome Sequencing ; Genotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.

METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.

RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.

CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.}, } @article {pmid38898231, year = {2024}, author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N}, title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.}, journal = {Nature reviews. Neuroscience}, volume = {25}, number = {8}, pages = {553-572}, pmid = {38898231}, issn = {1471-0048}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Central Nervous System Diseases/therapy/genetics ; Animals ; Translational Research, Biomedical/methods ; Gene Transfer Techniques/trends ; }, abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.}, } @article {pmid38904729, year = {2024}, author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC}, title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {775}, pmid = {38904729}, issn = {1573-4978}, support = {304496/2023-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; }, abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.}, } @article {pmid38906677, year = {2024}, author = {Au, WH and Miller-Fleming, L and Sanchez-Martinez, A and Lee, JA and Twyning, MJ and Prag, HA and Raik, L and Allen, SP and Shaw, PJ and Ferraiuolo, L and Mortiboys, H and Whitworth, AJ}, title = {Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.}, journal = {Life science alliance}, volume = {7}, number = {9}, pages = {}, pmid = {38906677}, issn = {2575-1077}, support = {/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Oxidative Stress ; *NF-E2-Related Factor 2/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; *Mitochondria/metabolism ; Animals ; *Disease Models, Animal ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Humans ; *Signal Transduction ; *Frontotemporal Dementia/genetics/metabolism ; *Phenotype ; Drosophila Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitophagy/genetics ; Dimethyl Fumarate/pharmacology ; Male ; }, abstract = {Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.}, } @article {pmid38909342, year = {2024}, author = {Réginault, T and Wibart, P and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Factors associated with survival after early at-home NIV initiation in ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5590-5597}, pmid = {38909342}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/physiopathology ; Male ; Female ; *Noninvasive Ventilation ; Middle Aged ; Retrospective Studies ; Aged ; Respiratory Insufficiency/therapy/mortality/etiology ; Home Care Services ; }, abstract = {BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.

OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival.

METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.

RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9].

CONCLUSION: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.}, } @article {pmid38909349, year = {2024}, author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD}, title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Clinical drug investigation}, volume = {44}, number = {7}, pages = {495-512}, pmid = {38909349}, issn = {1179-1918}, mesh = {Humans ; *Taurochenodeoxycholic Acid/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *Phenylbutyrates/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.}, } @article {pmid38914173, year = {2024}, author = {Tortarolo, M and Re Cecconi, AD and Camporeale, L and Margotta, C and Nardo, G and Pasetto, L and Bonetto, V and Galbiati, M and Crippa, V and Poletti, A and Piccirillo, R and Bendotti, C}, title = {Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106576}, doi = {10.1016/j.nbd.2024.106576}, pmid = {38914173}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Sunitinib/pharmacology ; *Muscle, Skeletal/drug effects/metabolism/pathology ; *STAT3 Transcription Factor/metabolism/antagonists & inhibitors ; *Mice, Transgenic ; *Indoles/pharmacology ; Mice ; *Disease Models, Animal ; *Spinal Cord/metabolism/drug effects/pathology ; *Mice, Inbred C57BL ; *Pyrroles/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Muscular Atrophy/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Disease Progression ; }, abstract = {Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.}, } @article {pmid38914219, year = {2024}, author = {Asahina, R and Takahashi, M and Takano, H and Yao, R and Abe, M and Goshima, Y and Ohshima, T}, title = {The role of CRMP4 in LPS-induced neuroinflammation.}, journal = {Brain research}, volume = {1841}, number = {}, pages = {149094}, doi = {10.1016/j.brainres.2024.149094}, pmid = {38914219}, issn = {1872-6240}, mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Microglia/metabolism/drug effects ; *Mice, Knockout ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; *Neuroinflammatory Diseases/metabolism/chemically induced ; Inflammation/metabolism/chemically induced ; Interleukin-10/metabolism ; Substantia Nigra/metabolism/drug effects ; Mice, Inbred C57BL ; Corpus Striatum/metabolism/drug effects ; Male ; Microfilament Proteins/metabolism ; Arginase/metabolism ; }, abstract = {Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4[-/-] mice compared to Crmp4[+/+]mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4[-/-] mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.}, } @article {pmid38914784, year = {2024}, author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP}, title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {38}, number = {4}, pages = {511-526}, pmid = {38914784}, issn = {1179-190X}, support = {R01 HL147028/HL/NHLBI NIH HHS/United States ; R35 GM140862/GM/NIGMS NIH HHS/United States ; R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; United States ; *United States Food and Drug Administration ; *Drug Approval ; RNA, Messenger/genetics/metabolism ; Animals ; RNA Splicing/drug effects ; }, abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].}, } @article {pmid38915796, year = {2024}, author = {Thonhoff, JR and Beers, DR and Zhao, W and Faridar, A and Thome, A and Wen, S and Zhang, A and Wang, J and Appel, SH}, title = {A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1415106}, pmid = {38915796}, issn = {1664-2295}, abstract = {OBJECTIVE: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.

METHODS: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 10[6] IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.

RESULTS: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.

CONCLUSION: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06307301.}, } @article {pmid38920997, year = {2024}, author = {Nowak, I and Paździor, M and Sarna, R and Madej, M}, title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5436-5453}, pmid = {38920997}, issn = {1467-3045}, abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.}, } @article {pmid38922880, year = {2025}, author = {Goldschmidt-Clermont, PJ and Khan, A and Jimsheleishvili, G and Graham, P and Brooks, A and Silvera, R and Goldschmidt, AJP and Pearse, DD and Dietrich, WD and Levi, AD and Guest, JD}, title = {Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1207-1216}, pmid = {38922880}, issn = {1673-5374}, abstract = {Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.}, } @article {pmid38923364, year = {2024}, author = {Yang, XD and Gong, B and Chen, W and Chen, JJ and Qian, C and Lu, R and Min, Y and Jiang, T and Li, L and Yu, HQ}, title = {In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {11}, number = {32}, pages = {e2402732}, pmid = {38923364}, issn = {2198-3844}, support = {//Program for Changjiang Scholars and Innovative Research Team in University/ ; 51821006//National Natural Science Foundation of China/ ; 52027815//National Natural Science Foundation of China/ ; 52192684//National Natural Science Foundation of China/ ; 22276217//National Natural Science Foundation of China/ ; }, abstract = {The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.}, } @article {pmid38924023, year = {2024}, author = {Spoden, C and Wenzel, O and Erdmann, A and Neitzke, G and Hirschberg, I}, title = {Coping and end-of-life decision-making in ALS: A qualitative interview study.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0306102}, pmid = {38924023}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; *Decision Making ; *Terminal Care/psychology ; Aged ; *Qualitative Research ; Adult ; Germany ; Interviews as Topic ; }, abstract = {How do people with amyotrophic lateral sclerosis (PALS) deal with their diagnosis and engage in end-of-life decision-making? What informational or supportive needs do they have for counselling about life-sustaining treatment and end-of-life care? Which correlating conditions and influences relate to these needs and how do they connect to the wish to die or wish to live? We conducted a qualitative interview study with 13 people with ALS in Germany from March 2019 to April 2021. Data collection and analysis followed a grounded theory-based approach and revealed close relationships between coping, informational needs and the preparedness for decision-making. We identified the coping strategies 'avoid thinking about end-of-life' and its counterpart, 'planning ahead to be well-prepared,' and differentiated the latter into the patterns 'withdrawing from life and taking precautions against life-prolongation' and 'searching for a new meaning in life and preparing for life-sustaining treatment'. The approaches are based on individual perceptions, attitudes and motives and can be positively/negatively reinforced by healthcare professionals (HCP), family and other interpersonal networks, but also by disease progression and in reaction to health care services. Type and degree of needs concerning information and counselling differed according to coping strategies. These strategies may vary over time, resulting in different support needs. Our findings signify that deep insight is needed into PALS' coping processes to understand their decision-making about life-sustaining treatment. Healthcare professionals should be sensitive to illness experiences beyond medical aspects and foster coping as a biographical process to better support people with ALS.}, } @article {pmid38924627, year = {2024}, author = {Burkitt-Creedon, JM and Boller, M and Fletcher, DJ and Brainard, BM and Buckley, GJ and Epstein, SE and Fausak, ED and Hopper, K and Lane, SL and Rozanski, EA and Wolf, J}, title = {2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {104-123}, doi = {10.1111/vec.13391}, pmid = {38924627}, issn = {1476-4431}, support = {//Boehringer Ingelheim Animal Health/ ; //Zoetis Animal Health/ ; }, mesh = {Dogs ; Animals ; Cats ; *Cardiopulmonary Resuscitation/veterinary/standards/methods ; *Cat Diseases/therapy ; Dog Diseases/therapy ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.

DESIGN: These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4 weeks.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.

CONCLUSIONS: While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10 years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.}, } @article {pmid38924633, year = {2024}, author = {Wolf, J and Buckley, GJ and Rozanski, EA and Fletcher, DJ and Boller, M and Burkitt-Creedon, JM and Weigand, KA and Crews, M and Fausak, ED and , }, title = {2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {44-75}, doi = {10.1111/vec.13389}, pmid = {38924633}, issn = {1476-4431}, support = {//Zoetis Animal Health/ ; //Boehringer Ingelheim Animal Health/ ; }, mesh = {Animals ; Dogs ; Cats ; *Dog Diseases/therapy/drug therapy ; Cardiopulmonary Resuscitation/veterinary/standards ; Cat Diseases/therapy/drug therapy ; Veterinary Medicine/standards ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.

DESIGN: Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.

CONCLUSIONS: These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.}, } @article {pmid38924779, year = {2024}, author = {Bratches, RWR and Cohen, J and Carpenter-Song, E and Mistler, L and Barr, PJ}, title = {The Feasibility and Acceptability of Sharing Video Recordings of Amyotrophic Lateral Sclerosis Clinical Encounters With Patients and Their Caregivers: Pilot Randomized Clinical Trial.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e57519}, pmid = {38924779}, issn = {2561-326X}, support = {T32 HS013852/HS/AHRQ HHS/United States ; }, abstract = {BACKGROUND: Multidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations.

OBJECTIVE: The objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers.

METHODS: This study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers.

RESULTS: Of the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10).

CONCLUSIONS: Video recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403.}, } @article {pmid38925911, year = {2024}, author = {De La Cruz, E and Esselin, F and Polge, A and Mouzat, K and Guissart, C}, title = {Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {12}, pages = {1219-1220}, doi = {10.1136/jnnp-2024-333939}, pmid = {38925911}, issn = {1468-330X}, } @article {pmid38928874, year = {2024}, author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K}, title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, pmid = {38928874}, issn = {2304-8158}, support = {533-0C20-GS0D-24//University of Gdansk/ ; }, abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.}, } @article {pmid38929462, year = {2024}, author = {De Marchi, I and Buffone, F and Mauro, A and Bruini, I and Vismara, L}, title = {Manual Therapy of Dysphagia in a Patient with Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {6}, pages = {}, pmid = {38929462}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Male ; *Deglutition Disorders/etiology/therapy ; Middle Aged ; Manipulation, Osteopathic/methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable rare neurodegenerative condition, with 45% of cases showing the symptom of dysphagia; its clinical signs are atrophy, weakness, and fasciculations of the facial muscles, tongue, and pharynx. Furthermore, dysphagia is the main cause of aspiration pneumonia. The traditional treatment for dysphagia varies based on the patient's difficulty of swallowing. The initial phase consists of dietary consistency adjustments, progressing to alternatives like nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) in advanced stages. Osteopathic manipulative treatment (OMT) is a complementary 'hands-on' approach that has already shown positive results as an add-on therapy in various health conditions. This study is a case report of a man diagnosed with ALS with initial dysphagia, managed with a protocol that extraordinarily included OMT. The patient showed somatic dysfunctions in the mediastinal region, upper cervical region, and occipital area which are all anatomically related to the nervous system, especially the glossopharyngeal reflex. At the end of the rehabilitation protocol, there was a reduction in the swallowing problems measured with Strand Scale and swallowing tests, and the patient reported an improved psycho-physical well-being assessed with the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Instead, the neurological function measured with ALSFRS-S remained stable. Although the nature of this study design prevents any causal assumption, the positive results should lead to future randomized controlled trials to assess the effectiveness of OMT as an adjunctive therapeutic proposal to improve the health of ALS patients.}, } @article {pmid38935506, year = {2024}, author = {Halim, DO and Krishnan, G and Hass, EP and Lee, S and Verma, M and Almeida, S and Gu, Y and Kwon, DY and Fazzio, TG and Gao, FB}, title = {The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114375}, pmid = {38935506}, issn = {2211-1247}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R01 HD104971/HD/NICHD NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.}, } @article {pmid38942541, year = {2024}, author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK}, title = {Drug repurposing for neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {207}, number = {}, pages = {249-319}, doi = {10.1016/bs.pmbts.2024.03.035}, pmid = {38942541}, issn = {1878-0814}, mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.}, } @article {pmid38944367, year = {2024}, author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB}, title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.}, journal = {Mitochondrion}, volume = {78}, number = {}, pages = {101926}, doi = {10.1016/j.mito.2024.101926}, pmid = {38944367}, issn = {1872-8278}, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; }, abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.}, } @article {pmid38946579, year = {2024}, author = {Trucco, AP and Backhouse, T and Mioshi, E}, title = {Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {603-610}, pmid = {38946579}, issn = {1473-6551}, mesh = {Humans ; *Frontotemporal Dementia/psychology/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; Behavioral Symptoms/etiology/diagnosis ; }, abstract = {PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature.

FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives.

SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.}, } @article {pmid38948094, year = {2024}, author = {Haider, KH}, title = {Priming mesenchymal stem cells to develop "super stem cells".}, journal = {World journal of stem cells}, volume = {16}, number = {6}, pages = {623-640}, pmid = {38948094}, issn = {1948-0210}, abstract = {The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.}, } @article {pmid38951798, year = {2024}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {651}, pmid = {38951798}, issn = {1471-2164}, support = {P01 AG007232/AG/NIA NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; T32 HL144442/HL/NHLBI NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Ethnicity/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; European People ; East Asian People ; African People ; Hispanic or Latino ; Middle Eastern People ; South Asian People ; Receptors, Peptide ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10[-39]; OR = 4.73, p = 2 × 10[-10]; OR = 2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38960099, year = {2024}, author = {Bhandari, UR and Danish, SM and Ahmad, S and Ikram, M and Nadaf, A and Hasan, N and Kesharwani, P and Ahmad, FJ}, title = {New opportunities for antioxidants in amelioration of neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {221}, number = {}, pages = {111961}, doi = {10.1016/j.mad.2024.111961}, pmid = {38960099}, issn = {1872-6216}, mesh = {Humans ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Oxidative Stress/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.}, } @article {pmid38960473, year = {2024}, author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD}, title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {141}, number = {}, pages = {177-201}, doi = {10.1016/bs.apcsb.2023.12.008}, pmid = {38960473}, issn = {1876-1631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Motor Neuron Disease/genetics/metabolism ; }, abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.}, } @article {pmid38967881, year = {2024}, author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X}, title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5591-5604}, pmid = {38967881}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Pain Management/methods ; Adult ; Pain/etiology/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.}, } @article {pmid38969143, year = {2024}, author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM}, title = {Cannabidiol and neurodegeneration: From molecular mechanisms to clinical benefits.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102386}, doi = {10.1016/j.arr.2024.102386}, pmid = {38969143}, issn = {1872-9649}, mesh = {Humans ; *Cannabidiol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.}, } @article {pmid38972199, year = {2024}, author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H}, title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123112}, doi = {10.1016/j.jns.2024.123112}, pmid = {38972199}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; *Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Disease Progression ; Adult ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.}, } @article {pmid38972779, year = {2024}, author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD}, title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {5}, pages = {e00388}, pmid = {38972779}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; *Mice, Transgenic ; Heat-Shock Proteins/genetics/metabolism ; Hydroxylamines/pharmacology/therapeutic use ; Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism ; Humans ; Mice, Inbred C57BL ; }, abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.}, } @article {pmid38973130, year = {2025}, author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P}, title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {15-21}, doi = {10.1080/21678421.2024.2375330}, pmid = {38973130}, issn = {2167-9223}, mesh = {*Riluzole/therapeutic use/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Deglutition Disorders/drug therapy/etiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.}, } @article {pmid38975145, year = {2024}, author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C}, title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e32688}, pmid = {38975145}, issn = {2405-8440}, abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.}, } @article {pmid38990927, year = {2024}, author = {Srinivasan, V and Homer, V and Barton, D and Clutterbuck-James, A and Jenkins, S and Potter, C and Brock, K and Logan, A and Smith, D and Bruce, L and Nagy, Z and Bach, SP}, title = {A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0291285}, pmid = {38990927}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Treatment Outcome ; Adult ; Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.

PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28.

FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection.

INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.}, } @article {pmid38996643, year = {2024}, author = {Sheehan, Y and Cochrane, A and Treloar, C and Grebely, J and Tedla, N and Lloyd, AR and Lafferty, L}, title = {Understanding hepatitis C virus (HCV) health literacy and educational needs among people in prison to enhance HCV care in prisons.}, journal = {The International journal on drug policy}, volume = {130}, number = {}, pages = {104516}, doi = {10.1016/j.drugpo.2024.104516}, pmid = {38996643}, issn = {1873-4758}, mesh = {Humans ; Male ; *Health Literacy ; *Hepatitis C ; *Prisoners/psychology ; Adult ; Australia ; *Prisons ; Middle Aged ; Health Knowledge, Attitudes, Practice ; Substance Abuse, Intravenous ; }, abstract = {BACKGROUND: Hepatitis C virus (HCV) is a significant concern within prison populations. Provision of HCV testing and treatment for people in prison is expanding and a key component of global elimination efforts. Despite growing service availability, several challenges remain in HCV testing and treatment engagement during incarceration. The PIVOT study demonstrated that a 'one-stop-shop' intervention (point-of-care HCV RNA testing, Fibroscan®, nurse-led clinical assessment, and fast-tracked direct-acting antiviral prescription) enhanced HCV testing and treatment at a reception prison in Australia. Utilising Squier et al's Health Literacy Skills Framework, this analysis aimed to understand HCV health literacy and educational needs among people at a reception prison in Australia.

METHODS: Semi-structured interviews were conducted with twenty-four male PIVOT study participants. Purposive sampling ensured comparable representation of those with: 1) prior HCV testing history (standard pathology / no prior testing), and 2) injecting drug use history (IDU; ever / never).

RESULTS: Varied HCV health literacy levels and educational needs were evident amongst people in prison. Whilst those with multiple incarceration episodes and IDU history (prior knowledge) appeared to have stronger HCV health literacy than those without, substantial gaps in HCV health literacy were evident. Knowledge of HCV transmission risks in prison was high, and most understood the importance of HCV testing and treatment in prison (comprehension), but ability to engage with HCV testing and treatment services, participation in safe injecting behaviours (health-related behaviours), and knowledge of re-infection and re-treatment, within the context of the prison environment, were suboptimal. There was a general desire for increased HCV education in prison.

CONCLUSION: Gaps in HCV health literacy among people in prison were evident, indicating opportunities for improvement. A targeted HCV education program for people in prison, addressing the gaps identified in this analysis, may enhance HCV testing, treatment, and prevention by fostering stronger HCV health literacy among people in prison.}, } @article {pmid38996764, year = {2024}, author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S}, title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.}, journal = {EBioMedicine}, volume = {106}, number = {}, pages = {105235}, pmid = {38996764}, issn = {2352-3964}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Female ; *Disease Models, Animal ; Mice ; *Spinal Cord/metabolism ; *Blood-Brain Barrier/metabolism ; *Insulin-Like Growth Factor I/metabolism ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism ; Ultrasonic Waves ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

METHODS: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.

FINDINGS: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.

INTERPRETATION: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.

FUNDING: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).}, } @article {pmid38997748, year = {2024}, author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H}, title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.}, journal = {Inflammation and regeneration}, volume = {44}, number = {1}, pages = {32}, pmid = {38997748}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.

METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.

RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.

CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.}, } @article {pmid38999371, year = {2024}, author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV}, title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.}, journal = {Journal of clinical medicine}, volume = {13}, number = {13}, pages = {}, pmid = {38999371}, issn = {2077-0383}, abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.}, } @article {pmid38999592, year = {2024}, author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y}, title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999592}, issn = {2223-7747}, support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; }, abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.}, } @article {pmid39002811, year = {2024}, author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS}, title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106603}, doi = {10.1016/j.nbd.2024.106603}, pmid = {39002811}, issn = {1095-953X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Basic Helix-Loop-Helix Proteins ; *Caffeine ; Central Nervous System Stimulants/therapeutic use ; Cognition/physiology/drug effects ; Cognitive Dysfunction/genetics ; Cytochrome P-450 CYP1A1/genetics ; *Cytochrome P-450 CYP1A2/genetics ; *Disease Progression ; *Polymorphism, Single Nucleotide ; Prospective Studies ; *Receptor, Adenosine A2A/genetics ; Receptors, Aryl Hydrocarbon/genetics ; Riluzole/therapeutic use ; }, abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.}, } @article {pmid39006715, year = {2024}, author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J}, title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62310}, pmid = {39006715}, issn = {2168-8184}, abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.}, } @article {pmid39006764, year = {2024}, author = {Yang, C and Liu, G and Chen, X and Le, W}, title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.}, journal = {MedComm}, volume = {5}, number = {7}, pages = {e638}, pmid = {39006764}, issn = {2688-2663}, abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.}, } @article {pmid39007083, year = {2024}, author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM}, title = {Superoxide dismutase and neurological disorders.}, journal = {IBRO neuroscience reports}, volume = {16}, number = {}, pages = {373-394}, pmid = {39007083}, issn = {2667-2421}, abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.}, } @article {pmid39017978, year = {2025}, author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J}, title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.}, journal = {Biological trace element research}, volume = {203}, number = {4}, pages = {2355-2364}, pmid = {39017978}, issn = {1559-0720}, support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/drug therapy ; *Selenium/cerebrospinal fluid ; Middle Aged ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Mutation ; Aged ; *Oligonucleotides/administration & dosage ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.}, } @article {pmid39019674, year = {2024}, author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C}, title = {[Proposals from a French expert panel for respiratory care in ALS patients].}, journal = {Revue des maladies respiratoires}, volume = {41}, number = {8}, pages = {620-637}, doi = {10.1016/j.rmr.2024.06.006}, pmid = {39019674}, issn = {1776-2588}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; Humans ; France/epidemiology ; *Noninvasive Ventilation/methods/standards/instrumentation ; *Respiratory Insufficiency/therapy/etiology ; Respiratory Therapy/methods/standards ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.

METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.

RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.

CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.}, } @article {pmid39020237, year = {2024}, author = {Yuan, ZL and Ren, J and Huang, ML and Qi, YF and Gao, X and Sun, YY and He, YL and Zhu, L and Xue, HD}, title = {A new magnetic resonance imaging-based PUMCH classification system for congenital cervical malformations: devising a standardised diagnosis pathway.}, journal = {Insights into imaging}, volume = {15}, number = {1}, pages = {177}, pmid = {39020237}, issn = {1869-4101}, support = {2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; }, abstract = {OBJECTIVES: To develop an innovative magnetic resonance imaging (MRI)-based PUMCH (Peking Union Medical College Hospital) classification system aimed at standardising the diagnosis of congenital cervical malformations (CCMs) by identifying their distinctive MRI features.

METHODS: Seventy-nine consecutive patients with CCM underwent pre-treatment pelvic MRI; three experienced gynaecological radiologists retrospectively analysed these images. Qualitative assessments included Rock et al's classification; PUMCH classification; haematometra; cervical signal features; ovarian endometriosis; haematosalpinx; and uterine, vaginal, urinary, and musculoskeletal malformations. Quantitative assessments involved the uterine volume, sagittal cervical length, and maximum ovarian cross-sectional area. The surgical treatment types were also recorded. Statistical methods were used to incorporate differences in clinical features and surgical methods into our classification.

RESULTS: Morphologically, CCMs were categorised into three types: type I (53%) was characterised by the presence of a cervix with visible cervical canals; type II (23%) featured an existing cervix with concealed cervical canals; and type III (24%) indicated cervical aplasia, which involves a blind end in the lower part of the uterine corpus. Haematometra was significantly more prevalent in patients with type I CCM than in those with type II (p < 0.001). There were three cervical signal patterns: no signal (27%), no evident layer differentiation (21%), and multi-layer differentiation with haematocele (52%). Most patients (94%) had complete vaginal atresia. Type I CCM patients had a higher likelihood of regaining normal uterovaginal anatomy compared to types II and III.

CONCLUSIONS: Our proposed PUMCH classification system has a high potential for enhancing the efficiency of clinical diagnosis among patients with CCM.

CRITICAL RELEVANCE STATEMENT: The proposed new PUMCH classification promised to elevate the conventional diagnostic trajectory for congenital cervical malformations, offering a valuable framework to refine the selection and planning of surgical interventions, thereby enhancing overall clinical efficacy.

KEY POINTS: Effective classification of congenital cervical malformations is desirable to optimise the diagnostic process. We presented a PUMCH classification of congenital cervical malformations using pelvic MRI. The new classification significantly aids clinical triage for congenital cervical malformations.}, } @article {pmid39022351, year = {2024}, author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G}, title = {Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {7}, pages = {1996-2005}, pmid = {39022351}, issn = {2575-9108}, abstract = {The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to β-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.}, } @article {pmid39025824, year = {2024}, author = {Lorenc, T and Khouja, C and Harden, M and Fulbright, H and Thomas, J}, title = {Defensive healthcare practice: systematic review of qualitative evidence.}, journal = {BMJ open}, volume = {14}, number = {7}, pages = {e085673}, pmid = {39025824}, issn = {2044-6055}, mesh = {Humans ; *Qualitative Research ; *Defensive Medicine ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice.

DESIGN: Systematic review of qualitative data.

DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations & Theses and PROSPERO were searched from 2000 to October 2023.

ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice.

DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically.

RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation.

CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.}, } @article {pmid39031772, year = {2024}, author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Weishaupt, JH and Weyen, U and Koch, JC and Günther, R and Regensburger, M and Boentert, M and Wiesenfarth, M and Koc, Y and Kolzarek, F and Kettemann, D and Norden, J and Bernsen, S and Elmas, Z and Conrad, J and Valkadinov, I and Vidovic, M and Dorst, J and Ludolph, AC and Hesebeck-Brinckmann, J and Spittel, S and Münch, C and Maier, A and Körtvélyessy, P}, title = {Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {333-345}, doi = {10.1002/mus.28182}, pmid = {39031772}, issn = {1097-4598}, support = {(H4017703513237604)//Boris Canessa ALS Stiftung (Düsseldorf, Germany) and Martin Herrenknecht Fonds for ALS Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Female ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; *Neurofilament Proteins/blood ; Treatment Outcome ; Disease Progression ; Adult ; Oligonucleotides/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany.

METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS).

RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80).

DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.}, } @article {pmid39033904, year = {2024}, author = {Lu, XY and Li, MQ and Li, YT and Yao, JY and Zhang, LX and Zeng, ZH and Yu-Liu, and Chen, ZR and Li, CQ and Zhou, XF and Li, F}, title = {Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.}, journal = {Neuropharmacology}, volume = {258}, number = {}, pages = {110089}, doi = {10.1016/j.neuropharm.2024.110089}, pmid = {39033904}, issn = {1873-7064}, mesh = {Animals ; *Valproic Acid/pharmacology/administration & dosage ; *Edaravone/pharmacology ; *Autism Spectrum Disorder/drug therapy/chemically induced ; *Disease Models, Animal ; Female ; *Oxidative Stress/drug effects ; Male ; Administration, Oral ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Brain/drug effects/metabolism/pathology ; Prenatal Exposure Delayed Effects/chemically induced ; Free Radical Scavengers/pharmacology/administration & dosage/therapeutic use ; Dose-Response Relationship, Drug ; Stereotyped Behavior/drug effects ; Behavior, Animal/drug effects ; Social Interaction/drug effects ; }, abstract = {Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.}, } @article {pmid39039445, year = {2024}, author = {Jonsdottir, G and Haraldsdottir, E and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Tryggvadottir, GB and Jonsdottir, H}, title = {Transition to end-of-life care in patients with neurological diseases in an acute hospital ward.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {253}, pmid = {39039445}, issn = {1471-2377}, support = {71545//The Icelandic Nurses´ Association/ ; }, mesh = {Humans ; Male ; *Terminal Care/methods/statistics & numerical data ; Female ; Aged ; Middle Aged ; Retrospective Studies ; *Nervous System Diseases/therapy/diagnosis/epidemiology ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/therapy/diagnosis/mortality ; }, abstract = {BACKGROUND: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously.

OBJECTIVE: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting.

METHOD: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson's disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status.

RESULTS: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007-1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034-2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219-3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision.

CONCLUSIONS: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.}, } @article {pmid39050823, year = {2024}, author = {Min, JH and Sarlus, H and Harris, RA}, title = {Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1408159}, pmid = {39050823}, issn = {1662-5099}, abstract = {The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.}, } @article {pmid39054363, year = {2024}, author = {Weishaupt, JH and Körtvélyessy, P and Schumann, P and Valkadinov, I and Weyen, U and Hesebeck-Brinckmann, J and Weishaupt, K and Endres, M and Andersen, PM and Regensburger, M and Dreger, M and Koch, JC and Conrad, J and Meyer, T}, title = {Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {150}, pmid = {39054363}, issn = {2730-664X}, abstract = {BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1[D91A] in Europe, exceeding 1% in Finno-Scandinavia.

METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1[D91A] allele for up to 16 months with tofersen.

RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1[D91A]. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1[D91A]. The results indicate that both mono- and bi-allelic SOD1[D91A] are causally relevant targets, with a possibly reduced effect size of SOD1[D91Ahet].

CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1[D91A] patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.}, } @article {pmid39054501, year = {2024}, author = {Rahimi Darehbagh, R and Seyedoshohadaei, SA and Ramezani, R and Rezaei, N}, title = {Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {386}, pmid = {39054501}, issn = {2047-783X}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Stem Cell Transplantation/methods/trends ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Neural Stem Cells/transplantation/physiology ; }, abstract = {Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.}, } @article {pmid39059407, year = {2024}, author = {van den Berg, LH and Rothstein, JD and Shaw, PJ and Babu, S and Benatar, M and Bucelli, RC and Genge, A and Glass, JD and Hardiman, O and Libri, V and Mobach, T and Oskarsson, B and Pattee, GL and Ravits, J and Shaw, CE and Weber, M and Zinman, L and Jafar-Nejad, P and Rigo, F and Lin, L and Ferguson, TA and Gotter, AL and Graham, D and Monine, M and Inra, J and Sinks, S and Eraly, S and Garafalo, S and Fradette, S}, title = {Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {901-912}, doi = {10.1016/S1474-4422(24)00216-3}, pmid = {39059407}, issn = {1474-4465}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/pharmacokinetics/administration & dosage/adverse effects/pharmacology ; Aged ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.

METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.

FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.

INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.

FUNDING: Biogen.}, } @article {pmid39061876, year = {2024}, author = {Magalhães, RSS and Monteiro Neto, JR and Ribeiro, GD and Paranhos, LH and Eleutherio, ECA}, title = {Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061876}, issn = {2076-3921}, support = {PROBRAL 88881.371325/2019-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; CNE 201.174/2022 and Posdoc Nota 10 202.267/2019//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; }, abstract = {This work aimed to study the effect of trehalose in protecting cells against Sod1 proteinopathy associated with amyotrophic lateral sclerosis (ALS). Humanized yeast cells in which native Sod1 was replaced by wild-type human Sod1 or an ALS mutant (WT-A4V Sod1 heterodimer) were used as the experimental model. Cells were treated with 10% trehalose (p/v) before or after the appearance of hSod1 proteinopathy induced by oxidative stress. In both conditions, trehalose reduced the number of cells with Sod1 inclusions, increased Sod1 activity, and decreased the levels of intracellular oxidation, demonstrating that trehalose avoids Sod1 misfolding and loss of function in response to oxidative stress. The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms.}, } @article {pmid39062592, year = {2024}, author = {Gao, J and Sterling, E and Hankin, R and Sikal, A and Yao, Y}, title = {Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {7}, pages = {}, pmid = {39062592}, issn = {2218-273X}, support = {W81XWH2210261//United States Department of Defense/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Animals ; Neuromuscular Junction/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.}, } @article {pmid39062967, year = {2024}, author = {Kisielewska, M and Filipski, M and Sebastianka, K and Karaś, D and Molik, K and Choromańska, A}, title = {Investigation into the Neuroprotective and Therapeutic Potential of Plant-Derived Chk2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39062967}, issn = {1422-0067}, mesh = {*Checkpoint Kinase 2/metabolism/antagonists & inhibitors ; Humans ; Animals ; Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry ; Neuroprotective Agents/pharmacology/therapeutic use ; Neoplasms/drug therapy ; DNA Damage/drug effects ; DNA Repair/drug effects ; }, abstract = {Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2's activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy.}, } @article {pmid39072497, year = {2025}, author = {Alonso, JP and Ini, N and Villarejo, A and Belizán, M and Roberti, J}, title = {Amyotrophic lateral sclerosis in Argentina: unveiling the burden of treatment through patient and caregiver perspectives.}, journal = {Disability and rehabilitation}, volume = {47}, number = {7}, pages = {1828-1835}, doi = {10.1080/09638288.2024.2385732}, pmid = {39072497}, issn = {1464-5165}, mesh = {Humans ; Argentina ; *Amyotrophic Lateral Sclerosis/psychology/therapy/rehabilitation/diagnosis/economics ; *Caregivers/psychology ; Female ; Male ; Middle Aged ; *Cost of Illness ; Qualitative Research ; Aged ; Interviews as Topic ; Adult ; Activities of Daily Living ; }, abstract = {PURPOSE: To examine the burden of treatment (BoT) experienced by people with Amyotrophic Lateral Sclerosis (ALS) in Argentina.

METHODS: Qualitative methodological design based on semi-structured interviews. Nineteen semi-structured interviews were conducted (PwALS = 7, informal caregivers= 12). The interview guides were designed based on the literature and BoT theory. Data were analysed following a framework analysis approach.

RESULTS: The research highlighted the arduous journey toward obtaining a diagnosis, marked by delays influenced by healthcare system inefficiencies, lack of disease awareness and pandemic-related anxiety. Receiving the diagnosis was a destabilising experience, triggering the need to reframe self-identity, a new reality. As the disease progressed, patients encountered significant challenges in their daily activities and basic tasks, affecting their ability to work, communicate, and manage personal care. The burden extended beyond the patients to their primary caregivers. Access to specialised care, bureaucratic complexities in securing treatment, and the financial impact of managing the disease posed substantial challenges.

CONCLUSION: The findings offer valuable insights into the experiences of PwALS and their caregivers in Argentina. They underscore the need for increased disease awareness, improved access to specialised care, and enhanced support networks to alleviate the burdens PwALS and their families face.}, } @article {pmid39084211, year = {2024}, author = {Sharma, S and Gilberto, VS and Rask, J and Chatterjee, A and Nagpal, P}, title = {Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {16}, pages = {3009-3021}, doi = {10.1021/acschemneuro.4c00160}, pmid = {39084211}, issn = {1948-7193}, mesh = {Humans ; *Prefrontal Cortex/drug effects/metabolism ; *Organoids/drug effects ; *Inflammasomes/metabolism ; Neuroprotective Agents/pharmacology ; Space Flight ; Weightlessness ; Neurodegenerative Diseases ; Alzheimer Disease/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.}, } @article {pmid39084789, year = {2024}, author = {Wang, H and Zhang, Y and Ren, Y and Liu, Y and Feng, Z and Dong, L}, title = {Mechanism of multiple resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in Avena fatua L. from China.}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105985}, doi = {10.1016/j.pestbp.2024.105985}, pmid = {39084789}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Oxazoles/pharmacology ; China ; *Phenylurea Compounds/pharmacology ; *Acetyl-CoA Carboxylase/genetics/metabolism ; *Propionates/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; Poaceae/drug effects ; Phenylpropionates/pharmacology ; Plant Proteins/genetics/metabolism ; Sulfonylurea Compounds ; }, abstract = {Avena fatua L. is one of the most damaging and malignant weeds in wheat fields in China. Fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon, which belong to Acetyl-CoA carboxylase- (ACCase), acetolactate synthase- (ALS), and photosystem II- (PS II) inhibitors, respectively, are commonly used in wheat fields and have a long history of use on A. fatua. An A. fatua population (R) resistant to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon was collected from a wheat field in 2020. This study explored the mechanisms of target site resistance (TSR) and non-target site resistance (NTSR) in the multi-resistant A. fatua. Whole-plant bioassays showed that the R population had evolved high resistance to fenoxaprop-P-ethyl and moderate resistance to mesosulfuron-methyl and isoproturon. However, no mutations were detected in the ACCase, ALS, or psbA genes in the R population. In addition, the ACCase and ALS gene expression levels in the R group were significantly higher than those in the susceptible population (S) after treatment with fenoxaprop-P-ethyl or mesosulfuron-methyl. In vitro ACCase and ALS activity assays showed that ACCase and ALS from the R population were insensitive to fenoxaprop and mesosulfuron-methyl, respectively, with resistance indices 6.12-fold and 17.46-fold higher than those of the S population. Furthermore, pretreatment with P450 inhibitors significantly (P < 0.05) reversed the multi-resistant A. fatua's resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon. Sethoxydim, flucarbazone‑sodium, chlortoluron, and cypyrafluone were effective in controlling multi-resistance A. fatua. Therefore, the overexpression of ACCase and ALS to synthesize sufficient herbicide-targeting proteins, along with P450-mediated metabolism, conferred resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in the R population.}, } @article {pmid39088003, year = {2024}, author = {Lai, HJ and Kuo, YC and Ting, CH and Yang, CC and Kao, CH and Tsai, YC and Chao, CC and Hsueh, HW and Hsieh, PF and Chang, HY and Wang, IF and Tsai, LK}, title = {Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4240-4253}, doi = {10.1093/brain/awae248}, pmid = {39088003}, issn = {1460-2156}, support = {108-2314-B-002-082-MY3//Ministry of Science and Technology, ROC/ ; MQ999//National Taiwan University Hospital/ ; 112-BIH001//National Taiwan University Hospital Hsinchu branch/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; *Superoxide Dismutase-1/genetics ; Mice ; Male ; Female ; *Mice, Transgenic ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics/metabolism ; Middle Aged ; Aged ; Axons/metabolism ; Disease Models, Animal ; Potassium Channels/metabolism/genetics ; Adult ; }, abstract = {The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS.}, } @article {pmid39091098, year = {2025}, author = {Annetta, MG and Barbato, G and Pisciaroli, E and Marche, B and Sabatelli, M and Pittiruti, M}, title = {Central venous catheter-related thrombosis in patients with amyotrophic lateral sclerosis.}, journal = {The journal of vascular access}, volume = {26}, number = {4}, pages = {1180-1186}, doi = {10.1177/11297298241262821}, pmid = {39091098}, issn = {1724-6032}, mesh = {Humans ; Retrospective Studies ; *Catheterization, Central Venous/adverse effects/instrumentation ; Male ; Female ; Middle Aged ; Risk Factors ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; *Central Venous Catheters ; *Catheterization, Peripheral/adverse effects/instrumentation ; Quadriplegia/diagnosis ; Time Factors ; Adult ; Paraplegia/diagnosis/complications ; *Upper Extremity Deep Vein Thrombosis/etiology/prevention & control/diagnostic imaging ; Risk Assessment ; Treatment Outcome ; Catheters, Indwelling ; }, abstract = {BACKGROUND: Central venous catheterization may be required in patients with amyotrophic lateral sclerosis (ALS) for parenteral nutrition, antibiotic treatment, or blood sampling. Different venous access devices can be taken into consideration-centrally inserted central catheters (CICC), peripherally inserted central catheters (PICC), and femorally inserted central catheters (FICCs)-depending on the clinical conditions of the patients. Regardless of the type of access, the presence of paraplegia or tetraplegia is commonly considered a risk factor for catheter-related thrombosis (CRT).

METHOD: This retrospective study analyzes the rate of CRT and other non-infectious complications associated with central venous access in a cohort of 115 patients with paraplegia or tetraplegia, most of them affected by ALS (n = 109).

RESULTS: In a period of 34 months, from January 2021 to October 2023, we inserted 75 FICCs, 29 CICCs, and 11 PICCs. PICCs were inserted only in patients with preserved motility of the upper limbs. All devices were inserted by trained operators adopting appropriate insertion bundles. We had no immediate or early complication. Though antithrombotic prophylaxis was adopted only in 61.7% of patients, we had no symptomatic CRT. Other non-infectious complications were infrequent (4 out of 115 patients).

CONCLUSION: These results suggest (a) that the presence of paraplegia or tetraplegia is not necessarily associated with an increased risk of CRT, (b) that the adoption of well-designed insertion bundles plays a key role in minimizing non-infectious complications, and (c) that the insertion of FICCs by direct cannulation of the superficial femoral vein at mid-thigh in paraplegic/tetraplegic patients may have the same advantages which have been described in the general population.}, } @article {pmid39104562, year = {2024}, author = {Haikal, A and Ali, AR}, title = {Chemical composition and toxicity studies on Lantana camara L. flower essential oil and its in silico binding and pharmacokinetics to superoxide dismutase 1 for amyotrophic lateral sclerosis (ALS) therapy.}, journal = {RSC advances}, volume = {14}, number = {33}, pages = {24250-24264}, pmid = {39104562}, issn = {2046-2069}, abstract = {Using the gas chromatography mass spectrometry method, the chemical components of essential oil from flowers of Lantana camara growing in Egypt are analyzed. Through this investigation, 22 chemicals from floral oil were identified. Most of the oil is made up of sesquiterpene caryophyllene (15.51%) and monoterpene sabinene (14.90%). When the oil's composition was compared to oils extracted from the same plant on several continents, we observed that the essential components were largely the same with some difference in proportions and some compounds due to geographical differences. A molecular docking study of essential oil components was conducted with human superoxide dismutase 1, a target involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). Isospathulenol showed a comparable docking score to the reference ligand bound to the dismutase enzyme. Isospathulenol showed a reasonable drug score with some safety concerns. In addition, isospathulenol is predicted to have high GI absorption, good permeability through the blood-brain barrier and reasonable bioavailability score with ease access to synthetic modifications. In addition, the same compound is devoid from any violation to Lipinski rules or any PAINS alerts. This may establish the promising characteristics of such a compound to be optimized into potential drug candidates for treatment of ALS.}, } @article {pmid39106020, year = {2024}, author = {Mirmotahari, SA and Aliomrani, M and Hassanzadeh, F and Sirous, H and Rostami, M}, title = {Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {32}, number = {2}, pages = {599-615}, pmid = {39106020}, issn = {2008-2231}, mesh = {*Dimethyl Fumarate/pharmacology/chemistry ; *Multiple Sclerosis/drug therapy ; Animals ; *Molecular Docking Simulation ; *Benzothiazoles/chemistry/pharmacology ; *Riluzole/pharmacology/chemistry ; Mice ; *Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Male ; Cuprizone ; Disease Models, Animal ; Computer Simulation ; Neuroprotective Agents/pharmacology/chemistry ; Remyelination/drug effects ; }, abstract = {BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.

OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.

METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model.

RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.}, } @article {pmid39111227, year = {2024}, author = {Torghabeh, FA and Moghadam, EA and Hosseini, SA}, title = {Simultaneous time-frequency analysis of gait signals of both legs in classifying neurodegenerative diseases.}, journal = {Gait & posture}, volume = {113}, number = {}, pages = {443-451}, doi = {10.1016/j.gaitpost.2024.07.302}, pmid = {39111227}, issn = {1879-2219}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; *Gait Analysis/methods ; Gait Disorders, Neurologic/classification/diagnosis/physiopathology/etiology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Wavelet Analysis ; Male ; Female ; Middle Aged ; Parkinson Disease/diagnosis/physiopathology/classification ; Deep Learning ; Signal Processing, Computer-Assisted ; Case-Control Studies ; Huntington Disease/physiopathology/diagnosis/classification ; Aged ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose significant challenges due to their debilitating nature and limited therapeutic options. Accurate and timely diagnosis is crucial for optimizing patient care and treatment strategies. Gait analysis, utilizing wearable sensors, has shown promise in assessing motor abnormalities associated with NDDs.

RESEARCH QUESTION: Research Question 1 To what extent can analyzing the interaction of both limbs in the time-frequency domain serve as a suitable methodology for accurately classifying NDDs? Research Question 2 How effective is the utilization of color-coded images, in conjunction with deep transfer learning models, for the classification of NDDs?

METHODS: GaitNDD database was used, comprising recordings from patients with Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and healthy controls. The gait signals underwent signal preparation, wavelet coherence analysis, and principal component analysis for feature enhancement. Deep transfer learning models (AlexNet, GoogLeNet, SqueezeNet) were employed for classification. Performance metrics, including accuracy, sensitivity, specificity, precision, and F1 score, were evaluated using 5-fold cross-validation.

RESULTS: The classification performance of the models varied depending on the time window used. For 5-second gait signal segments, AlexNet achieved an accuracy of 95.91 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.49 % and 92.73 %, respectively. For 10-second segments, AlexNet outperformed other models with an accuracy of 99.20 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.75 % and 95.00 %, respectively. Statistical tests confirmed the significance of the extracted features, indicating their discriminative power for classification.

SIGNIFICANCE: The proposed method demonstrated superior performance compared to previous studies, offering a non-invasive and cost-effective approach for the automated diagnosis of NDDs. By analyzing the interaction between both legs during walking using wavelet coherence, and utilizing deep transfer learning models, accurate classification of NDDs was achieved.}, } @article {pmid39116263, year = {2024}, author = {Aguilar-Vázquez, CA and Aguilar-Castillo, SJ and Raymundo-Carrillo, AD}, title = {[Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {1}, pages = {1-8}, pmid = {39116263}, issn = {2448-5667}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/therapy ; *Electrodiagnosis/methods ; }, abstract = {BACKGROUND: Vulpian-Bernhardt syndrome is an atypical form of the motor neuron disease described since the 19th century. The importance of a timely diagnosis lies in the increased survival present in this variant. Due to the clinical rarity and complex diagnosis we report a clinical case of this disease, which is why we describe the typical clinical presentation, the diagnostic approach, and we make a bibliographic review of this neurodegenerative disorder as well.

CLINICAL CASE: Latin American man whose clinical case onset was characterized by thoracic asymmetric and increasing limb weakness, showing affection from distal to proximal upper limbs area. Subsequently, symptoms worsened to the point of limiting day-to-day activities and conditioning patient's physical independence. Physical examination was consistent with motor neuron disease. Nerve conduction studies were performed and confirmed findings compatible with motor neuron involvement limited to thoracic limbs.

CONCLUSION: Vulpian-Bernhardt syndrome is an uncommon form of motor neuron disease. Due to the rarity of its presentation, it is frequent to confuse clinical profile even for trained physicians. The importance of electrodiagnosis relies in identifying the neurogenic origin of the disease, as well as the active denervation and reinnervation data. Considering that with this syndrome patients have a longer survival than with the classic form of amyotrophic lateral sclerosis, it is important to have a clear diagnosis approach in order to provide a better quality of life and supportive treatment.}, } @article {pmid39116956, year = {2024}, author = {Yang, N and Shi, L and Xu, P and Ren, F and Li, C and Qi, X}, title = {Identification of potential drug targets for amyotrophic lateral sclerosis by Mendelian randomization analysis based on brain and plasma proteomics.}, journal = {Experimental gerontology}, volume = {195}, number = {}, pages = {112538}, doi = {10.1016/j.exger.2024.112538}, pmid = {39116956}, issn = {1873-6815}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/drug therapy ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Proteomics/methods ; *Brain/metabolism ; *Protein Interaction Maps ; Anoctamins/genetics ; Bayes Theorem ; Blood Proteins/analysis/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.}, } @article {pmid39119372, year = {2024}, author = {Maristany, AJ and Sa, BC and Murray, C and Subramaniam, AB and Oldak, SE}, title = {Psychiatric Manifestations of Neurological Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64152}, pmid = {39119372}, issn = {2168-8184}, abstract = {Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.}, } @article {pmid39122743, year = {2024}, author = {Shin, B and Kwon, Y and Mittaz, M and Kim, H and Xu, X and Kim, E and Lee, YJ and Lee, J and Yeo, WH and Choo, HJ}, title = {All-in-one wearable drug efficacy assessment systems for bulbar muscle function using amyotrophic lateral sclerosis animal models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6803}, pmid = {39122743}, issn = {2041-1723}, support = {R21 EB031535/EB/NIBIB NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; R21EB031535//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy ; Animals ; *Disease Models, Animal ; *Wearable Electronic Devices ; *Electromyography/methods ; Drug Evaluation, Preclinical ; Deglutition Disorders/physiopathology/etiology ; Muscle, Skeletal/drug effects/physiopathology/innervation ; Humans ; Male ; Motor Neurons/drug effects/physiology ; Rats ; }, abstract = {Preclinical studies are crucial for developing amyotrophic lateral sclerosis drugs. Current FDA-approved drugs have been created by monitoring limb muscle function and histological analysis of amyotrophic lateral sclerosis model animals. Drug candidates for this disease have yet to be tested for bulbar-onset type due to the limitations of traditional preclinical tools: excessive animal use and discrete detection of disease progress. Here, our study introduces an all-in-one, wireless, integrated wearable system for facilitating continuous drug efficacy assessment of dysphagia-related muscles in animals during natural eating behaviors. By incorporating a kirigami-based strain-isolation mechanism, this device mounted on the skin of animals mitigates electromyography signal contamination caused by unpredictable animal movements. Our findings indicate this system, measuring the progression of motor neuron denervation, offers high precision in monitoring drug effects on dysphagia-responsible bulbar muscles. This study paves the way for more humane and efficient approaches to developing treatment solutions for degenerative neuromuscular diseases.}, } @article {pmid39126144, year = {2024}, author = {Briones, MRS and Campos, JH and Ferreira, RC and Schneper, L and Santos, IM and Antoneli, FM and , and Broach, JR}, title = {Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {862-872}, pmid = {39126144}, issn = {1097-4598}, support = {//Tow Foundation/ ; //NIH/ ; 2013/07838-0//FAPESP/ ; 2014/25602-6//FAPESP/ ; //CAPES/ ; 303912/2017-0//CNPq/ ; T32 LM012415/LM/NLM NIH HHS/United States ; 19-SI-459//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genome, Mitochondrial/genetics ; Male ; Female ; *Genome-Wide Association Study ; Middle Aged ; Haplotypes ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease/genetics ; Aged ; Genetic Variation/genetics ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.

METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.

RESULTS: We identified 51 mitogenome variants with p values <10[-7], of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.

DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.}, } @article {pmid39126203, year = {2024}, author = {Tabuchi, R and Momozawa, Y and Hayashi, Y and Noma, H and Ichijo, H and Fujisawa, T}, title = {SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.}, journal = {Database : the journal of biological databases and curation}, volume = {2024}, number = {}, pages = {0}, pmid = {39126203}, issn = {1758-0463}, support = {JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology ; Humans ; *Mutation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Databases, Protein ; Protein Conformation ; Databases, Genetic ; Superoxide Dismutase/genetics/chemistry/metabolism ; }, abstract = {A structural alteration in copper/zinc superoxide dismutase (SOD1) is one of the common features caused by amyotrophic lateral sclerosis (ALS)-linked mutations. Although a large number of SOD1 variants have been reported in ALS patients, the detailed structural properties of each variant are not well summarized. We present SoDCoD, a database of superoxide dismutase conformational diversity, collecting our comprehensive biochemical analyses of the structural changes in SOD1 caused by ALS-linked gene mutations and other perturbations. SoDCoD version 1.0 contains information about the properties of 188 types of SOD1 mutants, including structural changes and their binding to Derlin-1, as well as a set of genes contributing to the proteostasis of mutant-like wild-type SOD1. This database provides valuable insights into the diagnosis and treatment of ALS, particularly by targeting conformational alterations in SOD1. Database URL: https://fujisawagroup.github.io/SoDCoDweb/.}, } @article {pmid39130445, year = {2024}, author = {Phipps, AJ and Dwyer, S and Collins, JM and Kabir, F and Atkinson, RA and Chowdhury, MA and Matthews, L and Dixit, D and Terry, RS and Smith, J and Gueven, N and Bennett, W and Cook, AL and King, AE and Perry, S}, title = {HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1[G93A] mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e34587}, pmid = {39130445}, issn = {2405-8440}, abstract = {The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1[G93A] mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1[G93A] mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.}, } @article {pmid39134696, year = {2024}, author = {Visser, BS and Lipiński, WP and Spruijt, E}, title = {The role of biomolecular condensates in protein aggregation.}, journal = {Nature reviews. Chemistry}, volume = {8}, number = {9}, pages = {686-700}, pmid = {39134696}, issn = {2397-3358}, mesh = {Humans ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Amyloid/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid39135084, year = {2024}, author = {Ma, H and Zhu, M and Chen, M and Li, X and Feng, X}, title = {The role of macrophage plasticity in neurodegenerative diseases.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {81}, pmid = {39135084}, issn = {2050-7771}, support = {PX2023037//Beijing Municipal Administration of Hospitals Incubating Program/ ; }, abstract = {Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer's disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.}, } @article {pmid39138578, year = {2024}, author = {Wasielewska, JM and Chaves, JCS and Cabral-da-Silva, MC and Pecoraro, M and Viljoen, SJ and Nguyen, TH and Bella, V and Oikari, LE and Ooi, L and White, AR}, title = {A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {65}, pmid = {39138578}, issn = {2045-8118}, support = {PhD Scholarship//University of Queensland/ ; PhD Top-Up Scholarship//QIMR Berghofer Medical Research Institute/ ; APP1125796 and 1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Microbubbles ; *DNA-Binding Proteins/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Antibodies/administration & dosage ; Ultrasonic Waves ; Cells, Cultured ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS[+ MB]) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS[+ MB]-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS[+ MB] on human ALS BBB cells remain unexplored.

METHODS: Here we established the first FUS[+ MB]-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS[+ MB] bioeffects in vitro.

RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS[+ MB] as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS[+ MB] treated cells. This was accompanied by the molecular bioeffects of FUS[+ MB] in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS[+ MB] in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS[+ MB] can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model.

CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS[+ MB] and provides a fully-human platform for FUS[+ MB]-mediated drug delivery screening on an ALS BBB in vitro model.}, } @article {pmid39139642, year = {2024}, author = {Liu, X and Li, Y and Huang, L and Kuang, Y and Wu, X and Ma, X and Zhao, B and Lan, J}, title = {Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1450704}, pmid = {39139642}, issn = {1663-9812}, abstract = {The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.}, } @article {pmid39141064, year = {2024}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6667-6679}, pmid = {39141064}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Germany ; Middle Aged ; Aged ; *Disease Progression ; Mutation ; Adult ; Phenotype ; }, abstract = {Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.}, } @article {pmid39144569, year = {2024}, author = {Choudhury, C and Egleton, JE and Butcher, NJ and Russell, AJ and Minchin, RF}, title = {Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {8}, pages = {2326-2332}, pmid = {39144569}, issn = {2575-9108}, abstract = {Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.}, } @article {pmid39145609, year = {2024}, author = {Adil, O and Adeyeye, C and Shamsi, MH}, title = {Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.}, journal = {ACS sensors}, volume = {9}, number = {9}, pages = {4748-4757}, doi = {10.1021/acssensors.4c01150}, pmid = {39145609}, issn = {2379-3694}, support = {R15 GM147885/GM/NIGMS NIH HHS/United States ; }, mesh = {*Graphite/chemistry ; Humans ; *Biomarkers/cerebrospinal fluid ; *Electrochemical Techniques/methods ; *Lasers ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Electrodes ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.}, } @article {pmid39147172, year = {2024}, author = {Acton, S and O'Donnell, MM and Periyasamy, K and Dixit, B and Eishingdrelo, H and Hill, C and Paul Ross, R and Chesnel, L}, title = {LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models.}, journal = {Brain, behavior, and immunity}, volume = {121}, number = {}, pages = {384-402}, doi = {10.1016/j.bbi.2024.08.024}, pmid = {39147172}, issn = {1090-2139}, mesh = {*Bacillus/metabolism ; Animals ; Mice ; Humans ; *Neuroinflammatory Diseases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Male ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14-3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component.}, } @article {pmid39153346, year = {2025}, author = {Khazaei, K and Roshandel, P and Parastar, H}, title = {Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {124966}, doi = {10.1016/j.saa.2024.124966}, pmid = {39153346}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis ; Least-Squares Analysis ; *Principal Component Analysis ; *Spectroscopy, Near-Infrared/methods ; *Hyperspectral Imaging/methods ; Multivariate Analysis ; Discriminant Analysis ; }, abstract = {This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.}, } @article {pmid39153378, year = {2024}, author = {Maramai, S and Saletti, M and Paolino, M and Giuliani, G and Cazzola, J and Spaiardi, P and Talpo, F and Frosini, M and Pifferi, A and Ballarotto, M and Carotti, A and Poggialini, F and Vagaggini, C and Dreassi, E and Giorgi, G and Dondio, G and Cappelli, A and Rosario Biella, G and Anzini, M}, title = {Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.}, journal = {Bioorganic & medicinal chemistry}, volume = {112}, number = {}, pages = {117872}, doi = {10.1016/j.bmc.2024.117872}, pmid = {39153378}, issn = {1464-3391}, mesh = {Animals ; Humans ; Dose-Response Relationship, Drug ; Ligands ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Riluzole/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; Thiazepines/chemical synthesis/chemistry/pharmacology ; }, abstract = {Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na[+] and K[+] currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.}, } @article {pmid39154745, year = {2024}, author = {Vu, D and Park, M and Alhusayen, R}, title = {Response to Chawla et al, "Response to Vu et al's "Efficacy of moxifloxacin as a mono-antibiotic therapy for hidradenitis suppurativa: A retrospective cohort study"".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e177-e178}, doi = {10.1016/j.jaad.2024.08.013}, pmid = {39154745}, issn = {1097-6787}, } @article {pmid39154890, year = {2024}, author = {Brebner, C and Asamoah-Boaheng, M and Zaidel, B and Yap, J and Scheuermeyer, F and Mok, V and Hutton, J and Meckler, G and Schlamp, R and Christenson, J and Grunau, B}, title = {The association of intravenous vs. humeral-intraosseous vascular access with patient outcomes in adult out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {202}, number = {}, pages = {110360}, doi = {10.1016/j.resuscitation.2024.110360}, pmid = {39154890}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; *Infusions, Intraosseous/methods ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; *Registries ; Aged ; Humerus ; Emergency Medical Services/methods ; Treatment Outcome ; Adult ; Propensity Score ; }, abstract = {AIM: While intravenous (IV) vascular access for out-of-hospital cardiac arrest (OHCA) resuscitation is standard, humeral-intraosseous (IO) access is commonly used, despite few supporting data. We investigated the association between IV vs. humeral-IO and outcomes.

METHODS: We utilized BC Cardiac Arrest Registry data, including adult OHCA where the first-attempted intra-arrest vascular access route performed by advanced life support (ALS)-trained paramedics was IV or humeral-IO. We fit a propensity-score adjusted model with inverse probability treatment weighting to estimate the association between IV vs. humeral-IO routes and favorable neurological outcomes (CPC 1-2) and survival at hospital discharge. We repeated models within subgroups defined by initial cardiac rhythm.

RESULTS: We included 2,112 cases; the first-attempted route was IV (n = 1,575) or humeral-IO (n = 537). Time intervals from ALS-paramedic on-scene arrival to vascular access (6.6 vs. 6.9 min) and epinephrine administration (9.0 vs. 9.3 min) were similar between IV and IO groups, respectively. Among IV and humeral-IO groups, 98 (6.2%) and 20 (3.7%) had favorable neurological outcomes. Compared to humeral-IO, an IV-first approach was associated with improved hospital-discharge favorable neurological outcomes (AOR 1.7; 95% CI 1.1-2.7) and survival (AOR 1.5; 95% CI 1.0-2.3). Among shockable rhythm cases, an IV-first approach was associated with improved favorable neurological outcomes (AOR 4.2; 95% CI 2.1-8.2), but not among non-shockable rhythm cases (AOR 0.73; 95% CI 0.39-1.4).

CONCLUSION: An IV-first approach, compared to humeral-IO, for intra-arrest resuscitation was associated with an improved odds of favorable neurological outcomes and survival to hospital discharge. This association was seen among an initial shockable rhythm, but not non-shockable rhythm, subgroups.}, } @article {pmid39156432, year = {2024}, author = {Kaye, AD and Sala, KR and Dethloff, D and Norton, M and Moss, C and Plessala, MJ and Derouen, AG and Lopez Torres, Y and Kim, J and Tirumala, S and Shekoohi, S and Varrassi, G}, title = {The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64846}, pmid = {39156432}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.}, } @article {pmid39162129, year = {2024}, author = {Mazzini, L and De Marchi, F and Buzanska, L and Follenzi, A and Glover, JC and Gelati, M and Lombardi, I and Maioli, M and Mesa-Herrera, F and Mitrečić, D and Olgasi, C and Pivoriūnas, A and Sanchez-Pernaute, R and Sgromo, C and Zychowicz, M and Vescovi, A and Ferrari, D}, title = {Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {24}, number = {9}, pages = {933-954}, doi = {10.1080/14712598.2024.2392307}, pmid = {39162129}, issn = {1744-7682}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Stem Cell Transplantation ; Disease Models, Animal ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published.

AREAS COVERED: This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined.

EXPERT OPINION: Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.}, } @article {pmid39168358, year = {2024}, author = {Ueno, Y and Morishima, Y and Hata, T and Shindo, A and Murata, H and Saito, T and Nakamura, Y and Shindo, K}, title = {Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106639}, doi = {10.1016/j.nbd.2024.106639}, pmid = {39168358}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/blood/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population.

METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies.

CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.}, } @article {pmid39170265, year = {2024}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e35342}, pmid = {39170265}, issn = {2405-8440}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.

METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.

RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R [2] = 5.1 %; p-value = 3.2 × 10[-27]) and clinical characteristics.

CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, } @article {pmid39170988, year = {2024}, author = {Baroni, LM and Funari, MP and So Taa Kum, A and Bestetti, AM and de Oliveira, LB and de Carvalho, MF and Franzini, TAP and de Moura, DTH and Bernardo, WM and de Moura, EGH}, title = {Endoscopic Versus Surgical Treatment for Ampullary Lesions: A Systematic Review With Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e65076}, pmid = {39170988}, issn = {2168-8184}, abstract = {Ampullary lesions (ALs) can be treated through either an endoscopic approach (EA) or a surgical approach (SA). However, it is important to note that EAs carry a significant risk of incomplete resection, while opting for surgical interventions can result in substantial morbidity. We performed a systematic review and meta-analysis for R0 resection, recurrence, adverse events in general, major adverse events, mortality, and length of hospital stay between SAs and EAs. Electronic databases were searched from inception to 2023. We identified nine independent studies. The risk difference was -0.32 (95% CI: -0.50, -0.15; p <0.001) for R0, 0.12 (95% CI: 0.06, 0.19; p < 0.001) for recurrence, -0.22 (95% CI: -0.43, 0.00; p 0.05) for overall adverse events, -0.11 (95% CI: -0.32, 0.10; p = 0.31) for major complications, -0.01 (95% CI: -0.02, 0.01; p = 0.43) for mortality, and -14.69 (95% CI: -19.91, -9.47; p < 0.001) for length of hospital stay. As expected, our data suggest a higher complete resection rate and lower recurrence from surgical interventions, but this is associated with an elevated risk of adverse events and a longer hospital stay.}, } @article {pmid39173710, year = {2025}, author = {Weber, MP and Strobel, RJ and Norman, AV and Kareddy, A and Young, A and Young, S and El Moheb, M and Noona, SWW and Wisniewski, AM and Quader, M and Mazzeffi, M and Yarboro, LT and Teman, NR}, title = {Cardiac Surgical Unit-Advanced Life Support-certified centers are associated with improved failure to rescue after cardiac arrest: A propensity score-matched analysis.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {169}, number = {4}, pages = {1271-1281}, doi = {10.1016/j.jtcvs.2024.08.014}, pmid = {39173710}, issn = {1097-685X}, support = {T32 HL007849/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Heart Arrest/therapy/mortality ; Female ; Propensity Score ; Middle Aged ; Aged ; *Advanced Cardiac Life Support/standards/education ; *Certification ; *Cardiac Surgical Procedures/adverse effects ; *Failure to Rescue, Health Care/statistics & numerical data ; Retrospective Studies ; }, abstract = {OBJECTIVE: The impact of Cardiac Surgical Unit-Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA.

METHODS: Patients undergoing Society of Thoracic Surgeons index operations from 2020 to 2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS-certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with FTR-CA.

RESULTS: A total of 12,209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, 2 patient cohorts were formed (n = 3557). Patients at CSU-ALS centers had greater rates of intensive care unit readmission (3.9% vs 2.3%, P < .01) and total operating room time (340 minutes vs 323 minutes, P < .01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, P < .01). There was no difference in the rate of postoperative cardiac arrest (1.8% vs 2.2%, P = .24) or operative mortality (2.5% vs 2.9%, P = .30). After risk adjustment, CSU-ALS centers (odds ratio, 0.30; 95% confidence interval, 0.12-0.72, P < .01) and greater-volume centers (odds ratio, 0.15; confidence interval, 0.03-0.74, P = .02) had reduced odds of FTR-CA.

CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR-CA. This highlights the importance of well-trained staff and treatment algorithms in the care of patients postcardiac surgery.}, } @article {pmid39174305, year = {2025}, author = {Mohamed Yusoff, AA and Mohd Khair, SZN}, title = {Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {1}, pages = {53-90}, pmid = {39174305}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Mitochondria/metabolism ; Animals ; Mitochondrial Dynamics/physiology ; Mitochondrial Diseases/metabolism ; Mitophagy/physiology ; }, abstract = {Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.}, } @article {pmid39176177, year = {2024}, author = {Al Dera, H and AlQahtani, B}, title = {Molecular mechanisms and antisense oligonucleotide therapies of familial amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102271}, pmid = {39176177}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents considerable challenges in both diagnosis and treatment. It is categorized into sporadic and familial amyotrophic lateral sclerosis (fALS); the latter accounts for approximately 10% of cases and is primarily inherited in an autosomal dominant manner. This review summarizes the molecular genetics of fALS, highlighting key mutations that contribute to its pathogenesis, such as mutations in SOD1, FUS, and C9orf72. Central to this discourse is exploring antisense oligonucleotides (ASOs) that target these genetic aberrations, providing a promising therapeutic strategy. This review provides a detailed overview of the molecular mechanisms underlying fALS and the potential therapeutic value of ASOs, offering new insights into treating neurodegenerative diseases.}, } @article {pmid39177131, year = {2024}, author = {Sheremeta, CL and Yarlagadda, S and Smythe, ML and Noakes, PG}, title = {Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.}, journal = {Current drug targets}, volume = {25}, number = {13}, pages = {885-908}, pmid = {39177131}, issn = {1873-5592}, support = {Project grant,//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Prostaglandins/metabolism ; Animals ; *Central Nervous System/metabolism/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Signal Transduction/drug effects ; Multiple Sclerosis/drug therapy/metabolism ; Inflammation/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.}, } @article {pmid39180054, year = {2024}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {42}, pmid = {39180054}, issn = {2524-3489}, abstract = {OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.

METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n = 85) and user experiences after provision (experience group, n = 14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.

RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n = 85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n = 14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n = 10), and 28.6% (n = 4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was + 57 demonstrating strong patient satisfaction.

CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.}, } @article {pmid39180568, year = {2024}, author = {Yang, J and Tang, C}, title = {Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {35}, number = {4}, pages = {711-723}, pmid = {39180568}, issn = {1432-1777}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; *Phenotype ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Alzheimer Disease/genetics/diagnostic imaging ; Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Parkinson Disease/genetics/diagnostic imaging ; Brain/diagnostic imaging/pathology/metabolism ; Multiple Sclerosis/genetics/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.}, } @article {pmid39180748, year = {2024}, author = {Liu, Z and Zhang, H and Lu, K and Chen, L and Zhang, Y and Xu, Z and Zhou, H and Sun, J and Xu, M and Ouyang, Q and Thompson, GJ and Yang, Y and Su, N and Cai, X and Cao, L and Zhao, Y and Jiang, L and Zheng, Y and Zhang, X}, title = {Low-intensity pulsed ultrasound modulates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114660}, doi = {10.1016/j.celrep.2024.114660}, pmid = {39180748}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Disease Progression ; *Ultrasonic Waves ; *Mice, Transgenic ; *Motor Cortex/pathology/metabolism ; TRPV Cation Channels/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Cerebrovascular Circulation ; Ultrasonic Therapy/methods ; Mice, Inbred C57BL ; Male ; Endothelial Cells/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord, and there are no effective drug treatments. Low-intensity pulsed ultrasound (LIPUS) has garnered attention as a promising noninvasive neuromodulation method. In this study, we investigate its effects on the motor cortex and underlying mechanisms using the SOD1[G93A] mouse model of ALS. Our results show that LIPUS treatment delays disease onset and prolongs lifespan in ALS mice. LIPUS significantly increases cerebral blood flow in the motor cortex by preserving vascular endothelial cell integrity and increasing microvascular density, which may be mediated via the ion channel TRPV4. RNA sequencing analysis reveals that LIPUS substantially reduces the expression of genes associated with neuroinflammation. These findings suggest that LIPUS applied to the motor cortex may represent a potentially effective therapeutic tool for the treatment of ALS.}, } @article {pmid39180957, year = {2024}, author = {Harkins, AL and Ambegaokar, PP and Keeler, AM}, title = {Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {4}, pages = {e00435}, pmid = {39180957}, issn = {1878-7479}, support = {P01 HL158506/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Dependovirus/genetics/immunology ; *Genetic Therapy/methods ; *Genetic Vectors/immunology/administration & dosage ; Animals ; Central Nervous System/immunology ; Gene Transfer Techniques ; Central Nervous System Diseases/therapy/immunology ; }, abstract = {Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.}, } @article {pmid39181624, year = {2024}, author = {Mousele, C and Holden, D and Gnanapavan, S}, title = {Neurofilaments in neurologic disease.}, journal = {Advances in clinical chemistry}, volume = {123}, number = {}, pages = {65-128}, doi = {10.1016/bs.acc.2024.06.010}, pmid = {39181624}, issn = {2162-9471}, mesh = {Humans ; *Nervous System Diseases/pathology/metabolism/diagnosis ; *Biomarkers ; Neurofilament Proteins/cerebrospinal fluid/metabolism ; Intermediate Filaments/metabolism ; Animals ; }, abstract = {Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.}, } @article {pmid39182251, year = {2024}, author = {Peng, Y and Liu, G and Li, S and Li, Z and Song, J}, title = {A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {159}, number = {}, pages = {106691}, doi = {10.1016/j.jmbbm.2024.106691}, pmid = {39182251}, issn = {1878-0180}, mesh = {*Machine Learning ; *Mechanical Phenomena ; *Anterior Cruciate Ligament Reconstruction/methods ; Materials Testing ; Humans ; Anterior Cruciate Ligament/surgery ; Neural Networks, Computer ; Biomechanical Phenomena ; Ligaments/surgery ; Artificial Organs ; Mechanical Tests ; }, abstract = {The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.}, } @article {pmid39182589, year = {2024}, author = {Pupillo, E and Bianchi, E and Bonetto, V and Pasetto, L and Bendotti, C and Paganoni, S and Mandrioli, J and Mazzini, L and , }, title = {Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {122}, number = {}, pages = {456-462}, doi = {10.1016/j.bbi.2024.08.044}, pmid = {39182589}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; Middle Aged ; Double-Blind Method ; Vital Capacity ; Aged ; *Disease Progression ; Biomarkers/blood ; Treatment Outcome ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).

OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.

STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.

RESULTS: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline.

CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.

TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.}, } @article {pmid39184100, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4750719/v1}, pmid = {39184100}, issn = {2693-5015}, support = {R01 DA054992/DA/NIDA NIH HHS/United States ; }, abstract = {Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.}, } @article {pmid39184484, year = {2024}, author = {Ozceylan, O and Sezgin-Bayindir, Z}, title = {Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {9}, number = {33}, pages = {35223-35242}, pmid = {39184484}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, prion disease, and Huntington's disease, present a growing health concern as human life expectancy increases. Despite this, effective treatments to halt disease progression remain elusive due to various factors, including challenges in drug delivery across physiological barriers like the blood-brain barrier and patient compliance issues leading to treatment discontinuation. In response, innovative treatment approaches leveraging noninvasive techniques with higher patient compliance are emerging as promising alternatives. This Review aims to synthesize current treatment options and the challenges encountered in managing neurodegenerative diseases, while also exploring innovative treatment modalities. Specifically, noninvasive strategies such as intranasal administration and nanosized drug delivery systems are gaining prominence for their potential to enhance treatment efficacy and patient adherence. Nanosized drug delivery systems, including liposomes, polymeric micelles, and nanoparticles, are evaluated within the context of outstanding studies. The advantages and disadvantages of these approaches are discussed, providing insights into their therapeutic potential and limitations. Through this comprehensive examination, this Review contributes to the ongoing discourse surrounding the development of effective treatments for neurodegenerative diseases.}, } @article {pmid39185360, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Doretti, A and Boscarino, M and Maderna, L and Colombo, E and Soranna, D and Zambon, A and Ticozzi, N and Musumeci, G and Capone, F and Silani, V}, title = {Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101019}, pmid = {39185360}, issn = {2666-7762}, abstract = {BACKGROUND: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.

METHODS: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.

FINDINGS: Forty participants were randomly assigned to real (n = 21) or placebo stimulation (n = 19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09-0.80, p-value = 0.019).

INTERPRETATION: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.

FUNDING: The "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.}, } @article {pmid39187176, year = {2025}, author = {Althobaiti, NA}, title = {Heavy metals exposure and Alzheimer's disease: Underlying mechanisms and advancing therapeutic approaches.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115212}, doi = {10.1016/j.bbr.2024.115212}, pmid = {39187176}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/chemically induced ; *Metals, Heavy/adverse effects ; Animals ; Oxidative Stress/drug effects/physiology ; Environmental Exposure/adverse effects ; Brain/drug effects/metabolism ; }, abstract = {Heavy metals such as lead, cadmium, mercury, and arsenic are prevalent in the environment due to both natural and anthropogenic sources, leading to significant public health concerns. These heavy metals are known to cause damage to the nervous system, potentially leading to a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and attention-deficit hyperactivity disorder (ADHD). The present study examines the complex relationship between heavy metal exposure and AD, focusing on the underlying mechanisms of toxicity and potential therapeutic approaches. This review article highlights how these metals can impair brain function through mechanisms such as oxidative stress, inflammation, and neurotransmitter disruption, ultimately contributing to neurodegenerative diseases like AD. It also addresses the challenges in diagnosing heavy metal-induced cognitive impairments and emphasizes the need for further research to explore effective treatment strategies and preventive measures against heavy metal exposure.}, } @article {pmid39190906, year = {2024}, author = {Yu, J and Chen, S and Zhang, H and Zhang, S and Dong, D}, title = {Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.}, journal = {JMIR public health and surveillance}, volume = {10}, number = {}, pages = {e57353}, pmid = {39190906}, issn = {2369-2960}, mesh = {Humans ; China/epidemiology ; *Rare Diseases/epidemiology/economics ; Male ; Adult ; Female ; Cross-Sectional Studies ; Middle Aged ; *Cost of Illness ; Adolescent ; Child ; *Internet ; Child, Preschool ; Young Adult ; Surveys and Questionnaires ; Aged ; Infant ; }, abstract = {BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.

OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.

METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.

RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.

CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.}, } @article {pmid39192797, year = {2024}, author = {Luo, RC and Wu, XY and Yu, WW and Zheng, YJ and Wang, D}, title = {[Research progress on the relationship between TRAF6 and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {76}, number = {4}, pages = {653-662}, pmid = {39192797}, issn = {0371-0874}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/etiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/etiology ; Multiple Sclerosis/metabolism/physiopathology/etiology ; *Neurodegenerative Diseases/metabolism/etiology ; Parkinson Disease/metabolism/physiopathology ; *TNF Receptor-Associated Factor 6/metabolism/genetics/physiology ; Ubiquitination ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.}, } @article {pmid39193833, year = {2025}, author = {Jalaiei, A and Asadi, MR and Daneshmandpour, Y and Rezazadeh, M and Ghafouri-Fard, S}, title = {Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16200}, doi = {10.1111/jnc.16200}, pmid = {39193833}, issn = {1471-4159}, mesh = {Humans ; *Receptors, Nicotinic/genetics ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.}, } @article {pmid39194682, year = {2024}, author = {Sacharczuk, M and Mickael, ME and Kubick, N and Kamińska, A and Horbańczuk, JO and Atanasov, AG and Religa, P and Ławiński, M}, title = {The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.}, journal = {Current issues in molecular biology}, volume = {46}, number = {8}, pages = {7846-7861}, pmid = {39194682}, issn = {1467-3045}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.}, } @article {pmid39197801, year = {2025}, author = {Zhan, Y and Huang, J and Tang, X and Du, B and Yang, B}, title = {Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {336}, number = {}, pages = {118741}, doi = {10.1016/j.jep.2024.118741}, pmid = {39197801}, issn = {1872-7573}, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; *Membrane Proteins/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nucleotidyltransferases/metabolism ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy ; Spinal Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive.

AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms.

MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1[G93A] NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway.

RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1β mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-β mRNA, but also the levels of cGAS and STING protein in hSOD1[G93A] NSC-34 cells.

CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.}, } @article {pmid39198773, year = {2024}, author = {Lei, Y and Zhang, X and Liu, H and Xu, Z and Xu, P}, title = {Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {300}, pmid = {39198773}, issn = {1471-2377}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy/pathology ; *Sjogren's Syndrome/complications/diagnosis/drug therapy/pathology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals.

CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sjögren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen.

CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.}, } @article {pmid39200200, year = {2024}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Jeon, JE and Chung, JH and Lee, SY}, title = {Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200200}, issn = {2227-9059}, abstract = {UNLABELLED: The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients.

METHODS: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure.

RESULTS: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases.

CONCLUSIONS: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.}, } @article {pmid39201793, year = {2024}, author = {Martin, LJ and Koh, SJ and Price, A and Park, D and Kim, BW}, title = {Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201793}, issn = {1422-0067}, support = {R01 NS052098/NS/NINDS NIH HHS/United States ; R01 AG016282/AG/NIA NIH HHS/United States ; R01 NS034100/NS/NINDS NIH HHS/United States ; NS34100/NS/NINDS NIH HHS/United States ; R01 NS079348/NS/NINDS NIH HHS/United States ; R01 NS065895/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cell Nucleus/metabolism ; Disease Models, Animal ; *DNA Damage ; *Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; NADPH Oxidases/metabolism/genetics ; *Oxidative Stress ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.}, } @article {pmid39204338, year = {2024}, author = {O'Neill, R and Yoo, O and Burcham, P and Lim, LY}, title = {Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.}, journal = {Pharmaceutics}, volume = {16}, number = {8}, pages = {}, pmid = {39204338}, issn = {1999-4923}, support = {000990//Australian Government Research Training Program, Stan Perron Charitable Foundation/ ; }, abstract = {Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.}, } @article {pmid39206899, year = {2024}, author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z}, title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {8}, pages = {291}, doi = {10.31083/j.fbl2908291}, pmid = {39206899}, issn = {2768-6698}, support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.}, } @article {pmid39207520, year = {2024}, author = {Bjelica, B and Petri, S}, title = {Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6508-6513}, pmid = {39207520}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; *Sialorrhea/etiology/therapy/diagnosis ; *Deglutition Disorders/etiology/therapy/diagnosis/physiopathology ; Disease Management ; }, abstract = {The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.}, } @article {pmid39207717, year = {2024}, author = {Ling, Y and Crotti, A}, title = {Emerging Microglial Therapies and Targets in Clinical Trial.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {623-637}, pmid = {39207717}, issn = {2190-5215}, mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.}, } @article {pmid39211392, year = {2024}, author = {Matsuo, K and Nagamatsu, J and Nagata, K and Umeda, R and Shiota, T and Morimoto, S and Suzuki, N and Aoki, M and Okano, H and Nakamori, M and Nishihara, H}, title = {Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP [N345K/+])-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1357204}, pmid = {39211392}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP [N345K/+] carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP [K263E/K263E] and TARDBP [G295S/G295S]) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP [N345K/+] carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP [N345K/+])-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP [N345K/+] carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.}, } @article {pmid39217855, year = {2024}, author = {Zhang, J and Chen, K and Chen, Y and Hua, L and Chen, S and Chen, X and Zou, L and Li, S and Yang, X and Shen, Y}, title = {Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Ultrasonics}, volume = {144}, number = {}, pages = {107449}, doi = {10.1016/j.ultras.2024.107449}, pmid = {39217855}, issn = {1874-9968}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis ; *Disease Models, Animal ; Drug Delivery Systems ; Furans/pharmacology/administration & dosage ; Glucosides/pharmacology/administration & dosage ; *Mice, Transgenic ; Microbubbles ; *Motor Cortex/drug effects/physiopathology ; Mutation ; Superoxide Dismutase-1/genetics ; Ultrasonic Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.

OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.

METHODS: The ALS mouse model with the SOD1[G93A] mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.

RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.

CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.}, } @article {pmid39218010, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Garrahy, S and Habash-Bailey, H and Thomson, R and Opie-Martin, S and Javidnia, S and Leigh, PN and Al-Chalabi, A}, title = {Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {702-707}, pmid = {39218010}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/economics ; Male ; Female ; Middle Aged ; *Social Class ; Aged ; Adult ; Age of Onset ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.}, } @article {pmid39218769, year = {2024}, author = {Sun, J and Zhang, Y}, title = {Microbiome and micronutrient in ALS: From novel mechanisms to new treatments.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00441}, pmid = {39218769}, issn = {1878-7479}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/therapy ; Humans ; *Micronutrients/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; Microbiota/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.}, } @article {pmid39225243, year = {2024}, author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y}, title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {11}, pages = {5323-5349}, doi = {10.1002/ptr.8322}, pmid = {39225243}, issn = {1099-1573}, support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/drug therapy ; *Medicine, Chinese Traditional/methods ; Drugs, Chinese Herbal/pharmacology ; Animals ; }, abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.}, } @article {pmid39233146, year = {2024}, author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q}, title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102472}, doi = {10.1016/j.arr.2024.102472}, pmid = {39233146}, issn = {1872-9649}, mesh = {Humans ; *Glycolysis/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Aging/metabolism ; }, abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.}, } @article {pmid39233624, year = {2024}, author = {Garnier, M and Camdessanché, JP and Cassereau, J and Codron, P}, title = {From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2398199}, pmid = {39233624}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Diagnosis, Differential ; Electromyography/methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.}, } @article {pmid39236857, year = {2024}, author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P}, title = {Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102480}, doi = {10.1016/j.arr.2024.102480}, pmid = {39236857}, issn = {1872-9649}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; *Mitochondria/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.}, } @article {pmid39239063, year = {2024}, author = {Pezeshgi, S and Ghaderi, S and Mohammadi, S and Karimi, N and Ziaadini, B and Mohammadi, M and Fatehi, F}, title = {Diffusion tensor imaging biomarkers and clinical assessments in amyotrophic lateral sclerosis (ALS) patients: an exploratory study.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {9}, pages = {5080-5090}, pmid = {39239063}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Biomarkers are needed to improve diagnosis, gauge progression, and evaluate treatment. Diffusion tensor imaging (DTI) is a promising biomarker for detecting microstructural alterations in the white matter tracts. This study aimed to assess DTI metrics as biomarkers and to examine their relationship with clinical assessments in patients with ALS. Eleven patients with ALS and 21 healthy controls (HCs) underwent 3T MRI with DTI. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were compared between key motor and extra-motor tract groups. Group comparisons and correlations between DTI metrics also correlated with clinical scores of disability (ALSFRS-R), muscle strength (dynamometry), and motor unit loss (MUNIX). Widespread differences were found between patients with ALS and HCs in DTI metrics, including decreased FA and increased diffusivity metrics. However, MD and RD are more sensitive metrics for detecting white matter changes in patients with ALS. Significant interhemispheric correlations between the tract DTI metrics were also observed. DTI metrics showed symmetry between the hemispheres and correlated with the clinical assessments. MD, RD, and AD increases significantly correlated with lower ALSFRS-R and MUNIX scores and weaker dynamometry results. DTI reveals microstructural damage along the motor and extra-motor regions in ALS patients. DTI metrics can serve as quantitative neuroimaging biomarkers for diagnosis, prognosis, monitoring of progression, and treatment. Combined analysis of imaging, electrodiagnostic, and functional biomarkers shows potential for characterizing disease pathophysiology and progression.}, } @article {pmid39242252, year = {2024}, author = {Benmoussa, A and Assernannas, I and Maatoui-Belabbes, H and Dahmaoui, N and Qachouh, M and Cherkaoui, S and Lamchaheb, M and Rachid, M and Madani, A and Khoubila, N}, title = {[Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca].}, journal = {Bulletin du cancer}, volume = {111}, number = {10}, pages = {944-954}, doi = {10.1016/j.bulcan.2024.06.010}, pmid = {39242252}, issn = {1769-6917}, mesh = {Humans ; Male ; Female ; Infant ; Child, Preschool ; Child ; Adolescent ; Adult ; *Anemia, Aplastic/mortality/therapy ; Morocco/epidemiology ; Retrospective Studies ; Prognosis ; Time-to-Treatment ; *Cyclosporine/therapeutic use ; *Antilymphocyte Serum/therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Treatment Outcome ; Delayed Diagnosis ; }, abstract = {Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.}, } @article {pmid39251025, year = {2025}, author = {Del Rosso, JQ and Zaenglein, A and Callender, V and Schlosser, B and Graber, E and Keri, J and Weiss, J}, title = {Response to Reynolds et al's "Guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {1}, pages = {e15}, doi = {10.1016/j.jaad.2024.07.1528}, pmid = {39251025}, issn = {1097-6787}, } @article {pmid39254548, year = {2025}, author = {Zhang, M and Xiang, C and Niu, R and He, X and Luo, W and Liu, W and Gu, R}, title = {Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety.}, journal = {Neural regeneration research}, volume = {20}, number = {7}, pages = {1883-1899}, pmid = {39254548}, issn = {1673-5374}, abstract = {Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood-brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood-brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research.}, } @article {pmid39257530, year = {2024}, author = {Baird, MC and Likhite, SB and Vetter, TA and Caporale, JR and Girard, HB and Roussel, FS and Howard, AE and Schwartz, MK and Reed, AR and Kaleem, A and Zhang, X and Meyer, KC}, title = {Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {3}, pages = {101312}, pmid = {39257530}, issn = {2329-0501}, abstract = {Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 [G93A] microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 [G93A] mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.}, } @article {pmid39264833, year = {2024}, author = {Su, B and He, Z and Liu, J and Li, M and Huang, X}, title = {Mangiferin activates the nuclear factor erythroid 2-related factor pathway to protect SOD1-G93A induced NSC-34 motor neurons from oxidative stress and apoptosis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23849}, doi = {10.1002/jbt.23849}, pmid = {39264833}, issn = {1099-0461}, mesh = {*Xanthones/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Mice ; Animals ; *Motor Neurons/metabolism/drug effects/pathology ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; NAD(P)H Dehydrogenase (Quinone)/metabolism/genetics ; }, abstract = {One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.}, } @article {pmid39268612, year = {2025}, author = {Meyer, T and Schumann, P and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Grosskreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Vidovic, M and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Schmitt, P and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P}, title = {SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {162-171}, doi = {10.1080/21678421.2024.2401131}, pmid = {39268612}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Genetic Testing/methods ; Middle Aged ; *Mutation/genetics ; Aged ; Germany ; Adult ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {OBJECTIVE: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment.

METHODS: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed.

RESULTS: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy.

CONCLUSION: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.}, } @article {pmid39273435, year = {2024}, author = {Di Chiano, M and Sallustio, F and Fiocco, D and Rocchetti, MT and Spano, G and Pontrelli, P and Moschetta, A and Gesualdo, L and Gadaleta, RM and Gallone, A}, title = {Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273435}, issn = {1422-0067}, support = {1062//PON "RICERCA E INNOVAZIONE" 2014-2020-Innovazione/ ; Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - Next Generation EU//National Recovery and Resilience Plan (NRRP)/ ; Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001//Italian Ministry of University and Research, CUP D93C22000890001/ ; Codice progetto n. 2022H9MPZ5//MIUR- PRIN Progetti di Ricerca di Rilevante Interesse Nazionale 2022/ ; Id. 23239//AIRC IG 2019/ ; Call for tender No. 3138 of 16/12/2021 of Italian Ministry of University and Research funded by the European Union//National Recovery and Resilience Plan (NRRP)/ ; Project code: CN00000041, CUP H93C22000430007//NextGenerationEU/ ; PNRR-MR1-2022-12376395//European Union - Next Generation EU - PNRR M6C2/ ; "POFACS" - ARS01_00640 -", D.D. 1211/2020 and 1104/2021//Italian Ministry of University and Research (MIUR)/ ; PRA-HE 2021//University of Foggia/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Probiotics/therapeutic use ; Dysbiosis/microbiology ; Brain-Gut Axis ; Animals ; }, abstract = {Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.}, } @article {pmid39277366, year = {2024}, author = {Weng, WF and Yao, X and Zhao, M and Fang, Z and Yang, S and Ruan, JJ}, title = {Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106039}, doi = {10.1016/j.pestbp.2024.106039}, pmid = {39277366}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Fagopyrum/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; }, abstract = {Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.}, } @article {pmid39278909, year = {2024}, author = {Reis, ALG and Maximino, JR and Lage, LAPC and Gomes, HR and Pereira, J and Brofman, PRS and Senegaglia, AC and Rebelatto, CLK and Daga, DR and Paiva, WS and Chadi, G}, title = {Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.}, journal = {Stem cell research & therapy}, volume = {15}, number = {1}, pages = {301}, pmid = {39278909}, issn = {1757-6512}, support = {401922/2014-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 836458/2016//Ministério da Saúde/ ; 1701/22//Financiadora de Estudos e Projetos/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/therapy/metabolism ; Apolipoprotein A-I/cerebrospinal fluid/metabolism ; Apolipoproteins E/metabolism/genetics/cerebrospinal fluid ; Bone Marrow Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/metabolism ; Protein Interaction Maps ; *Proteomics/methods ; *Transplantation, Autologous ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS.

METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 10[6] cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129.

RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects.

CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.

TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.}, } @article {pmid39283513, year = {2025}, author = {Koopmann, A and Hoffmann, S and Riegler, A and Cordes, J and Kiefer, F}, title = {[Factors influencing hospital readmission rates in alcohol use disorder].}, journal = {Der Nervenarzt}, volume = {96}, number = {3}, pages = {278-283}, pmid = {39283513}, issn = {1433-0407}, mesh = {Humans ; *Patient Readmission/statistics & numerical data ; Male ; Female ; Middle Aged ; *Alcoholism/epidemiology/therapy/diagnosis/rehabilitation ; Germany/epidemiology ; Retrospective Studies ; Risk Factors ; Adult ; Comorbidity ; *Substance Withdrawal Syndrome/epidemiology ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND: According to data from the Federal Statistical Office, the diagnosis of alcohol use disorder (AUD) (F 10) is the second most common main diagnosis for hospital treatment. Those affected by this disorder are often repeatedly hospitalized at short intervals due to relapses; however, little is known about the factors that influence readmission rates after initial treatment.

AIM OF THE STUDY: The aim of this retrospective analysis is to analyze the effects of treatment type (qualified withdrawal treatment (QE) versus physical detoxification) and discharge mode on the probability of readmission in alcohol-dependent patients after inpatient treatment.

MATERIAL AND METHODS: Data from 981 male and female alcohol-dependent patients who completed either qualified withdrawal treatment (QE) (68% men; mean age 47.6 years) or inpatient detoxification (74% men; mean age 48.0 years) were analyzed. Predictors of regular discharge were determined separately for both types of treatment using stepwise logistic regression.

RESULTS: Patients who had completed a qualified withdrawal treatment were significantly more likely to be regularly discharged. Regular completion of the qualified withdrawal treatment (QE) led to a relative reduction in the readmission rate of 25.64% within 1 year compared to a physical detoxification.

CONCLUSION: In order to prevent readmission and chronic courses of alcohol use disorder (AUD), qualified withdrawal treatment should always be recommended to affected patients instead of physical detoxification. Aktuelle Daten des Statistischen Bundesamtes für das Jahr 2022 zeigen, dass die Diagnose "Psychische und Verhaltensstörungen durch Alkohol (F 10.X)" die zweithäufigste Hauptdiagnose bei Krankenhausbehandlungen darstellt [13]. Im Gesundheitssystem entstehen durch dieses Erkrankungsbild und seine somatischen und psychischen Folgeerkrankungen jährlich ca. 10 Mrd. € direkte Kosten [13]. Dieser Sachverhalt wird dadurch kontrastiert, dass die Krankenkassen die qualifizierte Entzugsbehandlung (QE) als leitliniengerechte Goldstandardtherapie [4] wiederholt infrage stellen [10].}, } @article {pmid39286440, year = {2024}, author = {Kew, SYN and Mok, SY and Goh, CH}, title = {Machine learning and brain-computer interface approaches in prognosis and individualized care strategies for individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {MethodsX}, volume = {13}, number = {}, pages = {102765}, pmid = {39286440}, issn = {2215-0161}, abstract = {Amyotrophic lateral sclerosis (ALS) characterized by progressive degeneration of motor neurons is a debilitating disease, posing substantial challenges in both prognosis and daily life assistance. However, with the advancement of machine learning (ML) which is renowned for tackling many real-world settings, it can offer unprecedented opportunities in prognostic studies and facilitate individuals with ALS in motor-imagery tasks. ML models, such as random forests (RF), have emerged as the most common and effective algorithms for predicting disease progression and survival time in ALS. The findings revealed that RF models had an excellent predictive performance for ALS, with a testing R2 of 0.524 and minimal treatment effects of 0.0717 for patient survival time. Despite significant limitations in sample size, with a maximum of 18 participants, which may not adequately reflect the population diversity being studied, ML approaches have been effectively applied to ALS datasets, and numerous prognostic models have been tested using neuroimaging data, longitudinal datasets, and core clinical variables. In many literatures, the constraints of ML models are seldom explicitly enunciated. Therefore, the main objective of this research is to provide a review of the most significant studies on the usage of ML models for analyzing ALS. This review covers a variation of ML algorithms involved in applications in ALS prognosis besides, leveraging ML to improve the efficacy of brain-computer interfaces (BCIs) for ALS individuals in later stages with restricted voluntary muscular control. The key future advances in individualized care and ALS prognosis may include the advancement of more personalized care aids that enable real-time input and ongoing validation of ML in diverse healthcare contexts.}, } @article {pmid39291146, year = {2023}, author = {Mathew, AM and Bhuvanendran, S and Nair, RS and K Radhakrishnan, A}, title = {Exploring the anti-inflammatory activities, mechanism of action and prospective drug delivery systems of tocotrienol to target neurodegenerative diseases.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {338}, pmid = {39291146}, issn = {2046-1402}, abstract = {A major cause of death in the elderly worldwide is attributed to neurodegenerative diseases, such as AD (Alzheimer's disease), PD (Parkinson's disease), ALS (Amyotrophic lateral sclerosis), FRDA (Friedreich's ataxia), VaD (Vascular dementia) etc. These can be caused due to multiple factors such as genetic, physiological problems like stroke or tumor, or even external causes like viruses, toxins, or chemicals. T3s (tocotrienols) exhibit various bioactive properties where it acts as an antioxidant, anti-inflammatory, anti-tumorigenic, and cholesterol lowering agent. Since T3 interferes with and influences several anti-inflammatory mechanisms, it aids in combating inflammatory responses that lead to disease progression. T3s are found to have a profound neuroprotective ability, however, due to their poor oral bioavailability, their full potential could not be exploited. Hence there is a need to explore other drug delivery techniques, especially focusing on aspects of nanotechnology. In this review paper we explore the anti-inflammatory mechanisms of T3 to apply it in the treatment of neurodegenerative diseases and also discusses the possibilities of nano methods of administering tocotrienols to target neurodegenerative diseases.}, } @article {pmid39291166, year = {2024}, author = {Gianferrari, G and Cuoghi Costantini, R and Crippa, V and Carra, S and Bonetto, V and Pansarasa, O and Cereda, C and Zucchi, E and Martinelli, I and Simonini, C and Vicini, R and Fini, N and Trojsi, F and Passaniti, C and Ticozzi, N and Doretti, A and Diamanti, L and Fiamingo, G and Conte, A and Dalla Bella, E and D'Errico, E and Scarian, E and Pasetto, L and Antoniani, F and Galli, V and Casarotto, E and , and D'Amico, R and Poletti, A and Mandrioli, J}, title = {Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae304}, pmid = {39291166}, issn = {2632-1297}, abstract = {In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.}, } @article {pmid39292338, year = {2025}, author = {Zhang, H and Gao, C and Yang, D and Nie, L and He, K and Chen, C and Li, S and Huang, G and Zhou, L and Huang, X and Wu, D and Liu, J and Huang, Z and Wang, J and Li, W and Zhang, Z and Yang, X and Zou, L}, title = {Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1[G93A] Transgenic Mice Via Activation of Mitophagy.}, journal = {Molecular neurobiology}, volume = {62}, number = {6}, pages = {6922-6937}, pmid = {39292338}, issn = {1559-1182}, mesh = {Animals ; Mice, Transgenic ; *Copper/toxicity ; *Mitophagy/drug effects ; *Coumarins/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/physiopathology ; Mice ; Motor Neurons/drug effects/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mitochondria/drug effects/metabolism ; Spinal Cord/pathology/drug effects/metabolism ; Male ; Astrocytes/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1[G93A] transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1[G93A] mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1[G93A] mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.}, } @article {pmid39292682, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Pei, X and Chen, Z and Huang, Y and Zhao, S and Guo, T and Liu, Z}, title = {Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308801}, pmid = {39292682}, issn = {1932-6203}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture, Ear/methods ; Combined Modality Therapy ; *Exercise Therapy/methods ; Low Back Pain/therapy ; Lumbar Vertebrae/physiopathology ; Lumbosacral Region ; Pain Measurement ; Prospective Studies ; Range of Motion, Articular ; Sprains and Strains/therapy ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes.

METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle.

DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.}, } @article {pmid39292705, year = {2024}, author = {Minnella, A and McCusker, KP and Amagata, A and Trias, B and Weetall, M and Latham, JC and O'Neill, S and Wyse, RK and Klein, MB and Trimmer, JK}, title = {Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0309893}, pmid = {39292705}, issn = {1932-6203}, mesh = {Animals ; *Ferroptosis/drug effects ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Humans ; *Parkinson Disease/drug therapy/metabolism/pathology ; Rats ; Mice ; alpha-Synuclein/metabolism ; Lipid Peroxidation/drug effects ; Neurons/drug effects/metabolism/pathology ; Fibroblasts/drug effects/metabolism ; Arachidonate 15-Lipoxygenase/metabolism ; Cells, Cultured ; Male ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.}, } @article {pmid39293800, year = {2024}, author = {Gao, J and Chai, N and Wang, T and Han, Z and Chen, J and Lin, G and Wu, Y and Bi, L}, title = {A new technique of percutaneous minimally invasive surgery assisted by magnetic resonance neurography.}, journal = {Bone & joint open}, volume = {5}, number = {9}, pages = {776-784}, pmid = {39293800}, issn = {2633-1462}, abstract = {AIMS: In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.

METHODS: A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients' clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al's objective assessments, respectively.

RESULTS: The contracture bands exhibited three typical types of shape - feather-like, striped, and mixed shapes - in MR images. Guided by MRN images, we designed minimally invasive approaches directed to each hip. These approaches resulted in a shortened incision length in each hip (0.3 cm (SD 0.1)), shorter surgery duration (25.3 minutes (SD 5.8)), less intraoperative bleeding (8.0 ml (SD 3.6)), and shorter time between the end of the operation and the patient's first off-bed activity (17.2 hours (SD 2.0)) in each patient. Meanwhile, no serious postoperative complications occurred in all patients. The mean HOS-Sports subscale of patients increased from 71.0 (SD 5.3) to 94.83 (SD 4.24) at six months postoperatively (p < 0.001). The follow-up outcomes from all patients were "good" and "excellent", based on objective assessments.

CONCLUSION: Preoperative MRN analysis can be used to facilitate the determination of the relationship between contracture band and normal tissues. The minimally invasive surgical design via MRN can avoid nerve damage and improve the release effect.}, } @article {pmid39296960, year = {2024}, author = {Keilholz, AN and Pathak, I and Smith, CL and Osman, KL and Smith, L and Oti, G and Golzy, M and Ma, L and Lever, TE and Nichols, NL}, title = {Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1441529}, pmid = {39296960}, issn = {1664-2295}, support = {R01 HL153612/HL/NHLBI NIH HHS/United States ; T32 OD011126/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons.

METHODS: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles.

RESULTS: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise.

CONCLUSION: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF.}, } @article {pmid39297377, year = {2024}, author = {Akyuz, E and Aslan, FS and Gokce, E and Ilmaz, O and Topcu, F and Kakac, S}, title = {Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6057-6090}, doi = {10.1111/ejn.16541}, pmid = {39297377}, issn = {1460-9568}, mesh = {Humans ; *Genetic Therapy/methods ; *Extracellular Vesicles/metabolism/genetics ; *CRISPR-Cas Systems ; *Huntington Disease/therapy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; Animals ; Gene Editing/methods ; Neurodegenerative Diseases/therapy/genetics ; }, abstract = {Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.}, } @article {pmid39300071, year = {2024}, author = {Castelli, S and Desideri, E and Laureti, L and Felice, F and De Cristofaro, A and Scaricamazza, S and Lazzarino, G and Ciriolo, MR and Ciccarone, F}, title = {N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {686}, pmid = {39300071}, issn = {2041-4889}, support = {GR-2019-1236998//Ministero della Salute (Ministry of Health, Italy)/ ; MNESYS PNRR - MUR PE00000006//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *Glycolysis/drug effects ; *Muscle Fibers, Skeletal/metabolism/drug effects ; Mice ; *Aspartic Acid/metabolism/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Oxidation-Reduction ; Cell Line ; Mice, Transgenic ; }, abstract = {N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected. Here we demonstrate that NAA treatment of differentiated C2C12 muscle cells increases lipid turnover, mitochondrial biogenesis and oxidative metabolism at the expense of glycolysis. These effects were ascribed to NAA catabolism, as CRISPR/Cas9 ASPA KO cells are insensitive to NAA administration. Moreover, the metabolic switch induced by NAA was associated with an augmented resistance to atrophic stimuli. Consistently with in vitro results, SOD1-G93A ALS mice show an increase in ASPA levels in those muscles undergoing the glycolytic to oxidative switch during the disease course. The impact of NAA on the metabolism and resistance capability of myotubes supports a role for this metabolite in the phenotypical adaptations of skeletal muscle in neuromuscular disorders.}, } @article {pmid39305312, year = {2024}, author = {Torres, P and Rico-Rios, S and Ceron-Codorniu, M and Santacreu-Vilaseca, M and Seoane-Miraz, D and Jad, Y and Ayala, V and Mariño, G and Beltran, M and Miralles, MP and Andrés-Benito, P and Fernandez-Irigoyen, J and Santamaria, E and López-Otín, C and Soler, RM and Povedano, M and Ferrer, I and Pamplona, R and Wood, MJA and Varela, MA and Portero-Otin, M}, title = {TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {45}, pmid = {39305312}, issn = {1432-0533}, support = {PI 20-00155//Instituto de Salud Carlos III/ ; 23-00176//Instituto de Salud Carlos III/ ; Programa Margarita Salas//Ministerio de Universidades/ ; SGR//Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya/ ; Ayuda Unzue//Fundación Luzon/ ; }, mesh = {Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Microtubule-Associated Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cysteine Endopeptidases/metabolism/genetics ; Male ; Spinal Cord/metabolism/pathology ; Autophagy/physiology ; Mice, Knockout ; RNA Splicing/genetics ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b[-/-] mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.}, } @article {pmid39307005, year = {2024}, author = {Austin, JM and Bailey, R and Velazquez, SG and Sainath, H and Jackson, C}, title = {Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123243}, doi = {10.1016/j.jns.2024.123243}, pmid = {39307005}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Medical Marijuana/therapeutic use ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; Disease Progression ; Cohort Studies ; Adult ; Anxiety/drug therapy/etiology ; }, abstract = {Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.}, } @article {pmid39307154, year = {2024}, author = {Pal, S and Chataway, J and Swingler, R and Macleod, MR and Carragher, NO and Hardingham, G and Selvaraj, BT and Smith, C and Wong, C and Newton, J and Lyle, D and Stenson, A and Dakin, RS and Ihenacho, A and Colville, S and Mehta, AR and Stallard, N and Carpenter, JR and Parker, RA and Keerie, C and Weir, CJ and Virgo, B and Morris, S and Waters, N and Gray, B and MacDonald, D and MacDonald, E and Parmar, MKB and Chandran, S and , }, title = {Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1097-1107}, doi = {10.1016/S1474-4422(24)00326-0}, pmid = {39307154}, issn = {1474-4465}, mesh = {Humans ; *Trazodone/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; *Memantine/therapeutic use ; Double-Blind Method ; *Motor Neuron Disease/drug therapy ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.

METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.

FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.

INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.

FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.}, } @article {pmid39311315, year = {2025}, author = {Ortiz-Corredor, F and Correa-Arrieta, C and Forero Diaz, JJ and Castellar-Leones, S and Gil-Salcedo, A}, title = {Profiles of disease progression and predictors of mortality in Colombian patients with amyotrophic lateral sclerosis: a comprehensive longitudinal study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {141-148}, doi = {10.1080/21678421.2024.2405587}, pmid = {39311315}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; *Disease Progression ; Female ; Colombia/epidemiology ; Male ; Middle Aged ; Longitudinal Studies ; Retrospective Studies ; Aged ; Prognosis ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia.

METHODS: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories.

RESULTS: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p < 0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners.

CONCLUSIONS: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.}, } @article {pmid39311426, year = {2024}, author = {Azzolino, D and Piras, R and Zulueta, A and Lucchi, T and Lunetta, C}, title = {Amyotrophic lateral sclerosis as a disease model of sarcopenia.}, journal = {Age and ageing}, volume = {53}, number = {9}, pages = {}, doi = {10.1093/ageing/afae209}, pmid = {39311426}, issn = {1468-2834}, mesh = {Humans ; *Sarcopenia/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle, Skeletal/pathology/physiopathology ; Aging/pathology ; Animals ; Age Factors ; Aged ; Risk Factors ; }, abstract = {Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.}, } @article {pmid39313211, year = {2025}, author = {Rahimi, M and Al Masry, Z and Templeton, JM and Schneider, S and Poellabauer, C}, title = {A Comprehensive Multifunctional Approach for Measuring Parkinson's Disease Severity.}, journal = {Applied clinical informatics}, volume = {16}, number = {1}, pages = {11-23}, pmid = {39313211}, issn = {1869-0327}, mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; Male ; Female ; *Severity of Illness Index ; Aged ; Middle Aged ; Neuropsychological Tests ; Machine Learning ; }, abstract = {OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multifunctional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach.

METHODS: We recruited 37 individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multifunctional. Then, the collected data were used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated the current PD staging schemes and developed a new approach based on the features selected and extracted using random forest and principal component analysis.

RESULTS: Our findings indicate a substantial bias in current PD staging systems toward fine motor skills, that is, other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system.

CONCLUSION: The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or amyotrophic lateral sclerosis.}, } @article {pmid39313512, year = {2024}, author = {Khan, AF and Iturria-Medina, Y}, title = {Beyond the usual suspects: multi-factorial computational models in the search for neurodegenerative disease mechanisms.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {386}, pmid = {39313512}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Neuroimaging/methods ; *Brain/diagnostic imaging/physiopathology ; Disease Progression ; Biomarkers ; Alzheimer Disease/diagnostic imaging/physiopathology ; Computer Simulation ; }, abstract = {From Alzheimer's disease to amyotrophic lateral sclerosis, the molecular cascades underlying neurodegenerative disorders remain poorly understood. The clinical view of neurodegeneration is confounded by symptomatic heterogeneity and mixed pathology in almost every patient. While the underlying physiological alterations originate, proliferate, and propagate potentially decades before symptomatic onset, the complexity and inaccessibility of the living brain limit direct observation over a patient's lifespan. Consequently, there is a critical need for robust computational methods to support the search for causal mechanisms of neurodegeneration by distinguishing pathogenic processes from consequential alterations, and inter-individual variability from intra-individual progression. Recently, promising advances have been made by data-driven spatiotemporal modeling of the brain, based on in vivo neuroimaging and biospecimen markers. These methods include disease progression models comparing the temporal evolution of various biomarkers, causal models linking interacting biological processes, network propagation models reproducing the spatial spreading of pathology, and biophysical models spanning cellular- to network-scale phenomena. In this review, we discuss various computational approaches for integrating cross-sectional, longitudinal, and multi-modal data, primarily from large observational neuroimaging studies, to understand (i) the temporal ordering of physiological alterations, i(i) their spatial relationships to the brain's molecular and cellular architecture, (iii) mechanistic interactions between biological processes, and (iv) the macroscopic effects of microscopic factors. We consider the extents to which computational models can evaluate mechanistic hypotheses, explore applications such as improving treatment selection, and discuss how model-informed insights can lay the groundwork for a pathobiological redefinition of neurodegenerative disorders.}, } @article {pmid39314138, year = {2025}, author = {Lv, Y and Li, H}, title = {Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2556-2570}, pmid = {39314138}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.}, } @article {pmid39315251, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39315251}, issn = {2693-5015}, support = {R56 NS112296/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10[S59L], and human cell models expressing CHCHD10[S59L], we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10[S59L]. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10[S59L]-induced diseases.

METHODS: An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10[S59L] mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.

RESULTS: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10[S59L]-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10[S59L]-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H[S81L]. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10[S59L].

CONCLUSION: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10[S59L]-induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, } @article {pmid39316747, year = {2024}, author = {de Calbiac, H and Renault, S and Haouy, G and Jung, V and Roger, K and Zhou, Q and Campanari, ML and Chentout, L and Demy, DL and Marian, A and Goudin, N and Edbauer, D and Guerrera, C and Ciura, S and Kabashi, E}, title = {Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.}, journal = {Autophagy}, volume = {20}, number = {10}, pages = {2164-2185}, pmid = {39316747}, issn = {1554-8635}, mesh = {*Motor Neurons/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Zebrafish ; *Mitophagy/genetics ; *Apoptosis/genetics ; Humans ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Dipeptides/pharmacology/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.}, } @article {pmid39328135, year = {2025}, author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R}, title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.}, journal = {Current molecular medicine}, volume = {25}, number = {8}, pages = {962-979}, pmid = {39328135}, issn = {1875-5666}, support = {CRG/2021/001009//DST-SERB, Govt. Of India/ ; }, mesh = {Humans ; *Flavonoids/therapeutic use/pharmacology/chemistry ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; Signal Transduction/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.}, } @article {pmid39330700, year = {2024}, author = {Everett, WH and Bucelli, RC}, title = {Tofersen for SOD1 ALS.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {5}, pages = {149-160}, pmid = {39330700}, issn = {1758-2032}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/antagonists & inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.}, } @article {pmid39337251, year = {2024}, author = {Escudier, O and Zhang, Y and Whiting, A and Chazot, P}, title = {Evaluation of a Synthetic Retinoid, Ellorarxine, in the NSC-34 Cell Model of Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337251}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Retinoids/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cell Line ; Humans ; Receptors, AMPA/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Benzoates/pharmacology ; Motor Neuron Disease/drug therapy/metabolism/pathology ; Calcium/metabolism ; Neurites/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3-30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca[2+] baseline, increased level of excitability, and reduced Ca[2+] spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS.}, } @article {pmid39337560, year = {2024}, author = {Malaguarnera, M and Cabrera-Pastor, A}, title = {Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337560}, issn = {1422-0067}, support = {PI23/00204//Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización de proyectos de I+D+i desarro/ ; CIGE/083//This research was funded by Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización d/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis ; Animals ; Central Nervous System Diseases/metabolism/therapy/diagnosis ; Blood-Brain Barrier/metabolism ; }, abstract = {The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.}, } @article {pmid39337696, year = {2024}, author = {Niazi, SK}, title = {Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs-Protocols and Advice for the FDA to Meet the ALS Act Vision.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337696}, issn = {1422-0067}, mesh = {Humans ; *United States Food and Drug Administration ; United States ; *Drug Approval ; *Biological Availability ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Clinical Trials as Topic ; }, abstract = {Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.}, } @article {pmid39337908, year = {2024}, author = {Wang, R and Chen, L and Zhang, Y and Sun, B and Liang, M}, title = {Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39337908}, issn = {2075-1729}, support = {YJXJ-JZ-2021-0014//Scientific Research Project of Beijing Yicheng Cooperative Development Foundation in 2021-Public welfare projects of rare disease related topics/ ; KM202310858001//R&D Program of Beijing Municipal Education Commission/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.}, } @article {pmid39338563, year = {2024}, author = {Dow, CT and Pierce, ES and Sechi, LA}, title = {Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?.}, journal = {Microorganisms}, volume = {12}, number = {9}, pages = {}, pmid = {39338563}, issn = {2076-2607}, abstract = {Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.}, } @article {pmid39340928, year = {2024}, author = {Dahl, R and Bezprozvanny, I}, title = {SERCA pump as a novel therapeutic target for treating neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {734}, number = {}, pages = {150748}, doi = {10.1016/j.bbrc.2024.150748}, pmid = {39340928}, issn = {1090-2104}, support = {R01 AG071310/AG/NIA NIH HHS/United States ; R56 AG078337/AG/NIA NIH HHS/United States ; R42 AG062001/AG/NIA NIH HHS/United States ; }, mesh = {*Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Humans ; Animals ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Molecular Targeted Therapy/methods ; *Neuroprotective Agents/pharmacology/therapeutic use ; Calcium Signaling/drug effects ; Calcium/metabolism ; }, abstract = {The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca[2+]) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca[2+] channels and Ca[2+] signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans.}, } @article {pmid39341507, year = {2024}, author = {Sivalingam, AM}, title = {Advances in understanding biomarkers and treating neurological diseases - Role of the cerebellar dysfunction and emerging therapies.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102519}, doi = {10.1016/j.arr.2024.102519}, pmid = {39341507}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/metabolism ; Animals ; *Cerebellar Diseases/therapy/diagnosis/metabolism/genetics ; Genetic Therapy/methods/trends ; Nervous System Diseases/therapy/diagnosis/metabolism ; Cerebellum/metabolism/pathology ; }, abstract = {Cerebellar dysfunction is increasingly recognized as a critical factor in various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Research has revealed distinct cerebellar atrophy patterns in conditions such as AD and multiple system atrophy, and studies in mice have highlighted its impact on motor control and cognitive functions. Emerging research into autism spectrum disorder (ASD) has identified key targets, such as elevated levels of chemokine receptors and ZIC family genes. Biomarkers, including cerebrospinal fluid (CSF), genetic markers, and advances in AI and bioinformatics, are enhancing early diagnosis and personalized treatment across neurodegenerative disorders. Notable advancements include improved diagnostic tools, gene therapy, and novel clinical trials. Despite progress, challenges such as the bloodbrain barrier and neuroinflammation persist. Current therapies for AD, PD, HD, and ALS, including antisense oligonucleotides and stem cell treatments, show promise but require further investigation. A comprehensive approach that integrates diagnostic methods and innovative therapies is essential for effective management and improved patient outcomes.}, } @article {pmid39341656, year = {2024}, author = {Paris, A and Lakatos, A}, title = {Cell and gene therapy for amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {205}, number = {}, pages = {217-241}, doi = {10.1016/B978-0-323-90120-8.00017-4}, pmid = {39341656}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disorder with rapidly progressive skeletal muscle weakness, which can also cause a variable cognitive deficit. Genetic causes are only identified in approximately 10% of all cases, with complex genotype-phenotype associations, making it challenging to identify treatment targets. What further hampers therapeutic development is a broad heterogeneity in mechanisms, possible targets, and disturbances across various cell types, aside from the cortical and spinal motor neurons that lie at the heart of the pathology of ALS. Over the last decade, significant progress in biotechnologic techniques, cell and ribonucleic acid (RNA) engineering, animal models, and patient-specific human stem cell and organoid models have accelerated both mechanistic and therapeutic discoveries. The growing number of clinical trials mirrors this. This chapter reviews the current state of human preclinical models supporting trial strategies as well as recent clinical cell and gene therapy approaches.}, } @article {pmid39341837, year = {2024}, author = {Hollingworth, D and Thomas, F and Page, DA and Fouda, MA and De Castro, RL and Sula, A and Mykhaylyk, VB and Kelly, G and Ulmschneider, MB and Ruben, PC and Wallace, BA}, title = {Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8426}, pmid = {39341837}, issn = {2041-1723}, support = {CC1078/WT_/Wellcome Trust/United Kingdom ; BB/105581//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; mutiple grants//Diamond Light Source/ ; BB/V0183511//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CF2-100001//Rosetrees Trust/ ; BB/S017844//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; studentship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Riluzole/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Humans ; *Neuroprotective Agents/pharmacology ; Voltage-Gated Sodium Channels/metabolism/chemistry ; HEK293 Cells ; Animals ; Sodium/metabolism ; Motor Neurons/drug effects/metabolism ; }, abstract = {Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na[+] conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.}, } @article {pmid39343443, year = {2024}, author = {O'Brien, D and Shaw, PJ}, title = {New developments in the diagnosis and management of motor neuron disease.}, journal = {British medical bulletin}, volume = {152}, number = {1}, pages = {4-15}, doi = {10.1093/bmb/ldae010}, pmid = {39343443}, issn = {1471-8391}, support = {NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 972-797//AMBRoSIA Biosampling Programme/ ; 764-780//MNDA (Sheffield Care and Research Centre for Motor Neuron Disorders/ ; }, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness.

SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'.

AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND.

AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe.

GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies.

Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.}, } @article {pmid39343990, year = {2024}, author = {Xia, L and Qiu, Y and Li, J and Xu, M and Dong, Z}, title = {The Potential Role of Artemisinins Against Neurodegenerative Diseases.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {6}, pages = {1641-1660}, doi = {10.1142/S0192415X24500642}, pmid = {39343990}, issn = {1793-6853}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Artemisinins/pharmacology ; *Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism ; Ferroptosis/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Huntington Disease/drug therapy/metabolism ; Autophagy/drug effects ; }, abstract = {Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.}, } @article {pmid39344189, year = {2025}, author = {Khorshidi, Z and Adibi, I and Ghasemi, M}, title = {Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {13-19}, pmid = {39344189}, issn = {1868-1891}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; *Hexosaminidases/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; }, abstract = {INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder.

CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant).

SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.}, } @article {pmid39346681, year = {2024}, author = {Fisher, RMA and Torrente, MP}, title = {Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1456052}, pmid = {39346681}, issn = {1662-5099}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD), and Amyotrophic lateral sclerosis (ALS) are complex and fatal neurodegenerative diseases. While current treatments for these diseases do alleviate some symptoms, there is an imperative need for novel treatments able to stop their progression. For all of these ailments, most cases occur sporadically and have no known genetic cause. Only a small percentage of patients bear known mutations which occur in a multitude of genes. Hence, it is clear that genetic factors alone do not explain disease occurrence. Chromatin, a DNA-histone complex whose basic unit is the nucleosome, is divided into euchromatin, an open form accessible to the transcriptional machinery, and heterochromatin, which is closed and transcriptionally inactive. Protruding out of the nucleosome, histone tails undergo post-translational modifications (PTMs) including methylation, acetylation, and phosphorylation which occur at specific residues and are connected to different chromatin structural states and regulate access to transcriptional machinery. Epigenetic mechanisms, including histone PTMs and changes in chromatin structure, could help explain neurodegenerative disease processes and illuminate novel treatment targets. Recent research has revealed that changes in histone PTMs and heterochromatin loss or gain are connected to neurodegeneration. Here, we review evidence for epigenetic changes occurring in AD, PD, and FTD/ALS. We focus specifically on alterations in the histone PTMs landscape, changes in the expression of histone modifying enzymes and chromatin remodelers as well as the consequences of these changes in heterochromatin structure. We also highlight the potential for epigenetic therapies in neurodegenerative disease treatment. Given their reversibility and pharmacological accessibility, epigenetic mechanisms provide a promising avenue for novel treatments. Altogether, these findings underscore the need for thorough characterization of epigenetic mechanisms and chromatin structure in neurodegeneration.}, } @article {pmid39347334, year = {2024}, author = {Aljehani, NS and Al-Gunaid, ST and Hobani, AH and Alhinti, MF and Khubrani, YA and Abu-Hamoud, LM and Alrayes, AA and Alharbi, LB and Sultan, AA and Turkistani, DA and Naiser, SS and Albraik, L and Alakel, AM and Alotaibi, M and Asiri, AY}, title = {Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e68008}, pmid = {39347334}, issn = {2168-8184}, abstract = {The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.}, } @article {pmid39352708, year = {2024}, author = {Crose, JJ and Crose, A and Ransom, JT and Lightner, AL}, title = {Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {3-4}, pages = {111-117}, pmid = {39352708}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Extracellular Vesicles ; Male ; Middle Aged ; Female ; Pilot Projects ; Aged ; Mesenchymal Stem Cells ; Mesenchymal Stem Cell Transplantation/methods ; Infusions, Intravenous ; Adult ; Treatment Outcome ; }, abstract = {Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.}, } @article {pmid39355247, year = {2024}, author = {Yang, JL and Wu, JY and Liu, JJ and Zheng, GQ}, title = {Herbal medicines for SOD1[G93A] mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1433929}, pmid = {39355247}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/genetics ; Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1/genetics ; Herbal Medicine ; }, abstract = {Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.}, } @article {pmid39360074, year = {2024}, author = {Puri, SN and Raghuveer, R and Jachak, S and Tikhile, P}, title = {Exploring the Impact of Personalized Physical Therapy on a Patient With Motor Neuron Disorder: A Case Study.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68373}, pmid = {39360074}, issn = {2168-8184}, abstract = {This case study examines the effect of a tailor-made physiotherapy regimen on an 85-year-old male patient who was suffering from bulbar motor neuron disease (MND) and had a history of stroke and COVID-19. The physiotherapy plan was designed to strategically address the patient's respiratory issues, generalized weakness affecting limb muscles, and speech and swallowing difficulties. Frequent evaluations made it possible to adjust the treatment plan, emphasizing a holistic strategy to improve the patient's overall quality of life. Improvements in scores on multiple functional scales and manual muscle testing were shown by outcome measures and follow-up evaluations. This case emphasizes how important customized physiotherapy is for maximizing functional outcomes and enhancing the quality of life for patients dealing with the complicated conditions of bulbar MND.}, } @article {pmid39362869, year = {2024}, author = {Ma, YY and Li, X and Yu, ZY and Luo, T and Tan, CR and Bai, YD and Xu, G and Sun, BD and Bu, XL and Liu, YH and Jin, WS and Gao, YQ and Zhou, XF and Liu, J and Wang, YJ}, title = {Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {415}, pmid = {39362869}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Edaravone/pharmacology/administration & dosage ; *Cognitive Dysfunction/etiology/drug therapy/prevention & control ; Mice ; *Oxidative Stress/drug effects ; Male ; *Hypoxia/complications/drug therapy/metabolism ; *Altitude ; Antioxidants/pharmacology/administration & dosage ; Mice, Inbred C57BL ; Administration, Oral ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration & dosage/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.}, } @article {pmid39367309, year = {2024}, author = {Makled, AF and Ali, SAM and Labeeb, AZ and Salman, SS and Shebl, DZM and Hegazy, SG and Sabal, MS}, title = {Characterization of Candida species isolated from clinical specimens: insights into virulence traits, antifungal resistance and molecular profiles.}, journal = {BMC microbiology}, volume = {24}, number = {1}, pages = {388}, pmid = {39367309}, issn = {1471-2180}, mesh = {Humans ; *Candida/genetics/pathogenicity/drug effects/isolation & purification/classification ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; *Virulence Factors/genetics ; *Candidiasis/microbiology ; *Biofilms/growth & development ; *Microbial Sensitivity Tests ; Virulence/genetics ; Multiplex Polymerase Chain Reaction ; Male ; Female ; Adult ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Candida species have emerged as a significant cause of opportunistic infections. Alongside the expression of various virulence factors, the rise of antifungal resistance among Candida species presents a considerable clinical challenge.

AIM: This study aimed to identify different Candida species isolated from clinical specimens, evaluate their antifungal sensitivity patterns, identify key genes regulating virulence mechanisms using multiplex PCR and to assess any correlation between their virulence profiles and antifungal resistance patterns.

METHOD: A total of 100 Candida spp. was isolated from 630 different clinical specimens and identified to the species level. Their antifungal susceptibility was phenotypically evaluated in accordance with CLSI guidelines using the Vitek-2 Compact System. Virulence markers, including biofilm formation capacity, protease production, melanin production, coagulase production and hemolysin production, were also phenotypically detected. The genetic determinants for biofilm formation and extracellular hydrolytic enzymes were assessed using a multiplex PCR assay.

RESULTS: The prevalence of Candida spp. was 15.9%, with C. albicans (48%) and C. glabrata (16%) being the most common. C. albicans showed the highest virulence, with strong biofilm formation, and high proteinase and melanin production. Multiplex PCR revealed Hlp in 22.0%, Hwp in 80.0%, Als in 56.0%, and Sap genes in 56.0% of isolates. Virulence genes were more common in C. albicans than in non-albicans Candida (NAC). Resistance patterns significantly correlated with virulence profiles, with notable associations between flucytosine resistance and the presence of Hlp and Hwp genes.

CONCLUSION: The significant correlation between virulent markers such as germination, coagulase, hemolysin production and resistance patterns among different Candida isolates is crucial for predicting the severity and outcomes of Candida infections. This understanding aids in guiding tailored treatment strategies.}, } @article {pmid39368179, year = {2025}, author = {Brito, ALB and Cardoso, IF and Viegas, LP and Fausto, R}, title = {Semi-quantitative chemometric models for characterization of mixtures of sugars using infrared spectral data.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125225}, doi = {10.1016/j.saa.2024.125225}, pmid = {39368179}, issn = {1873-3557}, mesh = {*Chemometrics/methods ; *Models, Chemical ; *Sugars/analysis ; Spectrophotometry, Infrared ; Principal Component Analysis ; Multivariate Analysis ; Least-Squares Analysis ; }, abstract = {Sugars (saccharides) are sweet-tasting carbohydrates that are abundant in foods and play very important roles in living organisms, particularly as sources and stores of energy, and as structural elements in cellular membranes. They are desirable therapeutic targets, as they participate in multiple metabolic processes as fundamental elements. However, the physicochemical characterization of sugars is a challenging task, mostly due to the structural similarity shared by the large diversity of compounds of this family. The need for fast, accurate enough, and cost-effective analytical methods for these substances is of extreme relevance, in particular because of the recently increasing importance of carbohydrates in Medicine and food industry. With this in view, this work focused on the development of chemometric models for semi-quantitative analysis of samples of different types of sugars (glucose, galactose, mannitol, sorbose and fructose) using infrared spectra as data, as an example of application of a novel approach, where the Principal Component Analysis (PCA) score plots are used to estimate the composition (weight-%) of the mixtures of the sugars. In these plots, polygonal geometric shapes emerge in the vectorial space of the most significant principal components, that allow grouping different types of samples on the vertices, edges, faces and interior of the polygons according to the composition of the samples. This approach was applied successfully to mixtures of up to 5 sugars and shown to appropriately extract the compositional information from the hyper-redundant complex spectral data. Thought the method has been applied here to a specific problem, it shall be considered as a general procedure for the semi-quantitative analysis of other types of mixtures and applicable to other types of data reflecting their composition. In fact, the methodology appears as an efficient tool to solve three main general problems: (i) use hyper-redundant (in variables) data, as spectral information, directly and with minimum pre-treatment, to evaluate semi-quantitatively the composition of mixtures; (ii) do this for systems which produce data that can be considered rather similar; and (iii) do it for a number of substances present in the mixtures that might be greater than that usually considered in chemistry, which in general is limited to 3 components. In addition, this work also demonstrates that, similarly to the developed analysis based on the PCA score plots, the Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) chemometric method can also be used successfully for the qualitative (when used without any previous knowledge of the components present in the samples) or semi-quantitative (when the pure components spectral profiles are provided as references) analyses of mixtures of (at least) up to 5 distinct sugars.}, } @article {pmid39368746, year = {2024}, author = {Sharma, R and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105876}, doi = {10.1016/j.neuint.2024.105876}, pmid = {39368746}, issn = {1872-9754}, mesh = {Animals ; *Oleanolic Acid/pharmacology/therapeutic use ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Male ; *Methylmercury Compounds/toxicity ; *Glycogen Synthase Kinase 3 beta/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Rats, Wistar ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Neuroprotection/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.}, } @article {pmid39370211, year = {2024}, author = {Kajitani, GS and Xavier, G and Villena-Rueda, BE and Karia, BTR and Santoro, ML}, title = {Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.}, journal = {Current topics in membranes}, volume = {94}, number = {}, pages = {299-336}, doi = {10.1016/bs.ctm.2024.06.002}, pmid = {39370211}, issn = {1063-5823}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Biomarkers/metabolism ; Mental Disorders/metabolism/drug therapy/therapy ; Animals ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.}, } @article {pmid39373990, year = {2024}, author = {Appel, SH and Thonhoff, JR}, title = {Barriers to Tofersen Therapy for Variant SOD1-Mediated ALS.}, journal = {JAMA neurology}, volume = {81}, number = {12}, pages = {1239-1240}, doi = {10.1001/jamaneurol.2024.3331}, pmid = {39373990}, issn = {2168-6157}, } @article {pmid39378530, year = {2025}, author = {Meng, T and Wu, W and Wang, B and Li, C and Li, J and Liu, J and Wang, J and Qie, R}, title = {Treating chronic pulmonary heart disease with traditional Chinese medicine: Systematic evaluation and mechanistic insights into the resolving phlegm and activating blood approach.}, journal = {Heart & lung : the journal of critical care}, volume = {69}, number = {}, pages = {111-126}, doi = {10.1016/j.hrtlng.2024.09.017}, pmid = {39378530}, issn = {1527-3288}, mesh = {Humans ; Chronic Disease ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Pulmonary Heart Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Chronic Pulmonary Heart Disease (CPHD) significantly impacts global health, especially among middle-aged and older adults. In China, the Traditional Chinese Medicine (TCM) technique of Resolving Phlegm and Activating Blood (RPAB) is widely used to treat CPHD, although high-quality evidence supporting its efficacy remains limited.

OBJECTIVES: The purpose of this study was to rigorously assess the clinical efficacy of RPAB for CPHD and elucidate the mechanisms underlying its primary herbal components.

METHODS: Through a detailed search of literature in both Chinese and English and strict inclusion and exclusion criteria, 18 randomized controlled trials (RCTs) were selected for meta-analysis. We identified RPAB's core herbal combinations using association rule analysis. This method statistically analyzes the frequency and correlation of herbal medicine usage. We then analyzed the chemical components of these combinations and investigated their potential intervention mechanisms on CPHD through network pharmacology.

RESULTS: The combination of RPAB with Western medicine was superior to Western medicine alone in improving blood gas analysis and pulmonary function and reducing plasma viscosity in CPHD patients. The core herbal combination identified was Astragalus membranaceus (Fisch.) Bunge, Ligusticum chuanxiong Hort. ex S. H. Qiu & al., and Stellaria alsine Grimm (ALS). This combination targeted 588 therapeutic and 27 core targets. It influenced ten core compounds across 34 pathways, primarily through the chemokine signaling pathway and the JAK-STAT signaling pathway.

CONCLUSION: RPAB with Western medicine significantly improves CPHD treatment outcomes. The study highlights the therapeutic potential of the ALS combination, which operates through multiple pathways to remodel pulmonary arteries, decrease inflammation, and lessen oxidative stress. These insights support the clinical application of RPAB in CPHD treatment and open new avenues for research and therapeutic development.}, } @article {pmid39382075, year = {2025}, author = {Liang, B and Khan, M and Storts, H and Zhang, EH and Zheng, X and Xing, X and Claybon, H and Wilson, J and Li, C and Jin, N and Fishel, R and Miles, WO and Wang, JJ}, title = {Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {1}, pages = {131-140}, pmid = {39382075}, issn = {1538-8514}, support = {R01 CA251753/CA/NCI NIH HHS/United States ; R01 CA208063/CA/NCI NIH HHS/United States ; R01CA215389//National Cancer Institute (NCI)/ ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA215389/CA/NCI NIH HHS/United States ; R01 CA067007/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Nucleotidyltransferases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; Mice ; *Membrane Proteins/metabolism ; Humans ; *Signal Transduction/drug effects ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/metabolism ; *Riluzole/pharmacology/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; }, abstract = {Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.}, } @article {pmid39386447, year = {2024}, author = {Rodemer, W and Ra, I and Jia, E and Gujral, J and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.24.612703}, pmid = {39386447}, issn = {2692-8205}, support = {R01 NS101156/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.

SIGNIFICANCE STATEMENT: Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.}, } @article {pmid39392186, year = {2025}, author = {Corcia, P and Piras, R and Lunetta, C}, title = {Why is the treatment and management of amyotrophic lateral sclerosis so difficult?.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {1}, pages = {1-3}, doi = {10.1080/14737175.2024.2415002}, pmid = {39392186}, issn = {1744-8360}, } @article {pmid39400020, year = {2026}, author = {Ali, A and Emad, NA and Sultana, N and Waheed, A and Aqil, M and Sultana, Y and Mujeeb, M}, title = {Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {25}, number = {3}, pages = {174-194}, doi = {10.2174/0118715273319597240927044906}, pmid = {39400020}, issn = {1996-3181}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Drug Repositioning/methods ; *Brain/drug effects/metabolism ; Administration, Intranasal ; *Drug Delivery Systems/methods ; *Theranostic Nanomedicine/methods ; Neuroprotective Agents/administration & dosage ; *Nanoparticles/administration & dosage ; Blood-Brain Barrier/drug effects ; }, abstract = {Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.}, } @article {pmid39401249, year = {2024}, author = {Pérez de la Lastra Aranda, C and Tosat-Bitrián, C and Porras, G and Dafinca, R and Muñoz-Torrero, D and Talbot, K and Martín-Requero, Á and Martínez, A and Palomo, V}, title = {Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {21}, pages = {3945-3953}, doi = {10.1021/acschemneuro.4c00328}, pmid = {39401249}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Proteome/metabolism ; Precision Medicine/methods ; Motor Neurons/metabolism/drug effects ; Lymphocytes/metabolism/drug effects ; Protein Aggregates/drug effects/physiology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical/methods ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.}, } @article {pmid39402174, year = {2025}, author = {Jellinger, KA}, title = {The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {2}, pages = {217-236}, pmid = {39402174}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/pathology/psychology ; *Mental Disorders/etiology/physiopathology ; *Brain/physiopathology/pathology ; }, abstract = {Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.}, } @article {pmid39408720, year = {2024}, author = {Du, X and Dong, Q and Zhu, J and Li, L and Yu, X and Liu, R}, title = {Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39408720}, issn = {1422-0067}, support = {XDB39050600//Strategic Priority Research Program of Chinese Academy of Sciences/ ; 82150107//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Rutin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Disease Models, Animal ; *Mice, Transgenic ; *Spinal Cord/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Protein Aggregation, Pathological/drug therapy/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.}, } @article {pmid39411168, year = {2024}, author = {An, D and Han, J and Fang, P and Bu, Y and Ji, G and Liu, M and Deng, J and Song, X}, title = {Evidence for the potential role of m6A modification in regulating autophagy in models of amyotrophic lateral sclerosis.}, journal = {CytoJournal}, volume = {21}, number = {}, pages = {33}, pmid = {39411168}, issn = {0974-5963}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Research indicates that N6-methyladenosine (m6A) modification plays a crucial role in cellular autophagy during ALS development. This study investigates the role of autophagy in ALS, with a focus on the effect of messenger ribonucleic acid m6A methylation modification on disease progression.

MATERIAL AND METHODS: We compared m6A levels and regulatory molecule expressions in transgenic superoxide dismutase (SOD1)-G93A and non-transgenic mice, categorized into end-stage and control groups, using quantitative polymerase chain reaction and Western blotting. The NSC-34 cell line, which was modified to model ALS, enabled the investigation of apoptosis, autophagy, and autophagy disruption through terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assays, Western blotting, and fluorescent staining.

RESULTS: Our findings indicate significantly elevated m6A methylation levels in ALS mice (0.262 ± 0.005) compared with the controls (0.231 ± 0.003) and in the ALS model cells (0.242±0.005) relative to those belonging to the wild-type control group (0.183 ± 0.007). Furthermore, the proteins involved in m6A RNA modification differed between groups, which suggest impaired autophagy flux in the ALS models.

CONCLUSION: These results suggest that m6A methylation may accelerate ALS progression through the disruption of autophagic processes. Our study underscores the role of m6A methylation in the pathology of ALS and proposes the targeting of m6A methylation as a potential therapeutic strategy for disease treatment. Although this study primarily used transgenic SOD1-G93A mice and NSC-34 cell models to investigate ALS pathology, potential differences in disease mechanisms between animal models and humans must be considered. Although a correlation was detected between m6A methylation levels and autophagy disruption in ALS, the study primarily established an association rather than provided detailed mechanistic insights.}, } @article {pmid39412921, year = {2024}, author = {Bahador, M and Soltaninejad, S and Mobasheri, M}, title = {Correlation of new two-dimensional geometrical parameters to lung and heart dose-volume parameters in breast cancer radiation therapy.}, journal = {Journal of cancer research and therapeutics}, volume = {20}, number = {5}, pages = {1570-1577}, doi = {10.4103/jcrt.jcrt_2351_23}, pmid = {39412921}, issn = {1998-4138}, mesh = {Humans ; Female ; *Heart/radiation effects/diagnostic imaging ; *Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods ; *Lung/radiation effects/diagnostic imaging/pathology ; *Breast Neoplasms/radiotherapy/pathology ; *Organs at Risk/radiation effects ; Tomography, X-Ray Computed/methods ; ROC Curve ; Middle Aged ; }, abstract = {OBJECTIVE: To develop new two-dimensional geometric parameters for pulmonary and cardiac dose estimation in left-sided breast cancer radiation therapy without dose-volume histogram (DVH).

METHODS: On the CT image of 90 patients with left breast cancer, treatment planning was performed using two opposed tangent fields with/without supraclavicular. The field-in-field technique and 6MV photons were used. From DVH dosimetric parameters of mean dose, Vx (x (Gy) =5, 10, 15, 20, 30, 40, 50) were calculated, and from heart and lung outlines on the beam's eye view, new geometric parameters of percent of lung area in tangent and supraclavicular fields (%area of the lung in the tangent (ALT), %ALS) and percent of heart in tangent field (%area of the heart in the tangent (AHT)) were measured. Correlation, regression, and diagnostic performance by receiver operating characteristic curve (ROC) were investigated for statistical analysis.

RESULTS: The Pearson coefficient between %ALT and Vx (x = 10, 15, 20, 30, 40) show strong correlation in patient treatment with only opposed tangents (>0.85) and weaker in treatment by opposed tangents with supraclavicular (0.56-0.88), the %ALS indicate weak correlation (<0.5) and %AHT show strong correlation (0.93-0.98). The regression analysis shows a positive relation between %ALT and mean dose (R2 = 0.8), V20Gy (R2 = 0.9) in the lung (tangent treatment), and between %AHT and mean dose (R2 = 0.9), V20Gy (R2 = 1.0) in the heart. The ROC analysis shows by %ALT <20.3 for treatment by just opposed fields, %ALT <22.1% for treatment tangents with supra, and %AHT <11.6%, practical lung and heart dose constraints are addressed.

CONCLUSION: The proposed geometric parameters could replace previous one-dimensional maximum and central distances for predicting doses to lung and heart.

ADVANCES IN KNOWLEDGE: This study presents simple geometric parameters that could estimate pulmonary and cardiac dose in left breast cancer treatment from a 2D radiograph.}, } @article {pmid39416141, year = {2024}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Li, D and Cheung, V and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416141}, issn = {2692-8205}, support = {R21 ES034919/ES/NIEHS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.}, } @article {pmid39418491, year = {2025}, author = {Kumar, R and Ghai, S and Finelli, A and Klotz, L and Kinnaird, A and Mannas, M and Bhindi, B and Sanchez-Salas, R and Anidjar, M and Ahmad, A and Chin, J and Inman, B and Perlis, N}, title = {The use of focal therapy for the treatment of prostate cancer in Canada Where are we, how did we get here, and where are we going?.}, journal = {Canadian Urological Association journal = Journal de l'Association des urologues du Canada}, volume = {19}, number = {2}, pages = {63-72}, pmid = {39418491}, issn = {1911-6470}, abstract = {INTRODUCTION: Focal therapy is an emerging treatment for localized prostate cancer (PCa). The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada.

METHODS: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up to 2020. We focused on studies reporting functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrials.gov.

RESULTS: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation, or transurethral ultrasound ablation.

CONCLUSIONS: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.}, } @article {pmid39419433, year = {2025}, author = {Majumder, P and Hsu, TI and Hu, CJ and Huang, JK and Lee, YC and Hsieh, YC and Ahsan, A and Huang, CC}, title = {Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {114999}, doi = {10.1016/j.expneurol.2024.114999}, pmid = {39419433}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; Female ; *Disease Models, Animal ; Male ; *DNA-Binding Proteins/metabolism/genetics ; *Estrogen Replacement Therapy/methods ; *Curcumin/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Aromatase/metabolism ; Estradiol/pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS.

METHODS: Prp-TDP-43[A315T] mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43[A315T] mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43[A315T] mice with or without SLCP were determined.

RESULTS: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43[A315T] mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43[A315T] mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes.

CONCLUSIONS: Our results showed that Prp-TDP-43[A315T] mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.}, } @article {pmid39420987, year = {2024}, author = {Sun, H and Tang, Q and Yan, X and Xie, W and Xu, Y and Zhang, W}, title = {Cathepsins and neurological diseases: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1454369}, pmid = {39420987}, issn = {1662-4548}, abstract = {BACKGROUND: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases.

METHODS: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis.

RESULTS: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases.

CONCLUSION: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.}, } @article {pmid39422938, year = {2024}, author = {Pappolla, MA and Wu, P and Fang, X and Poeggeler, B and Sambamurti, K and Wisniewski, T and Perry, G}, title = {Stem Cell Interventions in Neurology: From Bench to Bedside.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {s1}, pages = {S395-S416}, doi = {10.3233/JAD-230897}, pmid = {39422938}, issn = {1875-8908}, mesh = {Humans ; Animals ; *Stem Cell Transplantation/methods/trends ; Nervous System Diseases/therapy ; Neurology/trends/methods ; Translational Research, Biomedical/trends ; Neural Stem Cells/transplantation ; }, abstract = {Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.}, } @article {pmid39424560, year = {2024}, author = {Koch, JC and Leha, A and Bidner, H and Cordts, I and Dorst, J and Günther, R and Zeller, D and Braun, N and Metelmann, M and Corcia, P and De La Cruz, E and Weydt, P and Meyer, T and Großkreutz, J and Soriani, MH and Attarian, S and Weishaupt, JH and Weyen, U and Kuttler, J and Zurek, G and Rogers, ML and Feneberg, E and Deschauer, M and Neuwirth, C and Wuu, J and Ludolph, AC and Schmidt, J and Remane, Y and Camu, W and Friede, T and Benatar, M and Weber, M and Lingor, P and , }, title = {Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1133-1146}, pmid = {39424560}, issn = {1474-4465}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Male ; Double-Blind Method ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Adult ; *rho-Associated Kinases/antagonists & inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration & dosage ; Treatment Outcome ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".}, } @article {pmid39431591, year = {2025}, author = {Sheers, NL and Hannan, LM and Rautela, L and Graco, M and Jones, J and Retica, S and Saravanan, K and Burgess, N and McGaw, R and Donovan, A and Clohessy, T and Chao, C and Charles, C and Howard, ME and Berlowitz, DJ}, title = {NIV@Home: a pilot randomized controlled trial of in-home noninvasive ventilation initiation compared to a single-day admission model.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {239-248}, doi = {10.1080/21678421.2024.2416668}, pmid = {39431591}, issn = {2167-9223}, mesh = {Humans ; *Noninvasive Ventilation/methods ; Male ; Pilot Projects ; Female ; Middle Aged ; Aged ; *Home Care Services ; Single-Blind Method ; *Respiratory Insufficiency/therapy/etiology ; *Neuromuscular Diseases/complications/therapy ; Quality of Life ; Adult ; Polysomnography ; }, abstract = {Objective: Noninvasive ventilation (NIV) is the primary treatment for respiratory insufficiency in neuromuscular disease. NIV implementation is usually conducted within hospitals; however, in-home implementation with intensive follow-up is an effective alternative. This pilot study aimed to assess model feasibility, acceptability, and NIV usage at 12-weeks after a single visit in-home implementation of NIV with remote monitoring follow-up (NIV@Home) compared to an in-hospital day admission NIV initiation plus planned polysomnography (Usual care). Methods: A single-blinded randomized controlled trial (www.anzctr.org.au ACTRN12620000682943) of adults with neuromuscular disease referred for NIV implementation. Participants were stratified by disease (MND or Other diagnoses) and bulbar symptoms before randomization to NIV@Home or Usual care, with follow-up at 12-weeks. The primary outcome was NIV usage. Secondary outcomes included feasibility, health-related quality of life, symptoms, carer burden, and NIV experience (semi-structured qualitative interviews). Results: Twenty-three participants (MND bulbar = 9, MND non-bulbar = 11, Other = 3) were randomized (NIV@Home = 9). No statistical differences were observed in the percentage of MND participants using NIV for >4 hours/day (NIV@Home = 33% vs. Usual care = 60%, p = 0.370), average use (NIV@Home = 2.4 [1.5-9.3] vs. 5.3 [1.8-7.0] hours/day, p = 0.568), or secondary outcomes. In-home NIV implementation was feasible and safe but took more therapist time (NIV@Home = 278 [270-305] vs. 172 [130-200] minutes, p < 0.001). Participants in the NIV@Home group reported substantial advantages to receiving care in home. Conclusion: In-home NIV implementation is feasible and acceptable to people with MND but requires more therapist time. Larger studies are required to determine whether there are clinically important differences between this model of NIV initiation and a traditional hospital-based model.}, } @article {pmid39435635, year = {2025}, author = {Yang, X and Gao, X and Jiang, X and Yue, K and Luo, P}, title = {Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3076-3094}, pmid = {39435635}, issn = {1673-5374}, abstract = {Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.}, } @article {pmid39436867, year = {2025}, author = {Firozjae, AA and Shiran, MR and Rashidi, M}, title = {The neuropharmacological and clinical effects of lutein: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {27-38}, pmid = {39436867}, issn = {1868-1891}, mesh = {*Lutein/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; }, abstract = {OBJECTIVES: Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.

METHODS: A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.

RESULTS: We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.

CONCLUSIONS: 4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.}, } @article {pmid39437787, year = {2024}, author = {Saez-Atienzar, S and Souza, CDS and Chia, R and Beal, SN and Lorenzini, I and Huang, R and Levy, J and Burciu, C and Ding, J and Gibbs, JR and Jones, A and Dewan, R and Pensato, V and Peverelli, S and Corrado, L and van Vugt, JJFA and van Rheenen, W and Tunca, C and Bayraktar, E and Xia, M and , and , and , and , and Iacoangeli, A and Shatunov, A and Tiloca, C and Ticozzi, N and Verde, F and Mazzini, L and Kenna, K and Al Khleifat, A and Opie-Martin, S and Raggi, F and Filosto, M and Piccinelli, SC and Padovani, A and Gagliardi, S and Inghilleri, M and Ferlini, A and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Mandrioli, J and Mora, G and Lunetta, C and Tanel, R and Trojsi, F and Cardinali, P and Gallone, S and Brunetti, M and Galimberti, D and Serpente, M and Fenoglio, C and Scarpini, E and Comi, GP and Corti, S and Del Bo, R and Ceroni, M and Pinter, GL and Taroni, F and Bella, ED and Bersano, E and Curtis, CJ and Lee, SH and Chung, R and Patel, H and Morrison, KE and Cooper-Knock, J and Shaw, PJ and Breen, G and Dobson, RJB and Dalgard, CL and , and Scholz, SW and Al-Chalabi, A and van den Berg, LH and McLaughlin, R and Hardiman, O and Cereda, C and Sorarù, G and D'Alfonso, S and Chandran, S and Pal, S and Ratti, A and Gellera, C and Johnson, K and Doucet-O'Hare, T and Pasternack, N and Wang, T and Nath, A and Siciliano, G and Silani, V and Başak, AN and Veldink, JH and Camu, W and Glass, JD and Landers, JE and Chiò, A and Sattler, R and Shaw, CE and Ferraiuolo, L and Fogh, I and Traynor, BJ}, title = {Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100679}, pmid = {39437787}, issn = {2666-979X}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; ZIA AG000934/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Drug Repositioning ; *Frontotemporal Dementia/genetics/drug therapy ; Genomics/methods ; Riluzole/therapeutic use ; Male ; Female ; Neuroprotective Agents/therapeutic use/pharmacology ; DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.}, } @article {pmid39439710, year = {2024}, author = {Kelser, BM and Teichner, EM and Subtirelu, RC and Hoss, KN}, title = {A review of proposed mechanisms for neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1370580}, pmid = {39439710}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.}, } @article {pmid39448670, year = {2024}, author = {Stankiewicz-Kosyl, M and Wińska-Krysiak, M and Wrochna, M and Haliniarz, M and Marcinkowska, K}, title = {Regional diversity of the ALS gene and hormesis due to tribenuron-methyl in Centaurea cyanus L.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25197}, pmid = {39448670}, issn = {2045-2322}, support = {BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Hormesis ; *Herbicides/pharmacology ; *Centaurea/genetics ; Arylsulfonates/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Poland ; Plant Proteins/genetics ; Genetic Variation ; }, abstract = {Centaurea cyanus L. is a common field weed in Eastern Europe but only in Poland biotypes of this species with resistance to acetolactate synthase (ALS) inhibitors have been confirmed. This phenomenon is constantly developing and spreading to consecutive regions of Poland. This study aimed to assess the response of selected Polish C. cyanus populations to tribenuron-methyl and to analyse the genetic variability of the ALS gene of C. cyanus populations resistant to ALS inhibitors. Between 2017 and 2021, 13 seed samples were collected from eastern Poland and a dose-response study with tribenuron-methyl was performed. Eleven populations resistant to tribenuron-methyl were identified. All populations from this study as well as 6 additional resistant populations characterised in the previous dose-response studies were subjected to molecular analysis of the ALS gene. Target-site resistance due to mutations P197S, P197Q, P197T and P197A were identified in 8 populations from Warmia-Masuria and Podlaskie provinces. This is the first case of target-site resistance (TSR) in C. cyanus confirmed by sequencing of the ALS gene. Moreover in some resistant plants, ten changes in the amino acid ALS sequence were identified in comparison to those in the susceptible ones. In none of the populations were all mutations detected in the same individual. The highest frequency of mutations was detected in Warmia-Masuria province. Some C. cyanus populations resistant to ALS inhibitors showed hormesis effect concerning shoot fresh weight after tribenuron-methyl treatment. Stimulation due to half the recommended dose of tribenuron-methyl was the highest and the difference between untreated and treated plants was statistically significant in two populations from Warmia-Masuria and in one from Podlaskie province.}, } @article {pmid39449457, year = {2024}, author = {Rosa, D and Ingrande, L and Marcomini, I and Poliani, A and Villa, G and Sodano, M and Manara, DF}, title = {Perceived Pain in People Living with Amyotrophic Lateral Sclerosis-A Scoping Review.}, journal = {Nursing reports (Pavia, Italy)}, volume = {14}, number = {4}, pages = {3023-3039}, pmid = {39449457}, issn = {2039-4403}, abstract = {(1) Background: Pain is a common symptom in patients with Amyotrophic Lateral Sclerosis (ALS). There are no evidence-based pharmacological treatments for pain in ALS; recommendations are based on guidelines for chronic non-oncological pain and clinical experience. The aim is to map the literature on how people with ALS experience pain, and how this affects their daily activities and social relationships. (2) Methods: This scoping review included studies concerning patients with spinal/bulbar ALS aged ≥ 18 years who experience pain, focusing on perception, characteristics, treatment, and impact on quality of life. Temporal and linguistic criteria were applied when searching the MEDLINE, CINAHL, and SCOPUS databases. (3) Results: The management of pain in these patients is complex and involves the use of anti-inflammatory drugs, analgesics, and opioids. Pain is associated with other conditions such as depression and anxiety, which contribute to a deterioration in the quality of life. Moreover, pain may also negatively influence patient compliance with prescribed treatment regimens and the quality of care they perceive themselves to be receiving. (4) Conclusions: It is of the most importance to identify effective ways to assess and treat this issue, with health care professionals taking an active role in this process.}, } @article {pmid39451238, year = {2024}, author = {Crescioli, C and Paronetto, MP}, title = {The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.}, journal = {Cells}, volume = {13}, number = {20}, pages = {}, pmid = {39451238}, issn = {2073-4409}, mesh = {Humans ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.}, } @article {pmid39451396, year = {2024}, author = {Yang, CH and Huang, JL and Tsai, LK and Taniar, D and Pai, TW}, title = {An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {39451396}, issn = {2306-5354}, support = {MOST 111-2221-E-027-113-414 MY2//National Science and Technology Council (Taiwan)/ ; NSTC113-2221-E-027-109//National Science and Technology Council (Taiwan)/ ; MOST104-2321-B-019-009//National Science and Technology Council (Taiwan)/ ; }, abstract = {This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.}, } @article {pmid39454934, year = {2025}, author = {Takeda, T and Her, YR and Kim, JK and Jha, NN and Monani, UR}, title = {A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1[G86R] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115024}, pmid = {39454934}, issn = {1090-2430}, support = {R01 NS104218/NS/NINDS NIH HHS/United States ; R01 NS123292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8[G470R] in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.}, } @article {pmid39455931, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {185}, pmid = {39455931}, issn = {1528-3658}, support = {1181645//Agencia Nacional de Investigación y Desarrollo/ ; DI-06-24/REG//UNAB/ ; 1221745//Agencia Nacional de Investigación y Desarrollo/ ; 21151265//Agencia Nacional de Investigación y Desarrollo/ ; R01-638 EY014420//National Institute of Mental Health and Neurosciences/ ; R01-EY014074//National Institute of Mental Health and Neurosciences/ ; R03 EY014420/EY/NEI NIH HHS/United States ; 1151293//Agencia Nacional de Investigación y Desarrollo/ ; 13220203 explorador//Agencia Nacional de Investigación y Desarrollo/ ; NCN2023_32//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Axonal Transport ; Cell Death ; Disease Models, Animal ; Mutation ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1[G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid39457466, year = {2024}, author = {Moriyama, H and Yokota, T}, title = {Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457466}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Mutation ; Animals ; Oligonucleotides/therapeutic use/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.}, } @article {pmid39457505, year = {2024}, author = {Seta, Y and Kimura, K and Masahiro, G and Tatsumori, K and Murakami, Y}, title = {SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457505}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM).

METHODS: Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023.

RESULTS: While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant.

CONCLUSIONS: The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.}, } @article {pmid39457513, year = {2024}, author = {Montiel-Troya, M and Mohamed-Mohamed, H and Pardo-Moreno, T and González-Díaz, A and Ruger-Navarrete, A and de la Mata Fernández, M and Tovar-Gálvez, MI and Ramos-Rodríguez, JJ and García-Morales, V}, title = {Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457513}, issn = {2227-9059}, support = {PID2019-110960GB-I00//Ministry of Science and Innovation, Spain./ ; }, abstract = {(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.}, } @article {pmid39457678, year = {2024}, author = {Forrest, BD and Goyal, NA and Fleming, TR and Bracci, PM and Brett, NR and Khan, Z and Robinson, M and Azhir, A and McGrath, M}, title = {The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457678}, issn = {2227-9059}, support = {01//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months' treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis.

METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities.

RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years.

CONCLUSIONS: The findings from this study suggest that a 6 months' treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.}, } @article {pmid39457680, year = {2024}, author = {McGrath, MS and Zhang, R and Bracci, PM and Azhir, A and Forrest, BD}, title = {Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457680}, issn = {2227-9059}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.

METHODS: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.

CONCLUSIONS: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.}, } @article {pmid39458929, year = {2024}, author = {Giannakou, M and Akrani, I and Tsoka, A and Myrianthopoulos, V and Mikros, E and Vorgias, C and Hatzinikolaou, DG}, title = {Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39458929}, issn = {1424-8247}, support = {MIS-5000432//state scholarship foundation (GR)/ ; }, abstract = {BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.

METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC[®]) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.

RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 °C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 °C, suggesting possible interactions or non-specific binding.}, } @article {pmid39459030, year = {2024}, author = {Al-Khayri, JM and Ravindran, M and Banadka, A and Vandana, CD and Priya, K and Nagella, P and Kukkemane, K}, title = {Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39459030}, issn = {1424-8247}, support = {GRANT0000//Deanship of Scientific Research, King Faisal University/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.}, } @article {pmid39459490, year = {2024}, author = {Banciu, C and Chiriac, S and Pojoga, C and Marian, L and Fabian, A and Gogulescu, A and Simu, M and Parvanescu, R and Mioc, A and Racoviceanu, R and Munteanu, A}, title = {An Uncommon Overlap Syndrome Between Ankylosing Spondylitis and Amyotrophic Lateral Sclerosis-Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, pmid = {39459490}, issn = {1648-9144}, support = {//"Victor Babes" University of Medicine and Pharmacy Timisoara/ ; }, mesh = {Humans ; *Spondylitis, Ankylosing/complications/drug therapy ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Etanercept/therapeutic use ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Syndrome ; }, abstract = {This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS.}, } @article {pmid39461864, year = {2024}, author = {Imamura, K and Izumi, Y and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Murakami, T and Hanajima, R and Kataoka, H and Kiriyama, T and Nanaura, H and Sugie, K and Hirayama, T and Kano, O and Nakamori, M and Maruyama, H and Haji, S and Fujita, K and Atsuta, N and Tatebe, H and Tokuda, T and Takahashi, N and Morinaga, A and Tabuchi, R and Oe, M and Kobayashi, M and Lobello, K and Morita, S and Sobue, G and Takahashi, R and Inoue, H}, title = {Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e082142}, pmid = {39461864}, issn = {2044-6055}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Aniline Compounds/therapeutic use ; Clinical Trials, Phase II as Topic ; *Drug Repositioning ; Induced Pluripotent Stem Cells ; Japan ; Multicenter Studies as Topic ; *Nitriles/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; *Quinolines/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.

METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.

ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.

TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.}, } @article {pmid39462586, year = {2024}, author = {Kurita, H and Hirasawa, N and Yabe, S and Okuda, A and Murakami, T and Ohuchi, K and Ogata, A and Yoshioka, H and Kakita, A and Hozumi, I and Inden, M}, title = {MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.}, journal = {Biological & pharmaceutical bulletin}, volume = {47}, number = {10}, pages = {1717-1725}, doi = {10.1248/bpb.b24-00418}, pmid = {39462586}, issn = {1347-5215}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Endoplasmic Reticulum Stress/drug effects/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Zinc/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; HEK293 Cells ; Transfection ; Tunicamycin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.}, } @article {pmid39464461, year = {2024}, author = {Karunakaran, V and Dadgar, S and Paidi, SK and Mordi, AF and Lowe, WA and Mim, UM and Ivers, JD and Rodriguez Troncoso, JI and McPeake, JA and Fernandes, A and Tripathi, SD and Barman, I and Rajaram, N}, title = {Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.}, journal = {ACS omega}, volume = {9}, number = {42}, pages = {43025-43033}, pmid = {39464461}, issn = {2470-1343}, support = {P20 GM139768/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; R01 CA238025/CA/NCI NIH HHS/United States ; R15 CA238861/CA/NCI NIH HHS/United States ; }, abstract = {Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.}, } @article {pmid39468607, year = {2024}, author = {Liu, C and Wu, Y and Wang, F and Sun, S and Wei, J and Tao, L}, title = {Cost-utility analysis for sublingual versus intravenous edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {400}, pmid = {39468607}, issn = {1750-1172}, mesh = {*Edaravone/therapeutic use/economics/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; *Cost-Benefit Analysis ; Administration, Sublingual ; Antipyrine/analogs & derivatives/therapeutic use/economics/administration & dosage ; Free Radical Scavengers/therapeutic use/economics/administration & dosage ; Administration, Intravenous ; Male ; }, abstract = {BACKGROUND: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context.

METHODS: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed.

RESULTS: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of ¥12,670.04 and an additional 0.034 QALYs over 20 years (life time) of modeling analysis, and the ICER was ¥372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection.

CONCLUSIONS: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis.}, } @article {pmid39470847, year = {2025}, author = {Jellinger, KA}, title = {Mild cognitive impairment in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {3}, pages = {357-368}, pmid = {39470847}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Cognitive Dysfunction/etiology/diagnosis ; *Brain/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.}, } @article {pmid39473221, year = {2024}, author = {Ito, D and Okada, K}, title = {Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {12}, pages = {3054-3063}, pmid = {39473221}, issn = {2328-9503}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Oligonucleotides, Antisense/administration & dosage/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.}, } @article {pmid39473490, year = {2024}, author = {Fei, Y and Ding, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1475934}, pmid = {39473490}, issn = {1662-5102}, abstract = {Ferroptosis represents an iron[-] and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.}, } @article {pmid39480764, year = {2024}, author = {Perrin, S and Ladha, S and Maragakis, N and Rivner, MH and Katz, J and Genge, A and Olney, N and Lange, D and Heitzman, D and Bodkin, C and Jawdat, O and Goyal, NA and Bornstein, JD and Mak, C and Appel, SH and Paganoni, S}, title = {Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {10}, pages = {e1004469}, pmid = {39480764}, issn = {1549-1676}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Antibodies, Monoclonal/adverse effects/administration & dosage/therapeutic use ; Antibodies, Monoclonal, Humanized/adverse effects/administration & dosage/therapeutic use/pharmacokinetics ; Biomarkers/blood ; CD40 Ligand/blood ; Disease Progression ; Dose-Response Relationship, Drug ; Neurofilament Proteins/blood ; Pyrazines ; Treatment Outcome ; Imidazoles ; }, abstract = {BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).

METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.

CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.

TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.}, } @article {pmid39486809, year = {2024}, author = {Van Loon, FT and Seitidis, G and Mavridis, D and van Unnik, JWJ and Weemering, DN and van den Berg, LH and Bethani, I and Nikolakopoulos, S and van Eijk, RPA}, title = {Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e087970}, pmid = {39486809}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic ; Disease Progression ; Research Design ; Systematic Reviews as Topic ; Network Meta-Analysis as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.

METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.

ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.}, } @article {pmid39490684, year = {2024}, author = {Liu, YJ and Lee, CW and Liao, YC and Huang, JJ and Kuo, HC and Jih, KY and Lee, YC and Chern, Y}, title = {The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106715}, doi = {10.1016/j.nbd.2024.106715}, pmid = {39490684}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Adiponectin/metabolism ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; *AMP-Activated Protein Kinases/metabolism ; Aged ; Motor Neurons/metabolism ; Severity of Illness Index ; }, abstract = {Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.}, } @article {pmid39491419, year = {2023}, author = {Talebi, M and Sadoughi, MM and Ayatollahi, SA and Ainy, E and Kiani, R and Zali, A and Miri, M}, title = {Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115805}, doi = {10.1016/j.biopha.2023.115805}, pmid = {39491419}, issn = {1950-6007}, abstract = {Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits. This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington's disease, Alzheimer's disease, Parkinson's disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.}, } @article {pmid39491718, year = {2024}, author = {Sharma, R and Khan, Z and Mehan, S and Das Gupta, G and Narula, AS}, title = {Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons.}, journal = {Mutation research. Reviews in mutation research}, volume = {794}, number = {}, pages = {108518}, doi = {10.1016/j.mrrev.2024.108518}, pmid = {39491718}, issn = {1388-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.}, } @article {pmid39494098, year = {2024}, author = {Xu, AX and Zhao, ZF and Zhu, L and Zhang, YH and Li, Y and Wei, YF and Zhang, BY and Jiang, B and Gao, TZ and Li, MS and Liu, JY}, title = {Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment.}, journal = {World journal of gastroenterology}, volume = {30}, number = {40}, pages = {4380-4385}, pmid = {39494098}, issn = {2219-2840}, mesh = {Humans ; Drugs, Chinese Herbal/therapeutic use ; *Liver Neoplasms/therapy/pathology/mortality ; *Medicine, Chinese Traditional/methods ; Neoplasm Staging ; Quality of Life ; Treatment Outcome ; }, abstract = {Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.}, } @article {pmid39494653, year = {2025}, author = {Springer, SA}, title = {Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.}, journal = {Addiction (Abingdon, England)}, volume = {120}, number = {1}, pages = {21-22}, pmid = {39494653}, issn = {1360-0443}, support = {DP1 DA056106/DA/NIDA NIH HHS/United States ; NIDA DP1DA056106/DA/NIDA NIH HHS/United States ; }, abstract = {Provision of buprenorphine treatment for opioid use disorder is often stymied by clinicians’ concerns for precipitated opioid withdrawal. Gregory et al’s systematic review identified a low level of precipitated withdrawal with buprenorphine induction even among persons who reported fentanyl use. Evidence, not fear should guide treatment.}, } @article {pmid39503018, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {70}, pmid = {39503018}, issn = {2415-1289}, abstract = {BACKGROUND AND OBJECTIVE: Hepatobiliary diseases are a longstanding and significant medical challenge which, despite advances in surgical techniques, still carry risks for postoperative complications such as anastomotic leaks (ALs), which can include both postoperative pancreatic fistula (POPF) and bile leaks (BL). These complications incur significant human and economic costs on all those involved, including the patient, healthcare providers, and hospital systems. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs in the context of hepato-pancreato-biliary (HPB) procedures, and consequences of POPF and BL.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

KEY CONTENT AND FINDINGS: A universally accepted definition and grading system for POPF and BL continues to be lacking, leading to variability in reported incidence in the literature. Various groups have worked to publish guidelines for defining and grading POPF and BL, with the International Study Group in Pancreatic Surgery (ISGPS) and International Study Group for Liver Surgery (ISGLS) definitions the current most recommended definitions for POPF and BL, respectively. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: AL remains a significant challenge in HPB surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid39509425, year = {2024}, author = {Deng, YC and Liu, JW and Ting, HC and Kuo, TC and Chiang, CH and Lin, EY and Harn, HJ and Lin, SZ and Chang, CY and Chiou, TW}, title = {n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0311573}, pmid = {39509425}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Calcium/metabolism ; *Homeostasis/drug effects ; *Superoxide Dismutase-1/genetics/metabolism ; *Phthalic Anhydrides/pharmacology ; Cell Differentiation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.}, } @article {pmid39511965, year = {2025}, author = {Bhai, S and Levine, T and Moore, D and Bowser, R and Heim, AJ and Walsh, M and Shibani, A and Simmons, Z and Grogan, J and Goyal, NA and Govindarajan, R and Hussain, Y and Papsdorf, T and Schwasinger-Schmidt, T and Olney, N and Goslin, K and Pulley, M and Kasarskis, E and Weiss, M and Katz, SW and Moser, S and Jabari, D and Jawdat, O and Statland, J and Dimachkie, MM and Barohn, R and , }, title = {A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {63-72}, pmid = {39511965}, issn = {1097-4598}, support = {R01 FD003937/FD/FDA HHS/United States ; R01FD003937//FDA-OPD/ ; //U.S. Food and Drug Administration/ ; }, mesh = {Humans ; *Memantine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Disease Progression ; Treatment Outcome ; Young Adult ; Excitatory Amino Acid Antagonists/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.

AIMS: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.

METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.

RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.

DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.}, } @article {pmid39513379, year = {2025}, author = {Simkins, TJ and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and Shefner, JM and Bowser, R}, title = {Plasma neurofilament analysis in VITALITY-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {103-112}, doi = {10.1080/21678421.2024.2423707}, pmid = {39513379}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/drug therapy/diagnosis ; Double-Blind Method ; Disease Progression ; *Neurofilament Proteins/blood ; Aged ; Biomarkers/blood ; *Intermediate Filaments/metabolism ; Longitudinal Studies ; Adult ; }, abstract = {OBJECTIVE: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS).

METHODS: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP).

RESULTS: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r = 0.50, p < 0.001) and isRDP (r = 0.53, p < 0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period.

CONCLUSIONS: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.}, } @article {pmid39520580, year = {2024}, author = {Hyldgaard Andersen, S and Harsløf, S and Tøttrup, A}, title = {Laparoscopic ileopexy for afferent loop syndrome after restorative proctocolectomy-a retrospective case series.}, journal = {International journal of colorectal disease}, volume = {39}, number = {1}, pages = {180}, pmid = {39520580}, issn = {1432-1262}, mesh = {Humans ; *Proctocolectomy, Restorative/adverse effects ; *Laparoscopy/adverse effects ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Afferent Loop Syndrome/surgery/etiology ; *Ileum/surgery ; Aged ; Treatment Outcome ; Postoperative Complications/etiology/surgery ; }, abstract = {BACKGROUND: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP).

METHOD: Ileopexy has been the treatment of choice in patients with ALS for the last 5 years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up.

RESULTS: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5 weeks (2-80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1-9) to 2 (0-7) (p = 0.02) at the last follow-up.

CONCLUSIONS: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum.}, } @article {pmid39521135, year = {2025}, author = {Sajid, SL and Ur Rehman, MA and Sajid, SA and Shahid, N}, title = {Response to Valerio Nardone et al's "Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e53-e54}, doi = {10.1016/j.jaad.2024.08.084}, pmid = {39521135}, issn = {1097-6787}, } @article {pmid39521994, year = {2024}, author = {Liang, H and Zhou, X and Zhang, J and Xu, W and Liu, Y and Wang, X and Hu, Y and Xu, R and Li, X}, title = {The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {206}, pmid = {39521994}, issn = {1528-3658}, support = {81960244//National Natural Science Foundation of China/ ; 20212BAB216026//Jiangxi Natural Science Foundation/ ; 202110016//Science and Technology Plan of Jiangxi Provincial Health Commission/ ; 2022B975//Science and Technology Plan of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Animals ; *Apigenin/pharmacology/therapeutic use ; Mice ; *Signal Transduction/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; *NF-E2-Related Factor 2/metabolism/genetics ; Oxidative Stress/drug effects ; Aldehyde Dehydrogenase 1 Family/metabolism/genetics ; Humans ; Apoptosis/drug effects ; Retinal Dehydrogenase/metabolism/genetics ; Cell Line ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.

METHODS: We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.

RESULTS: APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.

CONCLUSIONS: Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.}, } @article {pmid39522697, year = {2024}, author = {Gao, L and Yang, XN and Dong, YX and Han, YJ and Zhang, XY and Zhou, XL and Liu, Y and Liu, F and Fang, JS and Ji, JL and Gao, ZR and Qin, XM}, title = {The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products.}, journal = {Pharmacology & therapeutics}, volume = {264}, number = {}, pages = {108751}, doi = {10.1016/j.pharmthera.2024.108751}, pmid = {39522697}, issn = {1879-016X}, mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.}, } @article {pmid39522723, year = {2025}, author = {Nardone, V and Esposito, A and D'Ippolito, E and Argenziano, G and Reginelli, A and Troiani, T}, title = {Response to Sajid et al's "Response to Valerio Nardone et al's 'Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e55-e56}, doi = {10.1016/j.jaad.2024.10.058}, pmid = {39522723}, issn = {1097-6787}, } @article {pmid39523613, year = {2024}, author = {Fukutake, T}, title = {[Diagnosis, Notification, and Managements of ALS: A Personal Perspective from 40 years of Experience as a Clinical Neurologist].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1205-1216}, doi = {10.11477/mf.1416202762}, pmid = {39523613}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; *Neurologists ; Female ; Middle Aged ; Male ; Aged ; }, abstract = {This narrative summary presents the author's 40-year experience as a clinical neurologist who treated patients with amyotrophic lateral sclerosis (ALS). Five representative cases from the author's first 20 years at Chiba University Hospital and its affiliated hospitals were selected, including a patient of respiratory-onset who was ignorantly extubated by a female relative for patient's distress to the intratracheal tube. Based on the latter 20 years of experience at the author's current hospital, the author first describes a famous patient with ALS who was being treated at this medical center before the author was assigned to this hospital and fought against ALS for 31 years before eventually succumbing to total locked-in syndrome. Thereafter, the author has summarized the ages, sex, phenotypes, comorbidities, responses to the available treatment options, and total number of years that have elapsed for the 24 patients that the author initially examined in the outpatient clinic. In terms of diagnostic delay, the author describes "foot drop" in patients who developed lower limb symptoms, and hoarseness in those who developed bulbar palsy. Furthermore, the author discusses issues regarding family caregiving capacity, patient's and families' understanding of notification, and medical management (i.e., medications, rehabilitation for ADL, nutrition and respiration, complications of frontotemporal dementia, and medical cooperation with other clinics and hospitals).}, } @article {pmid39523614, year = {2024}, author = {Yamakawa, I and Urushitani, M}, title = {[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1217-1223}, doi = {10.11477/mf.1416202763}, pmid = {39523614}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; }, abstract = {Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.}, } @article {pmid39523615, year = {2024}, author = {Ogino, M}, title = {[Palliative Care for Persons with Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1225-1232}, doi = {10.11477/mf.1416202764}, pmid = {39523615}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Analgesics, Opioid/administration & dosage ; Japan ; *Palliative Care ; }, abstract = {Palliative care in Japan is available mainly for patients with cancer, and palliative care specialists do not have sufficient experience with management of palliation in persons with amyotrophic lateral sclerosis (ALS). Treatment of ALS symptoms is an important component of palliative care, and it is important that neurologists and home care physicians familiarize themselves with palliative care for ALS in consultation with palliative care specialists. Notably, the use of opioids at the end of life differs from that of pain relief for cancer. Physicians should be mindful that opioids are not a perfect solution for palliative care of persons with ALS.}, } @article {pmid39523616, year = {2024}, author = {Ishiguro, T and Nagata, T and Yokota, T}, title = {[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1233-1239}, doi = {10.11477/mf.1416202765}, pmid = {39523616}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.}, } @article {pmid39523617, year = {2024}, author = {Iguchi, Y and Katsuno, M}, title = {[Current Status of Drug Development for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1241-1249}, doi = {10.11477/mf.1416202766}, pmid = {39523617}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; Clinical Trials as Topic ; Animals ; Riluzole/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.}, } @article {pmid39531940, year = {2024}, author = {Pioro, EP and Brooks, BR and Liu, Y and Zhang, J and Apple, S}, title = {Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.}, journal = {Journal of the neurological sciences}, volume = {467}, number = {}, pages = {123290}, doi = {10.1016/j.jns.2024.123290}, pmid = {39531940}, issn = {1878-5883}, mesh = {Humans ; *Edaravone/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Treatment Outcome ; Double-Blind Method ; Free Radical Scavengers/therapeutic use/administration & dosage ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups.

METHODS: Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories.

RESULTS: ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects.

CONCLUSIONS: This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.}, } @article {pmid39535924, year = {2024}, author = {Hannestad, J and Smith, S and Lam, A and Hurt, J and Harada, N and Kim, R and Das, A and Brunello, J and Whitaker, G and Chalmers, D and Senjoti, F and Lin, W and Coghill, J and Bansal, Y and Sidhu, S and Zann, V and Liu, E}, title = {A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.}, journal = {Clinical and translational science}, volume = {17}, number = {11}, pages = {e70064}, pmid = {39535924}, issn = {1752-8062}, mesh = {Humans ; Male ; *Food-Drug Interactions ; Adult ; Administration, Oral ; *Healthy Volunteers ; Young Adult ; Middle Aged ; Area Under Curve ; Double-Blind Method ; Dose-Response Relationship, Drug ; Methylcellulose/administration & dosage/analogs & derivatives/chemistry ; Spray Drying ; Suspensions ; Cross-Over Studies ; Placebos/administration & dosage ; }, abstract = {TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.}, } @article {pmid39536438, year = {2024}, author = {Henderson, NL and Ortiz-Olguin, E and Bourne, G and Pywell, C and Rose, JB and Williams, GR and Nipp, RD and Rocque, GB}, title = {Implementation of ePROs Into Multidisciplinary Tumor Board Discussions for Patients With Pancreatic Cancer: The INSPIRE Intervention.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {602-609}, doi = {10.6004/jnccn.2024.7052}, pmid = {39536438}, issn = {1540-1413}, support = {T32 CA047888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Female ; Male ; *Patient Reported Outcome Measures ; Aged ; Middle Aged ; Patient Care Team/standards ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The incorporation of electronic patient-reported outcomes (ePROs), such as the Geriatric Assessment (GA) and treatment preferences, into decision-making for pancreatic cancer has been limited by clinician- and system-level barriers concerning workflow. We hypothesized that ePRO inclusion within multidisciplinary tumor boards (MDTBs) would circumvent barriers and provide a venue for systematic consideration of critical patient-provided information.

PATIENTS AND METHODS: The INtegrating Systematic PatIent-Reported Evaluations (INSPIRE) intervention consists of (1) patient survey completion, including GA and patient preferences, and (2) screensharing patient ePROs during MDTBs. Proctor et al's implementation outcomes were assessed, with penetration (the proportion of consented patients who were presented at MDTBs) acting as the primary outcome (considered successful at 70%). Secondary outcomes included adoption, feasibility, acceptability, appropriateness, cost, and sustainability, assessed by clinician post-MDTB exit surveys, clinician postintervention surveys, clinician postintervention semistructured interviews, and time-coding analysis of recorded and transcribed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs.

RESULTS: A total of 50 patients completed surveys and all were presented at MDTBs (penetration=100%). All eligible clinicians (n=9) enrolled patients (adoption=100%) and reported that ePROs were useful in 90% and led to a change in treatment plan in 30% of cases. In postintervention surveys and interviews, clinicians primarily responded positively to feasibility, acceptability, and appropriateness questions. Time-coding analysis found a modest time cost of an additional 51.1 seconds in mean discussion time-per-patient between preintervention (mean [SD], 172.7 [111.4] seconds) and intervention patients (mean [SD], 223.8 [107.1] seconds); 86% of clinicians reported the intervention did not take too much time. All surveyed clinicians reported interest in continuing the intervention and suggested adaptations to further promote sustainability.

CONCLUSIONS: The integration of ePROs into pancreatic MDTBs was feasible and acceptable, providing a potential approach to increase the utilization of ePROs by clinical teams in their management of patients with pancreatic cancer.}, } @article {pmid39536963, year = {2025}, author = {Casiraghi, V and Sorce, MN and Santangelo, S and Invernizzi, S and Bossolasco, P and Lattuada, C and Battaglia, C and Venturin, M and Silani, V and Colombrita, C and Ratti, A}, title = {Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115057}, doi = {10.1016/j.expneurol.2024.115057}, pmid = {39536963}, issn = {1090-2430}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Oxidative Stress/drug effects/physiology ; *Sirolimus/pharmacology ; *TDP-43 Proteinopathies/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.}, } @article {pmid39538124, year = {2024}, author = {Sun, Y and Hu, S and Lan, Y and Wang, R and Wei, S and Huang, H and Cui, H and Li, X and Huang, Z}, title = {Investigation of resistance mechanisms to flucarbazone-sodium in wild oat (Avena fatua L.) from China.}, journal = {BMC plant biology}, volume = {24}, number = {1}, pages = {1073}, pmid = {39538124}, issn = {1471-2229}, mesh = {*Avena/genetics/drug effects ; China ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Plant Weeds/genetics/drug effects ; }, abstract = {BACKGROUND: Wild oat (Avena fatua L.) is a self-pollinating, allohexaploid species in the family Gramineae (grasses), which is a malignant weed that mainly harms crops such as wheat. In recent years, a decline in the control efficiency of flucarbazone-sodium against wild oat has occurred in some regions of China.

RESULTS: We identified an ALS-resistant A. fatua population (R population). Whole-plant response assays revealed that the R population exhibited a moderate level of resistance (5.9-fold) to flucarbazone-sodium. Pre-treatment with malathion significantly reduced flucarbazone-sodium resistance in the R population. The known mutation sites and ALS gene relative expression that confer resistance to ALS inhibitor herbicides were not found in R population. Following flucarbazone-sodium treatment, the expression of eight genes related to metabolic enzymes was investigated using quantitative real-time PCR (qRT-PCR). CYP92A6 and the Aldo/keto reductase family were highly expressed in the R population after the application of flucarbazone-sodium.

CONCLUSIONS: The mechanism of flucarbazone-sodium resistance in A. fatua is mediated by NTSR, nor TSR. Two genes, CYP92A6 and the Aldo/keto reductase family, were discovered to be possibly related in the metabolism of NTSR in the A. fatua population, justifying more functional studies. The results will serve as a data resource for further studies on the molecular mechanisms of A. fatua to flucarbazone-sodium.}, } @article {pmid39538364, year = {2025}, author = {Terra, R and Éthier, V and Busque, L and Morin-Quintal, A and D'Angelo, G and Hébert, J and Wang, X and Lépine, G and LeBlanc, R and Bergeron, J}, title = {Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {108}, number = {2}, pages = {116-127}, doi = {10.1002/cyto.b.22213}, pmid = {39538364}, issn = {1552-4957}, support = {//BD Biosciences/ ; }, mesh = {Humans ; *Flow Cytometry/methods/standards ; Immunophenotyping/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology/genetics ; Dendritic Cells/pathology ; Female ; Male ; Middle Aged ; *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/pathology ; Adult ; Aged ; }, abstract = {Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.}, } @article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, } @article {pmid39545975, year = {2024}, author = {Eickhoff, C and Schöne-Seifert, B and Kettemann, D and Bormann, E and Grehl, T and Boentert, M and Koch, JC and Schmitt, C and Schrank, B and Schröter, C and Meyer, T}, title = {[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {95}, number = {12}, pages = {1131-1138}, pmid = {39545975}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Male ; Female ; Middle Aged ; *Terminal Care/psychology ; Aged ; *Advance Directives/psychology ; Surveys and Questionnaires ; Germany ; Adult ; Aged, 80 and over ; Noninvasive Ventilation ; Palliative Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.

QUESTION: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?

MATERIAL AND METHOD: Between March 2017 and January 2019 patients with a clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a questionnaire. A total of 328 people returned the completed forms.

RESULTS: Of the participants 72% had already made an advance directive (AD), 25% planned to fill one out and only 3% refused to do so. In composing the AD most patients (90%) had support, although 56% lacked medical counselling and only 18% had drawn up the will together with the doctor and relatives, with the majority of the rest also wanting support from a doctor. A total of 37% of all patients wanted a contact person to talk about their illness but only 40% of them had such a contact person. Of the patients 22% stated that they had considered suicide and of these only 55% stated that they had no contact person for the psychological stress caused by the illness but 31% wished to have such a person.

DISCUSSION AND CONCLUSION: A coordinated care of ALS patients, which also takes the psychosocial aspects into account is urgently needed.}, } @article {pmid39547816, year = {2024}, author = {Salmerón-Mendoza, AN and Aguilar-Vázquez, CA and Aguilar-Castillo, SJ}, title = {[Electromyography in atypical variants of motor neuron disease: a case series].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {4}, pages = {1-6}, pmid = {39547816}, issn = {2448-5667}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Adult ; Aged, 80 and over ; Motor Neuron Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis.

CLINICAL CASES: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments.

CONCLUSIONS: ALS a spectrum of motor neuron disease, a neurodegenerative disease of the CNS, without curative treatment and one with a fatal outcome, the diagnosis of ELA is complex and becomes more complex for atypical phenotypes, as observed in the presented cases EMG is an essential part of the approach and part of the diagnostic criteria.}, } @article {pmid39552508, year = {2025}, author = {Zhong, R and Dionela, DLA and Kim, NH and Harris, EN and Geisler, JG and Wei-LaPierre, L}, title = {Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {542-557}, pmid = {39552508}, issn = {1531-8249}, support = {R56 NS117429/NS/NINDS NIH HHS/United States ; NS99545/NS/NINDS NIH HHS/United States ; R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; NS117429/NS/NINDS NIH HHS/United States ; NS127858/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology/genetics ; *2,4-Dinitrophenol/pharmacology/administration & dosage/therapeutic use ; Mice ; *Muscle, Skeletal/drug effects/physiopathology ; Mice, Transgenic ; *Recovery of Function/drug effects ; Disease Models, Animal ; Muscle Contraction/drug effects ; *Uncoupling Agents/pharmacology/administration & dosage ; Male ; Neuromuscular Junction/drug effects ; }, abstract = {OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.

METHODS: hSOD1[G93A] mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1[G93A] mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.

RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1[G93A] mice. Strikingly, symptomatic hSOD1[G93A] mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.

INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025;97:542-557.}, } @article {pmid39556113, year = {2025}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16255}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Polyadenylation/physiology ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, } @article {pmid39562997, year = {2024}, author = {Zheng, W and Xia, T and Zhang, X and Han, J and Li, Y and Tian, N and Zheng, G and Wang, J and Peng, Y and Yao, D and Long, F}, title = {Tailoring Multifunctional Amine Salts Based on Anisole Liquid Soaking for Fabricating Efficient and Stable Perovskite Solar Cells.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {48}, pages = {66643-66654}, doi = {10.1021/acsami.4c12455}, pmid = {39562997}, issn = {1944-8252}, abstract = {The post-treatment based on spin-coating (SC) organic amine salts is commonly used for surface modification of perovskite films to eliminate defects. However, there is still a lack of systematic study and a unified understanding of the functions and mechanisms of different organic amine salts. The SC method is also not conducive to the industrialization of solar cells. In this work, we study three different organic amine salts, and a passivation strategy for perovskite films based on green anisole liquid soaking (ALS) has been developed. Phenylethylammonium iodide (PEAI), diethylamine hydroiodide (DEAI), and guanidine hydroiodide (GAI) organic amine salt passivators are selected to modify perovskite films, and their effect and working mechanism are also systematically estimated. It is found that PEAI passivates shallow-level defects on the surface of perovskite films, while DEAI incorporates into the perovskite lattice to suppress point defects, and GAI eliminates excess PbI2 residuals in perovskite films. These three organic-amine-salt-modified devices achieve enhanced power conversion efficiencies (PCE) of 21.82% (PEAI-ALS), 21.74% (DEAI-ALS), and 22.21% (GAI-ALS), which is much higher than that of the pristine device without treatment (19.95%). The PCE of the PEAI-ALS device retains nearly 94% of the initial efficiency after 1200 h in unpackaged conditions and about 40% ambient humidity, achieving the best stability performance. Particularly, the PEAI-ALS device has the best comprehensive performance in efficiency and stability. And PEAI is estimated by the SC method and ALS method, and it is found that the PEAI-ALS device achieves a higher PCE compared to the PEAI-SC device (21.51%). We believe that the post-treatment based on a combination of appropriate amine salts and ALS enables a universal approach for fabrication of perovskite solar cells with enhanced photovoltaic performance.}, } @article {pmid39563026, year = {2025}, author = {Hawley, ZCE and Pardo, ID and Cao, S and Zavodszky, MI and Casey, F and Ferber, K and Luo, Y and Hana, S and Chen, SK and Doherty, J and Costa, R and Cullen, P and Liu, Y and Carlile, TM and Chowdhury, T and Doyle, B and Clarner, P and Mangaudis, K and Guilmette, E and Bourque, S and Koske, D and Nadella, MVP and Trapa, P and Hawes, ML and Raitcheva, D and Lo, SC}, title = {Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {1}, pages = {215-234}, pmid = {39563026}, issn = {1525-0024}, mesh = {Animals ; *Dependovirus/genetics ; Mice ; *MicroRNAs/genetics ; *Ganglia, Spinal/metabolism ; *Genetic Vectors/administration & dosage/genetics ; *RNA Interference ; Superoxide Dismutase-1/genetics ; Humans ; Neurons/metabolism ; Male ; }, abstract = {Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.}, } @article {pmid39564171, year = {2024}, author = {Byeon, H}, title = {Holistic approaches to mitigating psychological distress in gynecological cancer patients.}, journal = {World journal of psychiatry}, volume = {14}, number = {11}, pages = {1766-1771}, pmid = {39564171}, issn = {2220-3206}, abstract = {This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.}, } @article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death & disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, } @article {pmid39569650, year = {2025}, author = {Luo, S and Wang, X and Ma, B and Liu, D and Li, L and Wang, L and Ding, N and Zou, L and Wang, J and Pan, J and Sang, D and Zhou, H and Qu, H and Lu, Y and Yang, L}, title = {Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.}, journal = {Biomolecules & biomedicine}, volume = {25}, number = {3}, pages = {632-647}, pmid = {39569650}, issn = {2831-090X}, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Motor Neurons/drug effects/pathology ; Cell Survival/drug effects/genetics ; Mice, Inbred C57BL ; Animals ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; *Apolipoproteins A/genetics/metabolism ; Gene Expression Regulation/drug effects ; *Albumins/genetics/metabolism ; Axons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.}, } @article {pmid39570437, year = {2025}, author = {Maity, D and Kaundal, RK}, title = {Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1661-1686}, pmid = {39570437}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Humans ; *MicroRNAs/metabolism/genetics ; Early Diagnosis ; Biomarkers/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron degeneration, leading to muscle weakness and paralysis, with no effective treatments available. Early diagnosis could slow disease progression and optimize treatment. MicroRNAs (miRNAs) are being investigated as potential biomarkers due to their regulatory roles in cellular processes and stability in biofluids. However, variability across studies complicates their diagnostic utility in ALS. This study aims to identify significantly dysregulated miRNAs in ALS through meta-analysis to elucidate disease mechanisms and improve diagnostic strategies.

METHODS: We systematically searched PubMed, Google Scholar, and the Cochrane Library, following predefined inclusion and exclusion criteria. The primary effect measure was the standardized mean difference (SMD) with a 95% confidence interval, analyzed using a random-effects model. Additionally, we used network pharmacology to examine the targets of dysregulated miRNAs and their roles in ALS pathology.

RESULTS: Analysing 34 studies, we found significant upregulation of hsa-miR-206, hsa-miR-133b, hsa-miR-23a, and hsa-miR-338-3p, and significant downregulation of hsa-miR-218, hsa-miR-21-5p, and hsa-let-7b-5p in ALS patients. These miRNAs are involved in ALS pathophysiology, including stress granule formation, nuclear pore complex, SMCR8 and Sig1R dysfunction, histone methyltransferase complex alterations, and MAPK signaling perturbation, highlighting their critical role in ALS progression.

CONCLUSION: This study identifies several dysregulated miRNAs in ALS patients, offering insights into their role in the disease and potential as diagnostic biomarkers. These findings enhance our understanding of ALS mechanisms and may inform future diagnostic strategies. Validating these results and exploring miRNA-based interventions are crucial for improving ALS diagnosis and treatment outcomes.}, } @article {pmid39570667, year = {2025}, author = {Burks, CA and Brenner, MJ}, title = {Commentary on Von Sneidern et al's "Evaluation and Treatment of Acute Facial Palsy: Opportunities for Optimization at a Single Institution."-Bridging the Gap Between Guidelines and Practice.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {27}, number = {4}, pages = {319-320}, doi = {10.1089/fpsam.2024.0263}, pmid = {39570667}, issn = {2689-3622}, } @article {pmid39577228, year = {2025}, author = {Sojdeh, S and Safarkhani, M and Daneshgar, H and Aldhaher, A and Heidari, G and Nazarzadeh Zare, E and Iravani, S and Zarrabi, A and Rabiee, N}, title = {Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology's unexplored frontier.}, journal = {European journal of medicinal chemistry}, volume = {282}, number = {}, pages = {117080}, doi = {10.1016/j.ejmech.2024.117080}, pmid = {39577228}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Nanotechnology ; Genetic Therapy ; Animals ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.}, } @article {pmid39577830, year = {2025}, author = {Morikawa, K and Izumiya, Y and Takashio, S and Kawano, Y and Oguni, T and Kuyama, N and Oike, F and Yamamoto, M and Tabata, N and Ishii, M and Hanatani, S and Hoshiyama, T and Kanazawa, H and Matsuzawa, Y and Usuku, H and Yamamoto, E and Ueda, M and Tsujita, K}, title = {Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis.}, journal = {Journal of cardiology}, volume = {85}, number = {6}, pages = {440-446}, doi = {10.1016/j.jjcc.2024.11.003}, pmid = {39577830}, issn = {1876-4738}, mesh = {Humans ; Male ; Aged ; Female ; *Immunoglobulin Light-chain Amyloidosis/drug therapy/mortality ; *Antibodies, Monoclonal/administration & dosage/therapeutic use ; Middle Aged ; Retrospective Studies ; Survival Rate ; Treatment Outcome ; *Heart Diseases/drug therapy/mortality ; }, abstract = {BACKGROUND: Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Treatment with daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic response and better clinical outcomes compared with conventional treatment. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis.

METHODS AND RESULTS: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2 ± 10.4 years, male: 69 %) who underwent chemotherapy. We divided patients into a daratumumab group, which used daratumumab-containing regimens before second-line treatment (n = 32), and a conventional treatment group (n = 33). Compared with the conventional treatment group, the daratumumab group tended to be older, but there were no significant differences between groups in biomarkers and echocardiographic parameters. A total of 26 patients (40 %) died (median follow-up duration: 395 days). Kaplan-Meier survival analysis showed that the daratumumab group had significantly lower mortality compared with the conventional treatment group (p = 0.04; log-rank test). Cox hazard analysis revealed that use of daratumumab-containing regimens was associated with lower mortality after adjustment for the revised Mayo staging of AL amyloidosis (hazard ratio: 0.32; 95 % confidence interval: 0.12 to 0.85; p = 0.02).

CONCLUSION: Daratumumab-containing regimens may be associated with improved survival in patients with AL cardiac amyloidosis.}, } @article {pmid39578404, year = {2025}, author = {Phrathep, DD and Abdo, Z and Tadros, M and Lewandowski, E and Evans, J}, title = {The role of osteopathic manipulative treatment for dystonia: a literature review.}, journal = {Journal of osteopathic medicine}, volume = {125}, number = {4}, pages = {203-211}, pmid = {39578404}, issn = {2702-3648}, mesh = {Humans ; *Manipulation, Osteopathic/methods ; *Dystonia/therapy ; }, abstract = {CONTEXT: Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia.

OBJECTIVES: The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT's role for dystonia.

METHODS: A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review.

RESULTS: Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson's disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia.

CONCLUSIONS: Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.}, } @article {pmid39585060, year = {2024}, author = {Magni, E and Hochsprung, A and Cáceres-Matos, R and Pabón-Carrasco, M and Heredia-Camacho, B and Solís-Marcos, I and Luque-Moreno, C}, title = {Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1332-1342}, pmid = {39585060}, issn = {2035-8385}, abstract = {BACKGROUND: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications.

OBJECTIVES: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS.

METHODS: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger.

RESULTS: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up.

CONCLUSION: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.}, } @article {pmid39588282, year = {2024}, author = {Dash, BP and Freischmidt, A and Helferich, AM and Ludolph, AC and Andersen, PM and Weishaupt, JH and Hermann, A}, title = {Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1457704}, pmid = {39588282}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.}, } @article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, } @article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, } @article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, } @article {pmid39594452, year = {2024}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594452}, issn = {2076-3921}, abstract = {Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1-AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1-the bioactive LDAI extract-using both LC-MS/MS and 1D-NMR [[1]H, [13]C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.}, } @article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, } @article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, } @article {pmid39603574, year = {2024}, author = {Wen, J and Li, Y and Qin, Y and Yan, L and Zhang, K and Li, A and Wang, Z and Yu, F and Lai, J and Yang, W and Liu, YU and Qin, D and Su, H}, title = {Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107518}, doi = {10.1016/j.phrs.2024.107518}, pmid = {39603574}, issn = {1096-1186}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Phenanthridines/pharmacology/therapeutic use ; *Amaryllidaceae Alkaloids/pharmacology/therapeutic use ; *Caenorhabditis elegans/drug effects/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; *Disease Models, Animal ; TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; }, abstract = {Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97 % cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43[A315T] in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43[A315T] both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43[A315T]-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.}, } @article {pmid39604641, year = {2025}, author = {Mi, Y and Zhang, P and Hou, X and Ding, Y and Wang, Y and Du, H and Deng, M}, title = {A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {1}, pages = {191-203}, pmid = {39604641}, issn = {2240-2993}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Disease Progression ; Adult ; Aged ; Pedigree ; Mutation, Missense ; Genetic Variation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.}, } @article {pmid39611137, year = {2024}, author = {Valančius, D and Burnytė, B and Masaitienė, R and Morkūnienė, A and Klimašauskienė, A}, title = {Rapidly Progressing and Early-Onset Forms of Amyotrophic Lateral Sclerosis Caused by a Novel SOD1 Variant in a Lithuanian Family.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200217}, pmid = {39611137}, issn = {2376-7839}, abstract = {OBJECTIVES: To describe a novel familial variant of superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS) in a Lithuanian family, highlighting its variable progression and implications for treatment inclusion criteria.

METHODS: This study presents the clinical and genetic findings of a family with the novel SOD1 variant, including one member diagnosed with early-onset ALS (onset <40 years) and one with a particularly rapidly progressing course of ALS.

RESULTS: The SOD1 variant NM_000454.5:c.446T>C, NP_000445.1:p.(Val149Ala) was identified in affected family members and 4 asymptomatic members aged 32-56 years. We present detailed disease course of the affected family members obtained during follow-up. Clinically, this variant is associated with variable disease progression, with the time from symptom onset to death ranging from 5 to 77 months.

DISCUSSION: The novel SOD1 variant p.Val149Ala in this Lithuanian family causes ALS of variable onset and course, including a case of early-onset ALS and one case of rapidly progressing ALS, necessitating recognition by the scientific community and development of tailored therapeutic approaches.}, } @article {pmid39612826, year = {2025}, author = {Xu, H and Cheng, J and Leng, Q and Cao, R and Su, W and Sun, L and Xue, F and Han, Y and Wu, R}, title = {Characterization of acetolactate synthase genes and resistance mechanisms of multiple herbicide resistant Lolium multiflorum.}, journal = {Plant physiology and biochemistry : PPB}, volume = {219}, number = {}, pages = {109324}, doi = {10.1016/j.plaphy.2024.109324}, pmid = {39612826}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Lolium/genetics/enzymology/drug effects ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; Imidazoles/pharmacology ; Genes, Plant ; Mutation ; }, abstract = {Combining imidazolinone-tolerant wheat with imazamox presents an effective solution to combat weed resistance. However, Lolium multiflorum, a troublesome resistant weed infesting wheat fields, may have developed resistance to imazamox, and the potential resistance mechanisms are intriguing. In this study, we explored the susceptibility of L. multiflorum to imazamox and investigated the resistance mechanisms, including the contribution of the target enzyme acetolactate synthase (ALS) to resistance and the presence of non-target-site resistance (NTSR). Eight L. multiflorum populations suspected of being resistant to imazamox were collected, and six populations exhibited resistance, ranging from 2.45-fold to 16.32-fold. The LmALS1 gene from susceptible population D3 plants and multiple copies of the LmALS gene (LmALS1, LmALS2, LmALS2α, LmALS3, LmALS3α, LmALS3β) from resistant populations D5 and D8 plants were separately amplified. Two mutations (Pro/Gln197 to Thr, Trp574 to Leu) were found in LmALS1 in the resistant populations. Compared to D3, LmALS1 was overexpressed in D5 but not in D8. The presence of LmALS1 mutants (LmALS1-Thr197 and LmALS1- Leu574), along with LmALS2, LmALS3, and their subunits, contribute to the resistance phenotype by increasing bonding energies, weakening hydrogen bonds, or decreasing protein binding pocket volumes and surface area. Additionally, D5 and D8 populations exhibited multiple resistance (>40-fold) to three other ALS inhibitors: pyroxsulam, flucarbazone-sodium, and mesosulfuron-methyl. Pre-treatment with malathion and 4-chloro-7-nitrobenzoxadiazole (cytochrome P450 monooxygenase and glutathione S-transferase inhibitors respectively) reversed the resistance of the D8 population and partially reversed the resistance of the D5 population to imazamox. This study characterizes ALS genes and extends our knowledge into the ALS resistance mechanisms involved in L. multiflorum. It also deepens our understanding of the complex diversification resistance mechanisms, thereby facilitating advances in weed resistance management strategies in wheat fields.}, } @article {pmid39621188, year = {2025}, author = {Gerometta, M and Henderson, RD and Friend, R and Cooper, LT and Zhao, J and Boyd, AW and Bartlett, PF}, title = {Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.}, journal = {Clinical drug investigation}, volume = {45}, number = {1}, pages = {17-28}, pmid = {39621188}, issn = {1179-1918}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Adult ; Dose-Response Relationship, Drug ; Aged ; Healthy Volunteers ; *Receptor, EphA4/antagonists & inhibitors ; Half-Life ; Young Adult ; *Recombinant Fusion Proteins/pharmacokinetics/adverse effects/administration & dosage/therapeutic use ; }, abstract = {BACKGROUND: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.

OBJECTIVE: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.

METHODS: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.

RESULTS: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.

CONCLUSIONS: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.

CLINICAL TRIAL REGISTRATION: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).}, } @article {pmid39622292, year = {2025}, author = {Ojo, O and Boateng, J and Pacella, R and Hanrahan, A and Essex, R and Dibley, L}, title = {Factors Influencing the Care and Management of Diabetic Foot Ulcers: A Scoping Review.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {31}, number = {3}, pages = {380-389}, doi = {10.1016/j.eprac.2024.11.010}, pmid = {39622292}, issn = {1530-891X}, mesh = {Humans ; *Diabetic Foot/therapy ; *Health Knowledge, Attitudes, Practice ; Patient Education as Topic ; Disease Management ; }, abstract = {OBJECTIVE: The objective of this scoping review is to explore the experiences of patients' and healthcare practitioners on the factors that influence the care and management of diabetes-related foot ulcers (DFUs).

METHODS: Levac et al's 6-stage framework and the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, guided the review. The SPIDER tool was used to define key elements of the review question. Searches for relevant articles were conducted in electronic databases (PUBMED, CINAHL, AMED, Embase, Cochrane Database of Systematic Reviews, and PsycINFO), Google Scholar, and hand searches of reference lists.

RESULTS: Eight articles met the inclusion criteria and were included in the review. Three themes were identified: Communication and Education about DFUs; Challenges of managing DFUs; and Barriers to treatment and management. The themes are presented as a narrative synthesis.

CONCLUSION: Inadequate knowledge of diabetic foot care by patients and inconsistent communication by healthcare professionals were primary factors affecting the effective management of diabetes-related foot ulcers. Consistent, patient-focused education that is supported by knowledgeable health care professionals should form the foundation of effective diabetic foot ulcer care.}, } @article {pmid39623504, year = {2024}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {17}, number = {1}, pages = {54}, pmid = {39623504}, issn = {1756-0381}, support = {RSP2024R244//King Saud University/ ; }, abstract = {This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R[2] values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.}, } @article {pmid39624969, year = {2024}, author = {Yuan, D and Jiang, S and Xu, R}, title = {Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2399962}, pmid = {39624969}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy/epidemiology/genetics ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.}, } @article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, } @article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, } @article {pmid39629626, year = {2025}, author = {Boutin, RCT and Shobeirian, F and Adam, S and Lehman, A and Salvarinova, R and Friedman, JM}, title = {Immune Dysregulation in a Child With SOD1-Related Neurological Disease.}, journal = {American journal of medical genetics. Part A}, volume = {197}, number = {4}, pages = {e63949}, doi = {10.1002/ajmg.a.63949}, pmid = {39629626}, issn = {1552-4833}, support = {//Mining for Miracles (BCCH Foundation)/ ; //Genome British Columbia/ ; }, mesh = {Humans ; Male ; *Superoxide Dismutase-1/genetics ; Homozygote ; Young Adult ; Phenotype ; *Nervous System Diseases/genetics/immunology/pathology ; *Quadriplegia/genetics/pathology/immunology ; Child ; Mutation ; }, abstract = {Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.}, } @article {pmid39631325, year = {2024}, author = {Zhang, Y and Liu, Q and Xie, H and Zhang, W and Lin, X and Zhang, H and Yu, H and Ma, Y and Zhang, C and Geng, H and Shi, N and Cui, L and Li, B and Li, YF}, title = {Fecal microbiota transplantation as an effective way in treating methylmercury-poisoned rats.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177850}, doi = {10.1016/j.scitotenv.2024.177850}, pmid = {39631325}, issn = {1879-1026}, mesh = {Animals ; *Methylmercury Compounds/metabolism ; *Fecal Microbiota Transplantation ; Rats ; *Gastrointestinal Microbiome ; Male ; Feces/microbiology ; }, abstract = {Methylmercury (MeHg) can cause devastating neurotoxicity in animals and human beings. Gut microbiota dysbiosis has been found in MeHg-poisoned animals. Fecal microbiota transplantation (FMT) has been shown to improve clinical outcomes in a variety of diseases such as epilepsy, amyotrophic lateral sclerosis (ALS) and autism. The aim of this study was to investigate the effects of FMT on MeHg-poisoned rats. FMT treatment was applied to MeHg-poisoned rats for 14 days. The neurobehavior, weight changes, dopamine (DA), the total Hg and MeHg level were evaluated. Besides, the gut microbiota and metabolites change in feces were also checked. It was found that FMT helped weight gain, alleviated the neurological disorders, enhanced fecal mercury excretion and MeHg demethylation, reconstructed gut microbiome and promoted the production of gut-brain axis related-metabolites in MeHg-poisoned rats. This study elaborates on the therapeutic efficacy of FMT in treating of MeHg-poisoned rats, which sheds lights on the treatment of neurological diseases like Minamata Disease and even Parkinson's Disease.}, } @article {pmid39633494, year = {2024}, author = {Ko, VI and Ong, K and Kwon, DY and Li, X and Pietrasiewicz, A and Harvey, JS and Lulla, M and Bhat, G and Cleveland, DW and Ravits, JM}, title = {CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {187}, pmid = {39633494}, issn = {2051-5960}, support = {P30 NS047101/NS/NINDS NIH HHS/United States ; S10 OD026929/OD/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics ; *Casein Kinase Idelta/metabolism/genetics ; *Casein Kinase 1 epsilon/metabolism/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; }, abstract = {Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.}, } @article {pmid39633896, year = {2024}, author = {Bhaskaran, S and Piekarz, KM and Brown, J and Yang, B and Ocañas, SR and Wren, JD and Georgescu, C and Bottoms, C and Murphy, A and Thomason, J and Saunders, D and Smith, N and Towner, R and Van Remmen, H}, title = {The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505369}, pmid = {39633896}, issn = {1662-4548}, support = {I21 BX005619/BX/BLRD VA/United States ; IK6 BX005234/BX/BLRD VA/United States ; P30 AG050911/AG/NIA NIH HHS/United States ; }, abstract = {Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.}, } @article {pmid39634573, year = {2024}, author = {Braimah, RO and Taiwo, AO and Olasoji, HO and Legbo, JN and Amundson, M and Ibikunle, AA and Suleiman, IK and Bala, M and Ile-Ogedengbe, BO}, title = {Braimah-Taiwo et al New Classification System and Treatment Algorithm of Mandibulo-Maxillary Synostosis Related to Noma. Field Experience From Noma Children Hospital Sokoto, Nigeria.}, journal = {Craniomaxillofacial trauma & reconstruction}, volume = {17}, number = {4}, pages = {279-290}, pmid = {39634573}, issn = {1943-3875}, abstract = {STUDY DESIGN: This was a retrospective study at Noma Children Hospital, Sokoto, Nigeria, from January 2018 to December 2021.

OBJECTIVE: The main objective of this appraisal was to present Braimah-Taiwo et al's new classification system for mandibulo-maxillary synostosis secondary to noma and also to provide a guide to their treatment.

METHODS: Noma with mandibulo-maxillary synostosis was the main inclusion criteria. Excluded were cases of acute noma and noma without mandibulo-maxillary synostosis. Data retrieved include demographics of patients and extent of bony ankylosis and mandibulo-maxillary synostosis.

RESULTS: A total of 64 patients (30 (46.9%) males and 34 (53.1%) females) were managed. Ages ranged from 6 to 40 years with mean ± SD (18.2 ± 7.6) years. Regarding the new classification system of mandibulo-maxillary synostosis, 6 (9.4%) patients presented with Type 1 (Mild joint obliteration)±Soft tissue scarring, 24 (37.5%) presented with Type II (Total joint obliteration)±Soft tissue scarring, 21 (32.8%) presented with Type III (Coronoid, zygoma and maxilla) ±Soft tissue scarring, 4 (6.3%) presented with Type IV (Condyle, glenoid fossa, coronoid, sigmoid notch and zygoma) ±Soft tissue scarring, 7 (10.9%) presented with Type V (Condyle, glenoid fossa, coronoid, sigmoid notch, zygoma and pterygo-maxilla) ±Soft tissue scarring, while 2 (3.1%) patients presented with Type VI (condyle, glenoid fossa, coronoid, sigmoid notch, zygoma, pterygo-maxilla and the orbit) ±Soft tissue scarring.

CONCLUSIONS: Pattern of tissue destruction in noma patients is complex involving both soft and hard tissues. This new classification will guide surgeons in the effective management of these patients.}, } @article {pmid39635310, year = {2024}, author = {Yuan, J and Zhang, YJ and Wen, W and Liu, XC and Chen, FL and Yang, Y}, title = {Afferent loop syndrome of a patient with recurrent fever: A case report.}, journal = {World journal of radiology}, volume = {16}, number = {11}, pages = {678-682}, pmid = {39635310}, issn = {1949-8470}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare complication, Aoki et al reported that the incidence of distal gastrectomy in Billroth-II is 0.3%-1.0%. The clinical manifestations of ALS are atypical, which can manifest as severe abdominal pain, vomiting, obstructive jaundice, malnutrition, etc.

CASE SUMMARY: The patient was a 58-year-old man who complained of recurrent high fever for more than 1 week. Laboratory tests showed an increase in neutrophil ratio, procalcitonin, C-reactive protein, and abnormal liver function. Enhanced computed tomography scan of the abdomen showed small intestinal obstruction between the anastomosis of the gastrojejunum, bile duct, and pancreaticoduodenum. Gastroscopy revealed significant narrowing of the lumen 15 cm from the anastomosis into the afferent loop. After performing balloon dilation and placement of the nutrition tube, the patient did not experience further fever.

CONCLUSION: ALS is relatively rare after pancreaticoduodenectomy, and the treatment depends on the nature of the obstructive lesion. The traditional treatment method is surgery, and in recent years, endoscopy has provided a new treatment method for ALS.}, } @article {pmid39637982, year = {2025}, author = {Vallée, S and Deneux, V and Funaro, D and Marcoux, D and Powell, J and Hatami, A and Coulombe, J and Piram, M and McCuaig, CC}, title = {Long-term evolution of prepubertal-onset anogenital lichen sclerosus: A 35-year retrospective and cross-sectional study from a single tertiary care maternal and pediatric center.}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {1010-1014}, doi = {10.1016/j.jaad.2024.09.086}, pmid = {39637982}, issn = {1097-6787}, mesh = {Humans ; Retrospective Studies ; Female ; Child ; Cross-Sectional Studies ; Puberty ; *Vulvar Lichen Sclerosus/diagnosis ; Adolescent ; Quality of Life ; Tertiary Care Centers ; Age of Onset ; *Lichen Sclerosus et Atrophicus/diagnosis ; Disease Progression ; Follow-Up Studies ; Child, Preschool ; Time Factors ; }, abstract = {BACKGROUND: Anogenital lichen sclerosus (ALS) in children may persist after puberty with potential clinical repercussions.

OBJECTIVE: The purpose of this study was to evaluate postpubertal evolution of girls with ALS diagnosed in the prepubertal period based on physical examination, the persistence of functional symptoms, and the effect on quality of life.

METHODS: We retrospectively reviewed 65 cases of girls with prepubertal-onset ALS. Onset, signs/symptoms, photos, evolution, and treatment were collected from the medical records. Subsequently, 30 of these 65 patients were assessed for persistence of signs/symptoms by physical examination and/or standardized questionnaire.

RESULTS: Signs of active disease after puberty based on physical examination were present in 92% (N = 23) of examined patients. A high proportion of cases with persistent ALS after puberty were asymptomatic (47%, N = 14).

LIMITATIONS: This is a single-center retrospective study with a limited number of patients. Half of our original cohort could not be reached or declined a follow-up visit.

CONCLUSION: Prepubertal lichen sclerosus is a chronic condition that can be asymptomatic after puberty despite continued disease activity. We recommend long-term follow-up of patients with prepubertal ALS to prevent associated morbidity.}, } @article {pmid39640633, year = {2024}, author = {Nikafshan Rad, H and Su, Z and Trinh, A and Hakim Newton, MA and Shamsani, J and Nygc Als Consortium, and Karim, A and Sattar, A}, title = {Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e38583}, pmid = {39640633}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilizes an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signaling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.}, } @article {pmid39645043, year = {2025}, author = {Needle, C and Brinks, A and Shapiro, J and Lo Sicco, K}, title = {Response to Chen et al's "Emergence of Janus kinase inhibitors led to increase in proportion of severe alopecia areata patients receiving treatment: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e119-e120}, doi = {10.1016/j.jaad.2024.10.118}, pmid = {39645043}, issn = {1097-6787}, } @article {pmid39645085, year = {2025}, author = {Ediriweera, GR and Sivaram, AJ and Cowin, G and Brown, ML and McAlary, L and Lum, JS and Fletcher, NL and Robinson, L and Simpson, JD and Chen, L and Wasielewska, JM and Byrne, E and Finnie, JW and Manavis, J and White, AR and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {221-235}, doi = {10.1016/j.jconrel.2024.11.074}, pmid = {39645085}, issn = {1873-4995}, mesh = {Animals ; *Oligonucleotides, Antisense/administration & dosage/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy/genetics ; *Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; *Nanoparticles/administration & dosage/chemistry ; *Brain/metabolism ; Mice, Transgenic ; Lipids/chemistry/administration & dosage ; Mice ; Microbubbles ; Spinal Cord/metabolism ; Male ; Blood-Brain Barrier/metabolism ; Liposomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.}, } @article {pmid39645221, year = {2025}, author = {Bajpai, A and Bharathi, V and Patel, BK}, title = {Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.}, journal = {European journal of pharmacology}, volume = {987}, number = {}, pages = {177187}, doi = {10.1016/j.ejphar.2024.177187}, pmid = {39645221}, issn = {1879-0712}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Antioxidants/pharmacology/therapeutic use ; *Huntington Disease/metabolism/drug therapy/pathology/genetics ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.}, } @article {pmid39654532, year = {2025}, author = {Dave, KD and Oskarsson, B and Yersak, J and Krauss, R and Heiman-Patterson, T and Lomen-Hoerth, C and Selig, WKD and Halpern Paul, I and Schaeffer, M and Garcia-Trujillo, B and Waldo, D and Thakur, N and Babu, S}, title = {Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {215-224}, doi = {10.1080/21678421.2024.2432034}, pmid = {39654532}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Referral and Consultation ; *Neurologists ; United States ; Male ; Female ; Medicare ; Aged ; Time Factors ; Delayed Diagnosis ; }, abstract = {Objectives: To evaluate neurologists and other clinicians' contributions to U.S. ALS diagnostic timelines. Background: Over the past two decades, the average time to ALS diagnosis in the U.S. has remained unchanged at 12 months. ALS patients see 3-4 clinicians prior to referral to an ALS specialist for diagnosis confirmation and/or treatment initiation. There is an urgent need to identify where delays occur, so that targeted clinician awareness may be raised about early suspicion and referrals. Methods: Review of Medicare claims database for health care utilization patterns by ALS beneficiaries during diagnostic journey. Survey of typical clinic wait times for new consultations reported by 75-78 ALS Certified Treatment Centers of Excellence (2019-2021). Results: During 2011-2021, 78,520 Medicare beneficiaries were diagnosed with ALS (T0). The mean (median) timelines between first neurologist ambulatory visit and T0, is 16.5 (11.0) months; mean ± SD for ALS/neuromuscular providers being 9.6 ± 12.6 months versus 16.7 ± 17.5 months for non-neuromuscular neurologists. During the 12-months preceding T0, an ALS patient undergoes median(max) 1.5(4.0) brain-MRIs, 1.6(6.0) spine-MRIs, and 1.3(4.0) electromyography studies. Greater than 75% of ALS centers consistently report ≤ 4 week wait times for new ALS consults. This study introduces "thinkALS," an easy-to-use clinical diagnostic and referral guide for non-ALS neurologists to tackle this challenge. Conclusions: This study is the first to provide metrics on how non-neuromuscular/ALS specialists contribute to ALS diagnostic timelines in the U.S.}, } @article {pmid39655175, year = {2024}, author = {Palm, A and Ekström, M and Emilsson, Ö and Ersson, K and Ljunggren, M and Sundh, J and Grote, L}, title = {Control of hypercapnia and mortality in home mechanical ventilation: the population-based DISCOVERY study.}, journal = {ERJ open research}, volume = {10}, number = {6}, pages = {}, pmid = {39655175}, issn = {2312-0541}, abstract = {BACKGROUND: Studies on the survival of patients with home mechanical ventilation (HMV) are sparse. We aimed to analyse the impact of controlled hypercapnia on survival over 27 years among patients with HMV in Sweden.

STUDY DESIGN AND METHODS: Population-based cohort study of adult patients starting HMV in the Swedish Registry for Respiratory Failure (Swedevox) during 1996-2022 cross-linked with the National Cause of Death registry. Mortality risk factors were analysed using crude and multivariable Cox regression models, including adjustments for anthropometrics, comorbidities, the underlying diagnosis causing chronic hypercapnic respiratory failure (CRF) and the control of hypercapnia (P aCO2 ≤6.0 kPa) at follow-up.

RESULTS: We included 10 190 patients (50.1% women, age 62.9±14.5 years). Control of hypercapnia at follow-up after 1.3±0.9 years was associated with lower mortality, hazard ratio (HR) 0.74 (95% CI 0.68-0.80) and the association was strongest in those with pulmonary disease, restrictive thoracal disease (RTD), obesity hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS). Predictors for increased mortality included age, Charlson Comorbidity Index, supplemental oxygen therapy and acute start of HMV therapy. Median survival varied between 0.8 years (95% CI 0.8-0.9 (n=1401)) for ALS and 7.6 years (95% CI 6.9-8.6 (n=1061)) for neuromuscular disease. Three-year survival decreased from 76% (95% CI 71-80) between 1996 and 1998 to 52% (95% CI 50-55) between 2017 and 2019. When adjusting for underlying diagnosis and age, the association between start year and decreased survival disappeared, HR 1.00 (95% CI 0.99-1.01).

CONCLUSION: Controlling P aCO2 is a key treatment goal for survival in HMV therapy. Survival differed markedly between diagnosis and age groups, and survival rates have declined as the patient group has aged.}, } @article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Skłodowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, } @article {pmid39659885, year = {2024}, author = {Wan, H and Qian, W and Wei, B and Tian, K and Chen, Z and Zhang, J and Chen, F}, title = {A bibliometric analysis of gene editing and amyotrophic lateral sclerosis (from 2004 to 2024).}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499025}, pmid = {39659885}, issn = {1662-4548}, abstract = {OBJECTIVE: To learn more about gene editing and ALS, and to provide a comprehensive view of gene editing for further treatment of amyotrophic lateral sclerosis.

METHODS: We searched 1981 records from Web of Science core collection and Pubmed, Scopus, of which 1,292 records were obtained after exclusion. We then scientifically and metrologically analyzed these records for spatial and temporal distribution, author distribution, subject categories, subject distribution, references, and keywords using R, software CiteSpace and VOSviewer.

RESULTS: Our analysis provides basic information about research in the field, suggests that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research in this area is focused on inflammatory mechanisms, immune mechanisms, related diseases, and associated cytokines in ALS.

CONCLUSION: RNA Editing, Antisense Bligonucleotide, and Glycine Receptor are cutting-edge research topics in this field, which is undergoing rapid development. We hope that this work will provide new ideas for advancing the scientific research and clinical application of ALS.}, } @article {pmid39662651, year = {2025}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Mitochondria/drug effects/metabolism ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles ; }, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, } @article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration & dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, } @article {pmid39666071, year = {2024}, author = {de Boer, EMJ and de Vries, BS and Van Hecke, W and Mühlebner, A and Vincken, KL and Mol, CP and van Rheenen, W and Westeneng, HJ and Veldink, JH and Höglinger, GU and Morris, HR and Litvan, I and Raaphorst, J and Ticozzi, N and Corcia, P and Vandenberghe, W and Pijnenburg, YAL and Seelaar, H and Ingre, C and Van Damme, P and van den Berg, LH and van de Warrenburg, BPC and van Es, MA}, title = {Diagnosing primary lateral sclerosis: a clinico-pathological study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {46}, pmid = {39666071}, issn = {1432-1459}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/genetics ; Autopsy ; Brain/pathology/diagnostic imaging ; Diagnosis, Differential ; *Motor Neuron Disease/diagnosis/pathology ; DNA-Binding Proteins ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

METHODS: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.

RESULTS: Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.

CONCLUSIONS: This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS. Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.}, } @article {pmid39666202, year = {2024}, author = {van Eijk, RPA and van Loon, FT and van Unnik, JWJ and Weemering, DN and Seitidis, G and Mavridis, D and van den Berg, LH and Nikolakopoulos, S}, title = {Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {40}, pmid = {39666202}, issn = {1432-1459}, support = {EVIDENCE//Stichting ALS Nederland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Randomized Controlled Trials as Topic ; Patient Dropouts/statistics & numerical data ; }, abstract = {OBJECTIVES: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.

METHODS: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.

RESULTS: In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p = 0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p < 0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.

CONCLUSIONS: ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.}, } @article {pmid39670820, year = {2025}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2720-2741}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; MAP Kinase Kinase Kinases/antagonists & inhibitors/metabolism ; Neurons/drug effects/pathology/metabolism ; Drug Discovery ; Computer Simulation ; Structure-Activity Relationship ; Rats ; }, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, } @article {pmid39672208, year = {2025}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, mesh = {Humans ; *Neuroglia/pathology/metabolism/physiology ; *Nervous System Diseases/therapy/pathology/metabolism ; Animals ; *Cell Polarity/physiology ; Microglia/metabolism/pathology ; }, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, } @article {pmid39674307, year = {2025}, author = {Pistolesi, A and Ranieri, G and Calvani, M and Guasti, D and Chiarugi, A and Buonvicino, D}, title = {Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115095}, doi = {10.1016/j.expneurol.2024.115095}, pmid = {39674307}, issn = {1090-2430}, mesh = {Animals ; Mice ; *Microglia/drug effects ; Disease Models, Animal ; *Peroxidase/antagonists & inhibitors/metabolism ; Mice, Inbred NOD ; Female ; *Multiple Sclerosis, Chronic Progressive/pathology/drug therapy ; Disease Progression ; Reactive Oxygen Species/metabolism ; *Propionates/pharmacology/therapeutic use ; *Enzyme Inhibitors/therapeutic use/pharmacology ; Mitochondria/drug effects/metabolism ; *Nerve Degeneration/pathology/drug therapy ; Spinal Cord/pathology/drug effects ; Aminopyridines ; Pyrroles ; }, abstract = {Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.}, } @article {pmid39678053, year = {2024}, author = {Finsterer, J and Mehri, S}, title = {The Causality Spectrum of Dropped Head Syndrome is Broad and Includes Myopathy, Neurodegenerative Disorders, and Varia.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {382-383}, pmid = {39678053}, issn = {1300-0667}, abstract = {Dropped head syndrome is a common complication of various neurological disorders. Most commonly, dropped head syndrome is due to primary or secondary myopathy. However, neurodegenerative diseases and various other conditions can also be complicated by dropped head syndrome. Among the primary myopathies, dropped head occurs most commonly in association with mitochondrial disorders, congenital myasthenic syndrome, and axial myopathies. Among the secondary myopathies, dropped occurs most commonly in association with inflammatory myopathies. Myasthenia is the most common transmission disorder associated with dropped head syndrome. The neurodegenerative disorder most commonly associated with dropped head syndrome is Parkinson syndrome. The diagnosis and treatment of dropped head syndrome from any cause requires a multidisciplinary approach. Outcome varies considerably but early diagnosis and early treatment are associated with a more favourable outcome.}, } @article {pmid39681722, year = {2025}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {67-85}, pmid = {39681722}, issn = {1759-4766}, mesh = {Animals ; Humans ; Amyotrophic Lateral Sclerosis/immunology ; *Immunotherapy/methods ; Microglia/immunology ; Multiple Sclerosis/immunology ; *Neurodegenerative Diseases/immunology/therapy ; }, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, } @article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, } @article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, } @article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, } @article {pmid39694549, year = {2024}, author = {Ma, YL and Qiu, T and Xu, XL and Wang, LX and Zhuang, PY}, title = {[Analysis of clinical characteristics of amyotrophic lateral sclerosis patients initially diagnosed with abnormal laryngeal function].}, journal = {Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery}, volume = {59}, number = {12}, pages = {1293-1298}, doi = {10.3760/cma.j.cn115330-20240630-00388}, pmid = {39694549}, issn = {1673-0860}, support = {82271155//National Natural Science Foundation of China/ ; 2020J011212//Fujian Provincial Natural Science Foundation/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Larynx/physiopathology ; }, abstract = {Objective: To study the laryngeal functional characteristics of patients with amyotrophic lateral sclerosis (ALS)disease diagnosed at the voice clinic. Methods: A retrospective analysis(case series study) was conducted on the laryngeal functional characteristics of 7 patients [2 males, 5 females, age ranged from 43 to 76(60.85±13.18)]with motor neuron disease who visited the voice clinic and were ultimately diagnosed by neurologists. The data included laryngostroboscopy, fiberoptic endoscopic examination of swallowing(FEES), acoustic analysis and laryngeal electromyography(LEMG). Descriptive methods were used for analysis. Results: ①There were 2 males and 5 females, with an average age of (60.85±13.18) years. They had previously visited the otolaryngology department more than twice, visit frequency with an average of 3.57 and an average diagnosis time of 12.28 months. The main complaints of the patient at the time of treatment were voice change, dysphagia or vocal fatigue. ②LEMG: Among 7 cases, 4 cases demonstrated neurogenic damage, all of which were bilateral, and 3 cases showed normal findings on examination. Spontaneous potentials (SP) were present in three cases for more than 6 months, with the longest duration being 24 months. Three cases exhibited the coexistence of spontaneous potential and reinnervated motor unit potentials (MUPs), and two cases showed bundle tremor potential.③Laryngostroboscopy revealed bilateral vocal fold asymmetry and glottic insufficiency in 7 cases, and decreased vocal cord movement in 4 cases, and vocal cord atrophy in 5 cases. FEES showed that 7 patients presented with mild to severe swallowing dysfunction, 3 cases had soft palate insufficiency and mild to severe food residues in the epiglottic valley and pyriform fossa. 1 case showed leakage and 1 case showed aspiration. Conclusions: Patients presenting with initial symptoms of abnormal laryngeal function should be vigilant for the possibility of motor neuron disease, especially when laryngostroboscopy reveals abnormal vocal fold movement and swallowing dysfunction. LEMG examination reveals bilateral neurogenic damage, prolonged spontaneous potential, coexistence of spontaneous potential and reinnervated MUPs, and the appearance of bundle tremor potential, which is beneficial for early detection of motor neuron disease.}, } @article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka, and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, } @article {pmid39708835, year = {2025}, author = {Davalos, L and Kushlaf, H}, title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.}, journal = {Seminars in respiratory and critical care medicine}, volume = {46}, number = {3}, pages = {250-258}, doi = {10.1055/a-2463-3385}, pmid = {39708835}, issn = {1098-9048}, mesh = {Humans ; *Neuromuscular Diseases/drug therapy/physiopathology/therapy ; Chronic Disease ; Myasthenia Gravis/drug therapy ; }, abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.}, } @article {pmid39713159, year = {2024}, author = {Wang, YB and Jin, CZ}, title = {Roles of traditional Chinese medicine extracts in hyperuricemia and gout treatment: Mechanisms and clinical applications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {47}, pages = {5076-5080}, pmid = {39713159}, issn = {2219-2840}, mesh = {*Hyperuricemia/drug therapy/blood ; Humans ; *Gout/drug therapy ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Uric Acid/blood/metabolism ; Gout Suppressants/therapeutic use ; Animals ; }, abstract = {In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored.}, } @article {pmid39715100, year = {2025}, author = {Wu, Y and Tian, X and Ma, J and Lin, Y and Ye, J and Wang, Y and Lu, J and Yin, W}, title = {Label-free discrimination analysis of breast cancer tumor and adjacent tissues of patients after neoadjuvant treatment using Raman spectroscopy: a diagnostic study.}, journal = {International journal of surgery (London, England)}, volume = {111}, number = {2}, pages = {1788-1800}, doi = {10.1097/JS9.0000000000002201}, pmid = {39715100}, issn = {1743-9159}, mesh = {Humans ; *Spectrum Analysis, Raman/methods ; *Breast Neoplasms/therapy/pathology/diagnosis/surgery ; Female ; *Neoadjuvant Therapy ; Middle Aged ; Adult ; Mastectomy, Segmental ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVE: Breast-conserving surgery (BCS) plays a crucial role in breast cancer treatment, with a primary focus on ensuring cancer-free surgical margins, particularly for patients undergoing neoadjuvant treatment. After neoadjuvant treatment, tumor regression can complicate the differentiation between breast cancer tumor and adjacent tissues. Raman spectroscopy, as a rapid and non-invasive optical technique, offers the advantage of providing detailed biochemical information and molecular signatures of internal molecular components in tissue samples. Despite its potential, there is currently no research on using label-free Raman spectroscopy to distinguish between breast cancer tumors and adjacent tissues after neoadjuvant treatment. This study intends to distinguish between tumor and adjacent tissues after neoadjuvant treatment in breast cancer through label-free Raman spectroscopy.

METHODS: In this study, the intraoperative frozen samples of breast cancer tumor and adjacent tissue were collected from patients who underwent neoadjuvant treatment during surgery. The samples were examined using Raman confocal microscopy, and Raman spectra were collected by LabSpec6 software. Spectra were preprocessed by Savitz-Golay filter, adaptive iterative reweighted penalized least squares and MinMax normalization method. The differences in Raman spectra between breast cancer tumor and adjacent tissues after neoadjuvant treatment were analyzed by Wilcoxon rank-sum test, with a Bonferroni correction for multiple comparisons. Based on the support vector machine (SVM) method in machine learning, a predictive model for classification was established in the total group and subgroups of different hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and Ki-67 expression level. The independent test set was used to evaluate the performance of the model, and the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy of different models were obtained.

RESULT: This study comprised 4260 Raman spectra of breast cancer tumor and adjacent frozen tissue samples from 142 breast cancer patients treated with neoadjuvant treatment. The Raman peaks associated with nucleotides and their metabolites in the Raman spectra of breast cancer tumor tissues were higher in intensities than those of adjacent tissues after neoadjuvant therapy (676 cm -1 : Bonferroni adjusted P < 0.0001; 724 cm -1 : P < 0.0001; 754 cm -1 : P < 0.0001), and the Raman peaks from amide III bands were more intense (1271 cm -1 : P < 0.01). Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectra revealed reduced lipid content and increased collagen and nucleic acid content in breast cancer tumor tissues compared to adjacent tissues following neoadjuvant therapy. The predictive model based on the Raman spectral signature of breast cancer tumor and adjacent tissues after neoadjuvant treatment achieved an AUC of 0.98, with accuracy, sensitivity, and specificity values of 0.89, 0.97, and 0.83, respectively. The AUC of subgroup analysis according to different status of molecular pathological biomarkers was stably around 99%.

CONCLUSION: This study demonstrated that label-free Raman spectroscopy can differentiate tumor and adjacent tissues of breast cancer patients treated with neoadjuvant therapy thorough getting the panoramic perspective of the biochemical compounds for the first time. Our study provided a novel technique for determining the margin status in BCS in breast cancer following neoadjuvant treatment rapidly and precisely.}, } @article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.

AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.

EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, } @article {pmid39722495, year = {2025}, author = {García-Ramírez, Y and Cayuela-Fuentes, JM and Mira-Escolano, MP and Maceda-Roldán, LA and Mikulasova, E and Oliva-López, C and Sánchez-Escámez, A and Ciller-Montoya, P and Palomar-Rodríguez, JA}, title = {Characterization, epidemiology, and factors associated with evolution and survival in patients with amyotrophic lateral sclerosis in southeastern Spain, 2008-2021: a population-based study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {268-280}, doi = {10.1080/21678421.2024.2439454}, pmid = {39722495}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality/diagnosis ; Spain/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Prevalence ; Incidence ; Adult ; Disease Progression ; }, abstract = {OBJECTIVE: To describe the epidemiology, characteristics, and factors associated with the evolution and survival in patients with amyotrophic lateral sclerosis (ALS) in a region of southeastern Spain.

METHODS: An observational study was carried out in people with a diagnosis of ALS in the period 2008-2021 who were registered in the Information System of Rare Diseases of the Region of Murcia (SIER). We calculated crude and standardized incidence rate (SIR) using European Standard Population of 2013 and point prevalence. The Kaplan-Meier method and the log-rank test were used to estimate and compare survival curves.

RESULTS: We identified 374 cases. The mean age at diagnosis was 66.5 ± 11.7 and 50.3% persons were spinal onset. Mean time from the onset of symptoms to diagnosis was 0.9 ± 1.0 years. The global SIR was 1.95/100,000 person-years (95%CI: 1.77-2.12), which was higher in men (ratio 1.34), and the point prevalence in 2021 was 4.57 per 100,000 (95% CI: 4.46-4.68). There were 297 deaths with a mean age of 69.8 ± 10.8. The median survival from clinical onset was 2 years (95%CI: 1.0-3.0). Factors associated with lower survival were bulbar onset (p < 0.001), older age at the onset of symptoms (p < 0.001), and the absence of riluzole treatment (p = 0.003).

CONCLUSIONS: This study is one of few to evaluate the epidemiological, characteristics, and prognostic factors of ALS in Spain, with findings similar to previous population studies. The use of population-based registries offers reliable information on the magnitude, or evolution in these patients.}, } @article {pmid39725771, year = {2024}, author = {Pagliari, E and Taiana, M and Manzini, P and Sali, L and Quetti, L and Bertolasi, L and Oldoni, S and Melzi, V and Comi, G and Corti, S and Nizzardo, M and Rizzo, F}, title = {Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {29}, pmid = {39725771}, issn = {1420-9071}, support = {Craiplo Grant 2020-3623//Fondazione Cariplo/ ; 22739//SMA Europe Grant/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Muscular Atrophy, Spinal/therapy/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Neuromuscular Junction/metabolism/pathology ; Neuroprotection ; Dependovirus/genetics ; Genetic Therapy/methods ; }, abstract = {The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.}, } @article {pmid39728018, year = {2024}, author = {Jeyarajan, S and Ranjith, S and Veerapandian, R and Natarajaseenivasan, K and Chidambaram, P and Kumarasamy, A}, title = {Antibiofilm Activity of Epinecidin-1 and Its Variants Against Drug-Resistant Candida krusei and Candida tropicalis Isolates from Vaginal Candidiasis Patients.}, journal = {Infectious disease reports}, volume = {16}, number = {6}, pages = {1214-1229}, pmid = {39728018}, issn = {2036-7430}, support = {BT/PR2071/BBE/117/241/2016//Department of Biotechnology, India/ ; 311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education (TANSCHE)/ ; ICMR-NET- 61754/2010//Indian Council of Medical Research/ ; }, abstract = {Background/Objective: Indwelling intrauterine contraceptive devices (IUDs) have surfaces that facilitate the attachment of Candida spp., creating a suitable environment for biofilm formation. Due to this, vulvovaginal candidiasis (VVC) is frequently linked to IUD usage, necessitating the prompt removal of these devices for effective treatment. In this study, we evaluated the susceptibility of antimicrobial peptides in vitro against biofilm forming, Amphotericin B (MIC50 > 2 mg L[-1]) resistant Candida krusei and Candida tropicalis isolated from IUD users who had signs of vaginal candidiasis (hemorrhage, pelvic pain, inflammation, itching, and vaginal discharge). Three antimicrobial peptides, namely, epinecidin-1 (epi-1) and its two variants, namely, variant-1 (Var-1) and variant-2 (Var-2), which were reported to have enhanced antibacterial activity were tested against IUD isolates (C. krusei and C. tropicalis) with pathogenic form of Candida albicans as control. Variants of epi-1, namely, Var-1 and Var-2 were created by substituting lysine in the place of histidine and alanine. Methods: The antimicrobial activity was measured using the microbroth dilution method to determine the minimum inhibitory concentration (MIC) of peptides against C. albicans, C. krusei and C. tropicalis. The MIC of each peptide was used for biofilm assay by Crystal violet staining, Scanning Electron Microscopy, and Reactive Oxygen Species (ROS) assay. To find the possible mechanism of anti-biofilm activity by the peptides, their ability to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2 were determined through PatchDock. Results: The MIC values of peptides: epi-1, var-1 and var-2 against C. albicans are 128 μg mL[-1], 64 μg mL[-1] and 32 μg mL[-1], C. tropicalis are 256 μg mL[-1], 64 μg mL[-1,] and 32 μg mL[-1] and C. krusei are 128 µg mL[-1], 128 µg mL[-1] and 64 µg mL[-1], respectively. Both the variants outperformed epi-1. Specifically for tested Candida spp., var-1 showed two- to four-fold enhancements and var-2 showed two- to eight-fold enhancements compared to epi-1. Electron microscopy confirmed that the mechanism of action involves pore formation thus inducing reactive oxygen species in Candida spp. cell membrane. Computational analysis showed that the peptides have a high tendency to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2, thereby preventing biofilm formation. Conclusions: The in vitro evidence supports the potential use of epi-1 and its variants to be used as an anti-biofilm agent to coat IUDs in the future for therapeutic purposes.}, } @article {pmid39735276, year = {2024}, author = {Moyana, TN}, title = {Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.}, journal = {World journal of gastroenterology}, volume = {30}, number = {48}, pages = {5198-5204}, pmid = {39735276}, issn = {2219-2840}, mesh = {Humans ; *Small Cell Lung Carcinoma/therapy/secondary/pathology/diagnostic imaging ; *Stomach Neoplasms/pathology/therapy/diagnostic imaging ; *Lung Neoplasms/secondary/therapy/pathology/diagnostic imaging ; Prognosis ; Biomarkers, Tumor/analysis/metabolism ; Positron Emission Tomography Computed Tomography/methods ; Immune Checkpoint Inhibitors/therapeutic use ; Immunohistochemistry ; }, abstract = {Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.}, } @article {pmid39736981, year = {2024}, author = {Zhang, Y and Li, N and Ge, Z and Li, F}, title = {Blood component therapy for dry eye disease: a systematic review and network meta-analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1500160}, pmid = {39736981}, issn = {2296-858X}, abstract = {OBJECTIVE: Blood component therapy has shown promising potential as an emerging treatment for dry eye disease; however, it remains unclear which specific blood component is the most effective. This study aims to compare the efficacy of different blood components in the treatment of dry eye disease through a network meta-analysis, with the goal of providing the latest and most reliable evidence for clinical practice.

METHODS: We conducted a systematic search of the PubMed, Web of Science, Cochrane, Embase, and Scopus databases, with the search concluding on June 1, 2024. Two independent researchers performed literature screening, data extraction, and quality assessment.

RESULTS: A total of 16 randomized controlled trials (RCTs) involving 898 patients with dry eye disease were included. Six different blood components were utilized in treating dry eye disease, with platelet-rich plasma (PRP) being the most widely used. The results of the network meta-analysis indicated that platelet-rich plasma eye drops (PRPD) significantly outperformed artificial tears (AT) in improving the corneal fluorescein staining score (CFSS), while autologous serum (ALS) and umbilical cord serum (UCS) also demonstrated significantly better effects than AT in enhancing tear break-up time (TBUT). Additionally, ALS, PRP injection (PRPI), and PRPD showed significantly superior outcomes compared to AT in improving the ocular surface disease index (OSDI). However, no statistically significant differences were found among the various treatment modalities regarding their effects on Schirmer's I value, CFSS, TBUT, and OSDI. SUCRA analysis predicted that UCS was the most effective in improving Schirmer's I value and TBUT, while PRP excelled in enhancing CFSS and OSDI. Limitations such as publication bias and issues related to randomization, allocation concealment, and blinding may affect the reliability of the current findings.

CONCLUSION: Blood component therapy can significantly improve the pathological damage and ocular surface health in patients with dry eye disease. For those with aqueous-deficient dry eye, UCS may represent the optimal treatment option. In contrast, for patients with more severe corneal epithelial damage, PRP may offer a more effective therapeutic approach.

https://www.crd.york.ac.uk/PROSPERO/, CRD42024534091.}, } @article {pmid39743032, year = {2025}, author = {Li, Y and Zhang, W and Zhang, Q and Li, Y and Xin, C and Tu, R and Yan, H}, title = {Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110283}, doi = {10.1016/j.abb.2024.110283}, pmid = {39743032}, issn = {1096-0384}, mesh = {Humans ; *Mitophagy/drug effects ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; Antioxidants/therapeutic use/pharmacology ; Mitochondria/metabolism/pathology ; }, abstract = {Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.}, } @article {pmid39743546, year = {2025}, author = {Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {86-102}, pmid = {39743546}, issn = {1759-4766}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; }, abstract = {The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.}, } @article {pmid39744204, year = {2024}, author = {Morales-Galicia, AE and Ramírez-Mejía, MM and Ponciano-Rodriguez, G and Méndez-Sánchez, N}, title = {Revolutionizing the understanding of liver disease: Metabolism, function and future.}, journal = {World journal of hepatology}, volume = {16}, number = {12}, pages = {1365-1370}, pmid = {39744204}, issn = {1948-5182}, abstract = {The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.}, } @article {pmid39753665, year = {2025}, author = {Quintanilla, CA and Fitzgerald, Z and Kashow, O and Radojicic, MS and Ulupinar, E and Bitlis, D and Genc, B and Andjus, P and van Drongelen, W and Ozdinler, PH}, title = {High-density multielectrode arrays bring cellular resolution to neuronal activity and network analyses of corticospinal motor neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {732}, pmid = {39753665}, issn = {2045-2322}, support = {778405 "AUTOIGG"//EU H2020 MSCA RISE/ ; R01 AG061708/AG/NIA NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund of the Republic of Serbia/ ; R01AG061708-03/NH/NIH HHS/United States ; 5T32NS041234-18/NH/NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; Mice ; *Microelectrodes ; Motor Cortex/physiology ; Pyramidal Tracts/physiology ; Nerve Net/physiology ; Mice, Transgenic ; }, abstract = {Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.}, } @article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.

RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.

CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, } @article {pmid39756374, year = {2025}, author = {Loap, P and Loap, P and Kirova, Y}, title = {Initial Characterization and Outcome Assessment of Anal Lymphomas in a Large-Size Contemporary Cohort: A Population-Based SEER Database Study (2000-2022).}, journal = {Acta haematologica}, volume = {148}, number = {6}, pages = {610-617}, doi = {10.1159/000541595}, pmid = {39756374}, issn = {1421-9662}, mesh = {Humans ; Male ; Female ; SEER Program ; Middle Aged ; *Anus Neoplasms/therapy/epidemiology/mortality/diagnosis ; Aged ; Retrospective Studies ; Adult ; Aged, 80 and over ; *Lymphoma/therapy/epidemiology/mortality/diagnosis ; Young Adult ; Survival Rate ; United States/epidemiology ; }, abstract = {INTRODUCTION: Anal lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aimed to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.

METHODS: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL cases were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.

RESULTS: The majority of AL cases were diffuse large B-cell lymphoma (70.9%). Other notable subtypes included anaplastic T-cell lymphoma, marginal zone lymphoma, B-cell non-Hodgkin lymphoma, Burkitt lymphoma/leukemia (each accounting for 6.3%), followed by follicular lymphoma and mantle-cell lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0%, respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.

CONCLUSION: This research corresponds to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.}, } @article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, } @article {pmid39762986, year = {2025}, author = {Berlowitz, DJ and Rowe, D and Howard, ME and Piper, A and Graco, M and Braat, S and Singh, B and Souza, TV and Lannin, N and McLean, A and Sawyer, A and Carey, KA and Ahamed, Y and , }, title = {Polysomnographic titration of non-invasive ventilation in motor neurone disease (3TLA): study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {26}, number = {1}, pages = {10}, pmid = {39762986}, issn = {1745-6215}, mesh = {Humans ; *Noninvasive Ventilation/methods/adverse effects/instrumentation ; *Motor Neuron Disease/therapy/physiopathology ; *Polysomnography ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; Australia ; Multicenter Studies as Topic ; Time Factors ; Sleep ; Respiratory Insufficiency/therapy/physiopathology ; Quality of Life ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) uses positive pressure to assist people with respiratory muscle weakness or severe respiratory compromise to breathe. Most people use this treatment during sleep when breathing is most susceptible to instability. The benefits of using NIV in motor neurone disease (MND) are well-established. However, uptake and usage are low (~ 19%) and there is no consensus on how to best implement NIV in MND in Australia. Consequently, clinical practice models are highly variable. Our team has recently provided evidence that specific and individualised NIV titration using a sleep study (polysomnography; PSG) leads to better outcomes in people with MND. However, for this clinical practice model to result in sustained benefits, evidence of effectiveness across multiple sites, as well as culture and practice change, must occur.

METHODS: A two-arm, assessor-blinded, individual participant randomised controlled trial in MND care centres across Australia will be undertaken. Two-hundred and forty-four participants will be randomised (1:1) to either the intervention group (PSG-assisted commencement of NIV settings; PSG) or a control group (sham PSG). Participants will be asked to use their NIV device for 7 weeks and will then return for follow-up assessments. Respiratory, sleep and patient-reported outcome measures will be collected at baseline and follow-up. The primary aim is to determine if the proportion of participants using NIV for > 4 h/day during the intervention period is higher in the PSG than the control group. A process evaluation, health economic evaluation and 12-month cohort follow-up will be undertaken and reported separately.

DISCUSSION: The results of this trial will demonstrate the effects of PSG-assisted titration of NIV on usage of NIV in people with MND. We hypothesise that the PSG intervention will improve synchrony between the user and the machine, which will lead to greater NIV usage compared to the control group.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.}, } @article {pmid39764140, year = {2024}, author = {Akif, A and My Nguyen, TT and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764140}, issn = {2693-5015}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50[th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, } @article {pmid39766450, year = {2024}, author = {Donaghy, R and Pioro, EP}, title = {Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766450}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.}, } @article {pmid39768371, year = {2024}, author = {Orlova, A and Malygin, Y and Gofman, A and Sotulenko, S and Gandalian, V and Kartashov, I and Brylev, L and Bolevich, S and Nikolic Turnic, T and Jakovljevic, V}, title = {Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768371}, issn = {2075-1729}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients.

METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus.

RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation.

CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.}, } @article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Animals ; Humans ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Calmodulin/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Parkinson Disease/metabolism/pathology/therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; RNA-Binding Protein FUS/metabolism/genetics ; tau Proteins/metabolism ; Transglutaminases/metabolism ; Huntingtin Protein ; Superoxide Dismutase-1 ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, } @article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, } @article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, } @article {pmid39771101, year = {2024}, author = {Chetverikova, D and Bakaeva, M and Starikov, S and Kendjieva, A and Chetverikov, S}, title = {The Influence of Plant Growth-Stimulating Bacteria on the Glutathione-S-Transferase Activity and the Toxic Effect of the Herbicide Metsulfuron-Methyl in Wheat and Canola Plants.}, journal = {Toxics}, volume = {12}, number = {12}, pages = {}, pmid = {39771101}, issn = {2305-6304}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {The ability of some rhizosphere bacteria to mitigate herbicidal stress in cultivated plants may be useful in agriculture and bioremediation. There is poor understanding of how bacteria directly or through herbicide degradation affect the biochemical processes in plants exposed to sulfonylurea herbicides. In this study, treatment with a combination of herbicide metsulfuron-methyl (MSM) and bacteria (Pseudomonas protegens DA1.2 or P. chlororaphis 4CH) of wheat (Triticum aestivum L.) and canola (Brassica napus L.) plants was carried out. Activity of glutathione-S-transferase (GST), an important enzyme for the herbicide detoxification, and acetolactate synthase (ALS), a target for MSM in plants, was measured by spectrophotometric assays. MSM residues were analyzed using the HPLC-MS. Then, 24 h after bacterial treatment, GST activity increased by 75-91% in wheat and by 38-94% in canola. On the 30th day, a decrease in MSM in the soil associated with bacterial treatment was 54.6-79.7%. An increase in GST activity and acceleration of MSM degradation were accompanied by a decrease in inhibition of the ALS enzyme in plants, which indicated a mitigation of the toxic effect. The results obtained are evidence that rhizospheric bacteria can have beneficial effects on plants exposed to MSM due to the combination of abilities to directly affect detoxification enzymes in plants and degrade MSM in the soil.}, } @article {pmid39774976, year = {2025}, author = {Naito, H and Nakamori, M and Toko, M and Hayashi, Y and Tazuma, T and Watanabe, T and Ishihara, K and Tachiyama, K and Yamazaki, Y and Maruyama, H}, title = {A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1120}, pmid = {39774976}, issn = {2045-2322}, support = {23K16642//Japan Society for the Promotion of Science/ ; NA//ALS Foundation, Japan ALS Association/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Arginine/administration & dosage/adverse effects/therapeutic use ; Nutritional Status ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were - 0.37 kg, -1.1 kg/m[2], and - 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.}, } @article {pmid39775908, year = {2025}, author = {de Vries, E and Hagbohm, C and Ouellette, R and Granberg, T}, title = {Clinical 7 Tesla magnetic resonance imaging: Impact and patient value in neurological disorders.}, journal = {Journal of internal medicine}, volume = {297}, number = {3}, pages = {244-261}, pmid = {39775908}, issn = {1365-2796}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Nervous System Diseases/diagnostic imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging ; }, abstract = {Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnostics and treatment monitoring, particularly for diseases of the central nervous system. Although 1.5- and 3 Tesla (T) field strengths remain the clinical standard, the advent of 7 T MRI represents a transformative step forward, offering superior spatial resolution, contrast, and sensitivity for visualizing neuroanatomy, metabolism, and function. Recent innovations, including parallel transmission and deep learning-based reconstruction, have resolved many prior technical challenges of 7 T MRI, enabling its routine clinical use. This review examines the diagnostic impact, patient value, and practical considerations of 7 T MRI, emphasizing its role in facilitating earlier diagnoses and improving care in conditions, such as amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis (MS), dementia, parkinsonism, tumors, and vascular diseases. Based on insights from over 1200 clinical scans with a second-generation 7 T system, the review highlights disease-specific biomarkers such as the motor band sign in ALS and the new diagnostic markers in MS, the central vein sign, and paramagnetic rim lesions. The unparalleled ability of 7 T MRI to study neurological diseases ex vivo at ultra-high resolution is also explored, offering new opportunities to understand pathophysiology and identify novel treatment targets. Additionally, the review provides a clinical perspective on patient handling and safety considerations, addressing challenges and practicalities associated with clinical 7 T MRI. By bridging research and clinical practice, 7 T MRI has the potential to redefine neuroimaging and advance the understanding and management of complex neurological disorders.}, } @article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {91}, number = {5}, pages = {226-237}, pmid = {39778593}, issn = {1439-0221}, support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; }, mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Neurodegenerative Diseases/drug therapy ; *Network Pharmacology/methods ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.}, } @article {pmid39778888, year = {2025}, author = {Etxebeste-Mitxeltorena, M and Flores-Romero, H and Ramos-Inza, S and Masiá, E and Nenchova, M and Montesinos, J and Martinez-Gonzalez, L and Porras, G and Orzáez, M and Vicent, MJ and Gil, C and Area-Gomez, E and Garcia-Saez, AJ and Martinez, A}, title = {Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {2}, pages = {1179-1194}, pmid = {39778888}, issn = {1520-4804}, support = {/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Lipid Metabolism/drug effects ; *Small Molecule Libraries/pharmacology/chemistry ; Cholesterol/metabolism ; HCT116 Cells ; Mitochondria Associated Membranes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.}, } @article {pmid39783194, year = {2025}, author = {Smith, SE and McCoy-Gross, K and Malcolm, A and Oranski, J and Markway, JW and Miller, TM and Bucelli, RC}, title = {Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {2}, pages = {311-319}, pmid = {39783194}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Middle Aged ; Female ; *Superoxide Dismutase-1/genetics ; Aged ; Neurofilament Proteins/blood/cerebrospinal fluid ; Adult ; Disease Progression ; *Outcome Assessment, Health Care ; }, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.

METHODS: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.

RESULTS: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: -57.9%; mean change CSF pNFH: -67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85).

INTERPRETATION: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.}, } @article {pmid39783196, year = {2025}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {3}, pages = {491-498}, pmid = {39783196}, issn = {2328-9503}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Cohort Studies ; *Disease Progression ; *Glycemic Index/physiology ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Riluzole/pharmacology/administration & dosage ; }, abstract = {OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS).

METHODS: Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n = 304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates.

RESULTS: Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [β = -1.9, 95% CI (-4.1, -0.2), p = 0.07], third [β = -3.0, 95% CI (-5.1, -0.8), p < 0.01] and fourth [β = -2.2, 95% CI (-4.3, -0.01), p < 0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI < 47.2) among the RTG. Similarly, GL fourth quartile group (GL > 109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [β = -2.6, 95% CI (-4.7, -0.5), p < 0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups.

INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.}, } @article {pmid39786321, year = {2025}, author = {Kim, K and Kim, S and Katana, M and Terentyev, D and Radwański, PB and Munger, MA}, title = {Riluzole is associated with reduced risk of heart failure.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70033}, pmid = {39786321}, issn = {1468-1331}, support = {R01HL14488/HL/NHLBI NIH HHS/United States ; R01 NS121234/NS/NINDS NIH HHS/United States ; R01 HL142588/HL/NHLBI NIH HHS/United States ; R01 HL166604/HL/NHLBI NIH HHS/United States ; R01 HL155378/HL/NHLBI NIH HHS/United States ; R01HL166604/HL/NHLBI NIH HHS/United States ; R01HL155378/HL/NHLBI NIH HHS/United States ; }, mesh = {*Riluzole/therapeutic use ; Humans ; *Heart Failure/epidemiology/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Amyotrophic Lateral Sclerosis/epidemiology/drug therapy ; Aged, 80 and over ; Cohort Studies ; United States/epidemiology ; }, abstract = {BACKGROUND: Reduction of intracellular Na[+] accumulation through late Na[+] current inhibition has been recognized as a target for cardiac Ca[2+] handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na[+] channel blocker with enhancement of Ca[2+]-activated K[+] channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca[2+] leak and therefore may improve cardiac function.

OBJECTIVES: The study aim was to investigate whether riluzole lowers HF incidence.

METHODS: Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts.

RESULTS: The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p < 0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3 months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99].

CONCLUSIONS: Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.}, } @article {pmid39792201, year = {2025}, author = {Fu, Z and Feng, B and Akogo, HY and Ma, J and Liu, Y and Quan, H and Zhang, X and Hou, Y and Zhang, X and Ma, J and Cui, H}, title = {Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6383-6396}, pmid = {39792201}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Parkinson Disease/genetics/metabolism ; *Brain/metabolism/pathology ; *Gene Expression Profiling/methods ; *Transcriptome/genetics ; Gene Regulatory Networks ; Protein Interaction Maps/genetics ; MicroRNAs/genetics/metabolism ; }, abstract = {This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.}, } @article {pmid39793633, year = {2025}, author = {Baker, RS and Wang, JT and Rouatbi, N and Lu, Y and Al-Adhami, T and Asker, D and Rahman, KM and Al-Chalabi, A and Forbes, B and Bansal, S and Al-Jamal, KT}, title = {Brain distribution study of [[14]C]-Riluzole following intranasal administration in mice.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125195}, doi = {10.1016/j.ijpharm.2025.125195}, pmid = {39793633}, issn = {1873-3476}, mesh = {Animals ; Administration, Intranasal ; *Brain/metabolism ; Male ; Mice ; *Riluzole/administration & dosage/pharmacokinetics ; Tissue Distribution ; Tetrahydroisoquinolines/pharmacology/administration & dosage ; Acridines/pharmacology/administration & dosage ; Carbon Radioisotopes ; Biological Availability ; Blood-Brain Barrier/metabolism ; *Neuroprotective Agents/pharmacokinetics/administration & dosage ; }, abstract = {Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [[14]C]-RLZ was synthesised using an optimised one-pot method. [[14]C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ([1]H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.}, } @article {pmid39795334, year = {2024}, author = {Bhattacharya, S and Sen, MK and Hamouzová, K and Košnarová, P and Bharati, R and Menendez, J and Soukup, J}, title = {Pyroxsulam Resistance in Apera spica-venti: An Emerging Challenge in Crop Protection.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {39795334}, issn = {2223-7747}, support = {QL24010167//National Agency for Agricultural Research (NAZV)/ ; }, abstract = {Apera spica-venti, a prevalent weed in Czech winter wheat fields, has developed resistance to ALS-inhibiting herbicides due to their frequent use. This study reports a biotype of A. spica-venti resistant to pyroxsulam, with cross and multiple resistance to iodosulfuron, propoxycarbazone, pinoxaden, and chlortoluron. Dose-response experiments revealed high resistance of both R1 and R2 biotypes to pyroxsulam, with resistance factors (RF) of 6.69 and 141.65, respectively. Pre-treatment with malathion reduced RF by 2.40× and 1.25× in R1 and R2, indicating the potential involvement of cytochrome P450 (CytP450). NBD-Cl pre-treatment decreased RF only in R2, suggesting possible GST involvement. Gene analysis revealed no mutations (at previously reported sites) or overexpression in the acetolactate synthase (ALS) gene. However, a significant difference in ALS enzyme activity between resistant and susceptible biotypes points to target-site resistance mechanisms. Studies with [14]C-labeled pyroxsulam showed that reduced absorption and translocation were not likely resistance mechanisms. In summary, herbicide resistance in A. spica-venti appears to result from multiple mechanisms. Possible causes include target-site resistance from an unidentified ALS mutation (within coding or regulatory regions). Enhanced herbicide metabolism via CytP450s and GSTs is also a contributing factor. Further experimental validation is needed to confirm these mechanisms and fully understand the resistance. This evolution underscores the adaptive capacity of weed populations under herbicide pressure, emphasizing the need for alternative control strategies.}, } @article {pmid39796536, year = {2024}, author = {Cuffaro, F and Lamminpää, I and Niccolai, E and Amedei, A}, title = {Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796536}, issn = {2072-6643}, support = {PNRR-MAD-2022-12375798//Ministero della Salute/ ; PE0000006//Ministry of University and Research (MUR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/prevention & control/therapy/microbiology/diet therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics ; Dysbiosis ; Prebiotics/administration & dosage ; Fecal Microbiota Transplantation ; Oxidative Stress ; Fatty Acids, Omega-3/administration & dosage ; }, abstract = {Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.}, } @article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Energy Metabolism/physiology ; *Mitochondrial Dynamics/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, } @article {pmid39799324, year = {2025}, author = {Freiha, J and Grand, E and Marshall, B and Arunchalam, R and Pinto, A and Osman, C}, title = {Amyotrophic lateral sclerosis in a patient with chronic lymphocytic leukaemia and drug related sarcoid-like reaction.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {16}, pmid = {39799324}, issn = {1471-2377}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/chemically induced ; Middle Aged ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/complications ; *Sarcoidosis/chemically induced/diagnosis/complications ; Rituximab/adverse effects ; Sulfonamides/adverse effects ; }, abstract = {Sarcoid-like reaction is an immunological reaction that can affect lymph nodes and organs but does not meet the diagnostic criteria for systemic sarcoidosis. Anti-CD20 auto-antibodies have been reported to be responsible for such reactions. There are several reported associations between Chronic lymphocytic leukaemia (CLL), Amyotrophic lateral sclerosis (ALS) and Sarcoid-like reactions (SLR). We report a case of ALS developing in a patient with treated CLL and drug related SLR one day after exposure to Venetoclax and Rituximab. A 60-year-old male presented with lower limb rash, left leg weakness followed by bulbar symptoms which progressed over 12-months. Workup demonstrated a Cerebrospinal fluid (CSF) pleocytosis and inguinal lymphadenopathy. Skin and inguinal lymph node biopsies showed non-necrotising granulomata. Electromyography met diagnostic criteria for ALS. He was treated for presumed neurosarcoidosis mimicking ALS. Despite prednisolone and infliximab treatment, the motor symptoms rapidly progressed; Hence, we made a clinical diagnosis of ALS. We discuss the diagnostic and treatment challenges of this case.}, } @article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Apoptosis ; *Oxidative Stress ; *Neurodegenerative Diseases/metabolism/pathology ; *Nitrosative Stress ; Animals ; *Signal Transduction ; Oxidation-Reduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, } @article {pmid39801873, year = {2025}, author = {Kumar, AJ and Sathiyaseelan, N and Vinodh, JB and Vignesh, A and Rathi, NK}, title = {Recent Advances in Managing Ankylosing Spondylitis with Andersson Lesion: A Clinical Overview and Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {15}, number = {1}, pages = {21-25}, pmid = {39801873}, issn = {2250-0685}, abstract = {INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disorder that primarily affects the spine and sacroiliac joints, leading to pain, stiffness, and progressive thoracolumbar kyphotic deformity. A key complication in advanced AS is the development of Andersson lesions (AL), degenerative vertebral lesions resulting from the disease's progression. These lesions can cause significant mechanical pain, often mistaken for the chronic discomfort associated with AS. The exact cause of AL remains unclear, with hypotheses ranging from spinal stress fractures to delays in the ankylosing process. Understanding AL's pathophysiology is essential for timely diagnosis and effective management.

CASE REPORT: A 52-year-old male presented with a 20-year history of diffuse abdominal pain, later developing insidious lower back pain over the past 2 months. The pain was aggravated by walking and prolonged standing. Physical examination revealed tenderness in the D11 region of the spine, with limited chest expansion and positive findings on the modified Schober's test. Radiographic studies showed irregularities and erosions at the D11-D12 vertebral levels, and magnetic resonance imaging confirmed the presence of an AL associated with asymmetrical bilateral sacroiliitis. The patient tested positive for human leukocyte antigen-B27, supporting a diagnosis of AS with an AL. Medical management, including methotrexate, sulfasalazine, non-steroidal anti-inflammatory drugs, and corticosteroids, led to significant pain reduction and improved mobility. The patient's condition remained stable with continued treatment over a 2-year follow-up period.

CONCLUSION: AL s are chronic, often overlooked complications of AS that can lead to spinal instability and neurological deficits if untreated. Early recognition and management are critical to preventing progressive kyphotic deformities and associated complications. While conservative treatment remains the cornerstone for managing AL, surgical intervention may be required in cases of severe pain, deformity, or neurological involvement. Understanding AL's presentation and treatment options is vital for improving patient outcomes in AS.}, } @article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/diagnostic imaging ; *Riluzole/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Mice, Transgenic ; *Brain/drug effects/metabolism/diagnostic imaging ; Proton Magnetic Resonance Spectroscopy ; Disease Models, Animal ; Magnetic Resonance Imaging/methods ; Male ; *Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.

METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.

RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.

CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, } @article {pmid39811452, year = {2024}, author = {Li, R and Bao, T and Li, B and Xia, P and Zhang, T and Zhang, H and Huang, F}, title = {Effectiveness and safety of traditional Chinese therapies intreating patients with amyotrophic lateral sclerosis: a protocol for systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1519513}, pmid = {39811452}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic, progressive disease that affects both upper and lower motor neurons. Some physicians have used traditional Chinese therapies (TCT) to treat ALS. However, there has been no systematic review or meta-analysis to evaluate the effectiveness and safety of TCT interventions. This review aims to analyze the effects of TCT interventions for patients with amyotrophic lateral sclerosis.

METHODS AND ANALYSIS: This study will include randomized, non-randomized, and quasi-experimental clinical trials, with participants being any age Amyotrophic Lateral Sclerosis (ALS) patients who have undergone TCT treatment. Two researchers will independently search databases including CENTRAL, PubMed, PEDro, EMBASE, CNKI, CBM, and SPORTDiscus, without restrictions on language or publication date. These researchers will independently screen titles and abstracts and extract data from the included studies. If deemed suitable for meta-analysis, data synthesis will be conducted using Review Manager V.5.3 software; any discrepancies will be resolved by a third researcher. The meta-analysis will compare the effects of TCT with placebo or other interventions. The main endpoint evaluated was the decrease in the overall score of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; scoring from 0 to 48, where higher scores denote greater functionality) over a period of 24 weeks. Additional endpoints included the reduction rates in isometric muscle power, levels of phosphorylated axonal neurofilament H subunits in plasma, and slow vital capacity measurements. Furthermore, the study monitored the duration until occurrence of death, tracheostomy, or the need for long-term ventilation, as well as the time until death, tracheostomy, long-term ventilation, or hospital admission.

ETHICS AND DISSEMINATION: Throughout the entire process of this systematic review, no personal information was used, hence ethical review is not required. The results of this meta-analysis will be disseminated through publication in peer-reviewed journals and/or conference presentations.}, } @article {pmid39817131, year = {2025}, author = {Lampridis, S}, title = {Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {101477}, pmid = {39817131}, issn = {1948-5204}, abstract = {Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.}, } @article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, } @article {pmid39820267, year = {2025}, author = {Martinez-Thompson, JM and Mazurek, KA and Parra-Cantu, C and Naddaf, E and Gogineni, V and Botha, H and Jones, DT and Laughlin, RS and Barnard, L and Staff, NP}, title = {Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {7}, pages = {2320-2330}, pmid = {39820267}, issn = {1460-2156}, support = {UL1 TR002377/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Artificial Intelligence ; Retrospective Studies ; *Neural Conduction/physiology ; Adult ; }, abstract = {Nerve conduction F-wave studies contain crucial information about subclinical motor dysfunction that can be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46 802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular and tibial nerves. Wavelet coefficient statistics, onset age, sex and body mass index were features for training a Gradient Boosting Machine model on 40 095 patients (5329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis, cervical radiculopathy, lumbar radiculopathy or peripheral neuropathy, which can mimic ALS symptoms. Factors affecting survival were estimated through Cox proportional hazards regression. The model trained using wavelet features on the full waveform had 90% recall, 87% precision and 88% accuracy. Similar model performance was measured using features from only the M-wave or F-wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (P < 0.001, ANOVA, Tukey's post hoc test). Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at a specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS in comparison to other mimicking diagnoses, such as inclusion body myositis, cervical or lumbar radiculopathy or peripheral neuropathy. These probabilities provide clinicians with additional information that they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians to diagnose ALS sooner and manage treatment based on estimated survival, which might improve outcomes and the quality of life of patients.}, } @article {pmid39821843, year = {2025}, author = {Zhang, J and Guo, R and Zhou, Z and Fu, Z and Akogo, HY and Li, Y and Zhang, X and Wang, N and Liu, Y and Li, H and Feng, B and Cui, H and Ma, J}, title = {Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6521-6536}, pmid = {39821843}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Animals ; Humans ; *Neural Stem Cells/transplantation/cytology ; *Stem Cell Transplantation/methods ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.}, } @article {pmid39824655, year = {2025}, author = {Jia, M and Li, P and Yan, Y and Liu, X and Gao, L and Zhu, G and Chen, Z}, title = {Antimicrobial susceptibility and genomic characterization of Vibrio cholerae non-O1/non-O139 isolated from clinical and environmental samples in Jiaxing City, China.}, journal = {FEMS microbiology letters}, volume = {372}, number = {}, pages = {}, doi = {10.1093/femsle/fnaf009}, pmid = {39824655}, issn = {1574-6968}, support = {2024KY1697//Medical Science and Technology Project of Zhejiang Province/ ; 2023AY31028//Science and Technology Bureau of Jiaxing City/ ; }, mesh = {China ; Humans ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Multilocus Sequence Typing ; *Vibrio cholerae non-O1/genetics/drug effects/isolation & purification/pathogenicity/classification ; Drug Resistance, Bacterial/genetics ; Virulence/genetics ; Environmental Microbiology ; Virulence Factors/genetics ; Genome, Bacterial ; Genetic Variation ; }, abstract = {Non-O1/non-O139 (NOVC) strains inhabit aquatic environments and sporadically induce human illnesses. This study involved the virulence and antimicrobial genetic characterization of 176 NOVC strains, comprising 25 from clinical samples and 151 from environmental sources, collected between 2021 and 2023. The antimicrobial susceptibility of the examined NOVC population was predominantly high, exhibiting only poor susceptibility to colistin, with 89.2% resistance. The examination of virulence genes revealed that the majority of strains were positive for glucose metabolism (als gene) (169/176, 96.0%). Through multilocus sequence typing, the 176 NOVC strains were categorised into 121 sequence types, 79 of which were novel. NOVC strains demonstrate significant genetic variability and frequently engage in recombination. This work offers genetic characterization of the pathogenicity and antimicrobial resistance of a NOVC community. Our findings offer insights that may aid in the development of preventative and treatment methods for this pathogen.}, } @article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, mesh = {*Genistein/therapeutic use/pharmacology ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, } @article {pmid39831022, year = {2025}, author = {Okpete, UE and Byeon, H}, title = {Brain-derived neurotrophic factor alterations and cognitive decline in schizophrenia: Implications for early intervention.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {102131}, pmid = {39831022}, issn = {2220-3206}, abstract = {This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in first-episode schizophrenia patients. The study revealed that higher levels of interleukin-6 and tumor necrosis factor-α correlated with reduced BDNF levels and poorer cognitive performance. Schizophrenia is a severe psychiatric disorder impacting approximately 1% of the global population, characterized by positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation and cognitive impairments) and disorganized thoughts and behaviors. Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting. The findings from Cui et al's study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes. Effective treatment approaches involve a combination of pharmacological and non-pharmacological interventions tailored to individual patient needs. Hence, monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life. Consequently, this manuscript highlights the need for an integrated approach to schizophrenia management, considering both clinical symptoms and underlying neurobiological changes.}, } @article {pmid39835009, year = {2024}, author = {Frolov, A and D'sa, E and Henderson, C and Guzman, MA and Hayat, G and Martin, JR}, title = {Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e76027}, pmid = {39835009}, issn = {2168-8184}, abstract = {A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the C9ORF72 gene. C9ORF72 mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic AHNAK2, GLI3, PTIRM1, and ZNF254 variants, warranting a closer look at their potentially important role in fALS as C9ORF72 genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.}, } @article {pmid39835561, year = {2025}, author = {Rai, A and Shukla, S and Gupta, RK and Mishra, A}, title = {ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy.}, journal = {Current pharmaceutical design}, volume = {31}, number = {17}, pages = {1328-1346}, pmid = {39835561}, issn = {1873-4286}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Motor Neurons/drug effects/pathology ; *Medicine, Chinese Traditional ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.}, } @article {pmid39836043, year = {2025}, author = {Berry, JD and Hagan, M and Zhang, J and Liu, Y and Ciepielewska, M}, title = {Longer disease progression milestone-free time in people with amyotrophic lateral sclerosis treated versus not treated with intravenous edaravone: results from an administrative claims analysis.}, journal = {Journal of comparative effectiveness research}, volume = {14}, number = {2}, pages = {e240007}, pmid = {39836043}, issn = {2042-6313}, mesh = {Humans ; *Edaravone/administration & dosage/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Retrospective Studies ; Middle Aged ; Disease Progression ; Aged ; Administration, Intravenous ; *Free Radical Scavengers/therapeutic use/administration & dosage ; }, abstract = {Aim: To estimate time-to-progression milestones in people with amyotrophic lateral sclerosis (PALS) treated versus not treated with intravenous (IV) edaravone (Radicava[®] IV, Mitsubishi Tanabe Pharma America [MTPA], hereafter "IV edaravone") in a real-world setting. Background: IV edaravone is US FDA approved for the treatment of ALS and was shown in clinical trials to slow the rate of physical functional decline. Patients & methods: This retrospective observational analysis included PALS continuously enrolled in Optum's Clinformatics[®] Data Mart between 8 August 2017 and 31 December 2021. Cases treated with IV edaravone and controls not treated with IV edaravone were propensity score matched for: age, sex, race, US region of residence, pre-index disease duration, insurance, riluzole prescription; and pre-index claims for cardiovascular disease, artificial nutrition/gastrostomy tube, noninvasive ventilation and all-cause hospitalization. The index date was the first IV edaravone claim for cases; for controls, the index date was randomly assigned after IV edaravone market availability. Restricted mean time lost was calculated for the following disease progression milestones: new use of canes/walkers/wheelchairs, artificial nutrition, noninvasive ventilation, invasive ventilation, speech-generating devices and hospice. Results: Cases (n = 395) were matched to controls (n = 395). Cases had less restricted mean time lost, indicating longer disease progression milestone-free time, for all disease progression milestones. From 0 to 24 months post index, more cases (n = 129) than controls (n = 103) reported no milestones and more controls (n = 232) than cases (n = 131) reported deaths. Conclusion: In a US-based real-world setting, IV edaravone-treated PALS had a longer time to disease progression milestone events and fewer deaths in 2 years compared with PALS not treated with IV edaravone.}, } @article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {40}, number = {4}, pages = {693-703}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; *Mitochondria/genetics/metabolism ; *Genetic Predisposition to Disease/genetics ; Quantitative Trait Loci/genetics ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.}, } @article {pmid39839897, year = {2025}, author = {Jiang, QR and Zeng, DW}, title = {Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt: Mechanistic and clinical implications.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {100752}, pmid = {39839897}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Hypertension, Portal/microbiology/surgery/virology/etiology ; *Portasystemic Shunt, Transjugular Intrahepatic/adverse effects ; *Hepatic Encephalopathy/microbiology/etiology/diagnosis ; *Liver Cirrhosis/virology/microbiology/surgery ; Hepatitis B virus/pathogenicity ; *Hepatitis B/complications ; Dysbiosis ; }, abstract = {In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.}, } @article {pmid39845577, year = {2025}, author = {Ludolph, A and Wiesenfarth, M}, title = {Tofersen and other antisense oligonucleotides in ALS.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251313915}, pmid = {39845577}, issn = {1756-2856}, abstract = {The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?}, } @article {pmid39854930, year = {2025}, author = {Drouet, C and Priou, P and Gagnadoux, F and Trzepizur, W}, title = {Constraints to the initiation of home non-invasive ventilation and short-term efficacy in different diagnostic groups (as a prelude to an ambulatory shift).}, journal = {Respiratory medicine and research}, volume = {87}, number = {}, pages = {101154}, doi = {10.1016/j.resmer.2025.101154}, pmid = {39854930}, issn = {2590-0412}, mesh = {Humans ; *Noninvasive Ventilation/methods/statistics & numerical data ; Retrospective Studies ; Male ; Female ; Aged ; Middle Aged ; Cross-Sectional Studies ; *Respiratory Insufficiency/therapy/etiology ; Longitudinal Studies ; Pulmonary Disease, Chronic Obstructive/complications/therapy ; Treatment Outcome ; *Home Care Services ; Obesity Hypoventilation Syndrome/complications ; Amyotrophic Lateral Sclerosis/complications ; *Ambulatory Care ; }, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF.

METHODS: This retrospective study with cross-sectional and longitudinal analysis included patients initiated with NIV at Angers University Hospital. Patients were separated according to the following aetiologies: obesity hypoventilation syndrome (OHS), chronic obstruction pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), myopathy and chest wall disease. Implementation constraints were assessed by analysing the variability of NIV settings, the number of masks tried and the duration of hospitalisation. NIV effectiveness was assessed by measuring residual PaCO2 (arterial pressure in CO2), apnoea hypopnea index (AHIflow) and tidal volume (VT) (as displayed by the NIV software).

RESULTS: Between October 2020 and May 2022, 102 patients were started with NIV, including a majority of ALS patients. We found a moderate variability in NIV settings (pressure, slope, triggers, etc.) within the different etiological groups, particularly in ALS. On the other hand, ALS patients required more interface trials than other groups and often had unmet efficacy criteria at hospital discharge. Interestingly, longitudinal follow-up showed a progressive improvement in efficacy criteria, particularly in patients who were initially inadequately ventilated.

CONCLUSION: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting.}, } @article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, mesh = {Humans ; *Inflammasomes/metabolism/immunology ; Animals ; *Calcium-Binding Proteins/metabolism ; *Nervous System Diseases/drug therapy/immunology/metabolism ; *CARD Signaling Adaptor Proteins/metabolism ; *Apoptosis Regulatory Proteins/metabolism ; Neurodegenerative Diseases/drug therapy/immunology ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, } @article {pmid39857620, year = {2024}, author = {Frawley, L and Taylor, NT and Sivills, O and McPhillamy, E and To, TD and Wu, Y and Chin, BY and Wong, CY}, title = {Stem Cell Therapy for the Treatment of Amyotrophic Lateral Sclerosis: Comparison of the Efficacy of Mesenchymal Stem Cells, Neural Stem Cells, and Induced Pluripotent Stem Cells.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857620}, issn = {2227-9059}, support = {Australian Government New Colombo Plan (NCP) scheme//Australian Government New Colombo Plan (NCP) scheme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.

METHODS: This review evaluates the efficacy of three stem cell types in ALS treatment: mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs).

RESULTS: MSCs, derived from various tissues, show neuroprotective and regenerative qualities, with clinical trials suggesting potential benefits but limited by small sample sizes and non-randomised designs. NSCs, isolated from the fetal spinal cord or brain, demonstrate promise in animal models but face functional integration and ethical challenges. iPSCs, created by reprogramming patient-specific somatic cells, offer a novel approach by potentially replacing or supporting neurons. iPSC therapy addresses ethical issues related to embryonic stem cells but encounters challenges regarding genotoxicity and epigenetic irregularities, somatic cell sources, privacy concerns, the need for extensive clinical trials, and high reprogramming costs.

CONCLUSIONS: This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.}, } @article {pmid39857761, year = {2025}, author = {Sun, C and Chen, Y and Xu, L and Wang, W and Zhang, N and Fournier, CN and Li, N and Fan, D}, title = {Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857761}, issn = {2227-9059}, support = {82001347//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; 81701067//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.}, } @article {pmid39863029, year = {2025}, author = {Liu, X and Li, T and Tu, X and Xu, M and Wang, J}, title = {Mitochondrial fission and fusion in neurodegenerative diseases:Ca[2+] signalling.}, journal = {Molecular and cellular neurosciences}, volume = {132}, number = {}, pages = {103992}, doi = {10.1016/j.mcn.2025.103992}, pmid = {39863029}, issn = {1095-9327}, mesh = {Humans ; *Mitochondrial Dynamics/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Calcium Signaling ; Animals ; *Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca[2+] signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca[2+] signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca[2+] signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca[2+] signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.}, } @article {pmid39863163, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Gutierrez, D and Lo Sicco, KI}, title = {Response to Sood et al's "Systemic Janus kinase inhibitor treatment for vitiligo: An evidence-based review".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {e155-e156}, doi = {10.1016/j.jaad.2025.01.059}, pmid = {39863163}, issn = {1097-6787}, } @article {pmid39865792, year = {2025}, author = {Murakami, E and Shibata, T and Tomemori, M and Kawai, G and Nakatani, K}, title = {The role of spatial arrangement of aromatic rings on the binding of N,N'-diheteroaryl guanidine ligands to the G2C4/G2C4 motif DNA.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {6}, pages = {3341-3350}, doi = {10.1039/d4cp03213f}, pmid = {39865792}, issn = {1463-9084}, mesh = {*DNA/chemistry/metabolism ; Ligands ; Surface Plasmon Resonance ; *Guanidine/chemistry/analogs & derivatives ; Circular Dichroism ; Hydrogen Bonding ; Humans ; }, abstract = {Non-canonical DNA structures formed by aberrantly expanded repeat DNA are implicated in promoting repeat instability and the onset of repeat expansion diseases. Small molecules that target these disease-causing repeat DNAs hold promise as therapeutic agents for such diseases. Specifically, 1,3-di(quinolin-2-yl)guanidine (DQG) has been identified to bind to the disease-causing GGCCCC (G2C4) repeat DNA associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we investigate the structure-binding relationships between DQG analogs and double-stranded DNA (dsDNA) containing a G2C4/G2C4 unit. Our findings, derived from UV melting temperature, circular dichroism spectra, and surface plasmon resonance (SPR) analyses of DQG analogs, highlight the crucial role of the spatial arrangements of aromatic rings in binding to the G2C4/G2C4 unit. Among the tested DQG analogs, N,N'-di(quinazolin-2-yl)guanidine (DQzG) stands out for its ability to form seven planar conformers. These conformers enable ADD-DAA hydrogen bonding with cytosine and multiple spatial arrangements of aromatic rings, including those resembling DQG. Our binding analyses revealed that DQzG exhibits the highest affinity binding for the G2C4/G2C4 unit. NMR analysis of the DQzG-bound G2C4/G2C4-dsDNA further suggested that DQzG binds to the G2C4/G2C4 unit via hydrogen bonding. Moreover, SPR analysis demonstrated that DQzG binds more strongly to G2C4 repeat DNA compared to DQG. These results position DQzG as a promising lead compound for targeting the G2C4 repeat, offering potential therapeutic avenues for the treatment of ALS/FTD and other repeat expansion diseases.}, } @article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Brain/immunology ; Immunotherapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, } @article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein & peptide science}, volume = {26}, number = {6}, pages = {451-466}, pmid = {39871559}, issn = {1875-5550}, mesh = {Humans ; *Molecular Chaperones/metabolism ; Animals ; Protein Folding/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; Heat-Shock Proteins/metabolism ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Protein Aggregates/drug effects ; Molecular Targeted Therapy ; *Proteostasis Deficiencies/drug therapy/metabolism ; }, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, } @article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {25}, number = {20}, pages = {2440-2452}, pmid = {39871563}, issn = {1873-4294}, support = {82301506//National Natural Science Foundation of China/ ; 220XQD090//Research Foundation of Scientific Research Program of University of South China/ ; 2023JJ40560//Provincial Natural Science Foundation of Hunan/ ; S202410555234, S202410555259, S202410555262//Science and Technology Innovation Project for College Students/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/antagonists & inhibitors/chemistry ; Animals ; Small Molecule Libraries/chemistry/pharmacology ; }, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, } @article {pmid39879320, year = {2025}, author = {Guillot, SJ and Lang, C and Simonot, M and Beckett, D and Lulé, D and Balz, LT and Knehr, A and Stuart-Lopez, G and Vercruysse, P and Dieterlé, S and Weydt, P and Dorst, J and Kandler, K and Kassubek, J and Wassermann, L and Rouaux, C and Arthaud, S and Da Cruz, S and Luppi, PH and Roselli, F and Ludolph, AC and Dupuis, L and Bolborea, M}, title = {Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.}, journal = {Science translational medicine}, volume = {17}, number = {783}, pages = {eadm7580}, doi = {10.1126/scitranslmed.adm7580}, pmid = {39879320}, issn = {1946-6242}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/drug therapy ; Disease Models, Animal ; Humans ; *Orexins/antagonists & inhibitors/metabolism ; Mice ; *Sleep/drug effects ; Male ; *Orexin Receptor Antagonists/therapeutic use/pharmacology ; Female ; Melanins/pharmacology/therapeutic use ; Pituitary Hormones/pharmacology/therapeutic use ; Hypothalamic Hormones/pharmacology/therapeutic use/administration & dosage ; Motor Neurons/pathology/drug effects ; Wakefulness/drug effects ; Mice, Transgenic ; Middle Aged ; *Sleep Wake Disorders/drug therapy/complications/physiopathology ; Polysomnography ; }, abstract = {Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non-rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (Sod1[G86R], Fus[ΔNLS/+], and TDP43[Q331K]). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1[G86R] mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.}, } @article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Pluripotent Stem Cells/transplantation/cytology ; Animals ; *Cell- and Tissue-Based Therapy/methods ; *Stem Cell Transplantation/methods ; Clinical Trials as Topic ; }, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, } @article {pmid39882923, year = {2025}, author = {Koltsova, E and Smotraiev, R and Nehrii, A and Zhekeev, M and Ratnaweera, H}, title = {Mechanisms for removing phosphorus species through sequential coagulation using inorganic coagulants and organic polymers.}, journal = {Water science and technology : a journal of the International Association on Water Pollution Research}, volume = {91}, number = {2}, pages = {202-218}, pmid = {39882923}, issn = {0273-1223}, mesh = {*Phosphorus/chemistry/isolation & purification ; *Polymers/chemistry ; *Water Pollutants, Chemical/chemistry/isolation & purification ; Alum Compounds/chemistry ; *Waste Disposal, Fluid/methods ; *Water Purification/methods ; Flocculation ; Phosphates/chemistry ; }, abstract = {The need for stringent phosphorus removal from domestic wastewater is increasing to mitigate eutrophication, while efficient phosphate reuse is critical due to the global phosphate crisis. Combining aluminum sulfate (ALS) with high molecular weight organic polymers achieved 95-99% removal of particles, turbidity, and phosphates, reducing ALS usage by 40%. We propose mechanisms to explain the enhanced treatment efficiency. Particle and turbidity removal is more influenced by polymer charge density than molecular weight, while orthophosphate (OP) removal is linked to a change in zeta potential from negative to positive, allowing additional OP binding through complex formation with hydrolysis products and polymers. Enhanced phospholipid (PL) removal likely results from adsorption and neutralization of micelle PL charges by intermediate positively charged aluminum hydroxyphosphate ions. Higher PL removal with low ALS doses is attributed to a two-stage dosing process that optimizes coagulant and polymer dosages. The combined removal of OP and PL improves phosphorus bioavailability, increasing the sludge's fertilizer value.}, } @article {pmid39884579, year = {2025}, author = {Liu, WW and Wei, JC}, title = {Response to Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {5}, pages = {e157-e158}, doi = {10.1016/j.jaad.2024.12.044}, pmid = {39884579}, issn = {1097-6787}, } @article {pmid39891383, year = {2025}, author = {Chen, M and Cui, H and Zhang, X and Ma, S and Guo, J and Liu, Z and Gu, D and Fan, Y}, title = {Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline-arginine) by Inducing the Expression of KPNA2/KPNB1.}, journal = {Cell biochemistry and function}, volume = {43}, number = {2}, pages = {e70053}, doi = {10.1002/cbf.70053}, pmid = {39891383}, issn = {1099-0844}, support = {//This work was supported by the National Natural Science Foundation of China (31970616, 82070505) and Jiangsu Provincial Natural Science Foundation (BK20211330)./ ; }, mesh = {Humans ; *alpha Karyopherins/genetics/metabolism ; *C9orf72 Protein/metabolism/genetics ; Cell Nucleus/metabolism ; Triazoles/pharmacology ; Cell Death/drug effects ; Azepines ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.}, } @article {pmid39893487, year = {2025}, author = {Pilotto, F and Smeele, PH and Scheidegger, O and Diab, R and Schobesberger, M and Sierra-Delgado, JA and Saxena, S}, title = {Kaempferol enhances ER-mitochondria coupling and protects motor neurons from mitochondrial dysfunction and ER stress in C9ORF72-ALS.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {21}, pmid = {39893487}, issn = {2051-5960}, support = {725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Animals ; *Endoplasmic Reticulum Stress/drug effects/physiology ; *Kaempferols/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/pathology/genetics/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Humans ; C9orf72 Protein/genetics/metabolism ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Endoplasmic Reticulum/drug effects/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; Rats ; }, abstract = {Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology.}, } @article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology/genetics ; *Homeostasis ; Zinc/metabolism ; Copper/metabolism ; Animals ; Parkinson Disease/metabolism/genetics/drug therapy/pathology ; Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Manganese/metabolism ; Oxidative Stress ; Chelating Agents/therapeutic use ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, } @article {pmid39902643, year = {2025}, author = {Abad-Yang, N and Raguseo, F and Di Michele, L and Patani, R and Di Antonio, M}, title = {The potential of multimolecular G-quadruplex structures for targeted treatment of Amyotrophic Lateral Sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {29}, number = {1-2}, pages = {1-4}, doi = {10.1080/14728222.2025.2463361}, pmid = {39902643}, issn = {1744-7631}, } @article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; *Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; Scoping Reviews as Topic ; *Translational Research, Biomedical ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.

METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.

CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, } @article {pmid39910731, year = {2025}, author = {Singh, S and Khan, S and Khan, S and Ansari, O and Malhotra, N and Shukla, SK and Narang, J}, title = {Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {4}, pages = {563-587}, doi = {10.1021/acschemneuro.4c00664}, pmid = {39910731}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/genetics ; Humans ; *Biosensing Techniques/methods ; Biomarkers ; Electromyography/methods ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients' speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.}, } @article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Biological Products/therapeutic use/administration & dosage ; Nanoparticles/chemistry ; Liposomes ; Anti-Inflammatory Agents ; Biological Availability ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, } @article {pmid39932195, year = {2025}, author = {Ruggieri, V and Scaricamazza, S and Bracaglia, A and D'Ercole, C and Parisi, C and D'Angelo, P and Proietti, D and Cappelletti, C and Macone, A and Lozanoska-Ochser, B and Bouchè, M and Latella, L and Valle, C and Ferri, A and Giordani, L and Madaro, L}, title = {Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115123}, doi = {10.1016/j.celrep.2024.115123}, pmid = {39932195}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Polyamines/metabolism ; *Muscle Fibers, Skeletal/metabolism/pathology ; Mice ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology ; Muscle, Skeletal/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1[G93A] mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1[G93A] mice, opening new perspectives for the treatment of ALS.}, } @article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Animals ; }, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, } @article {pmid39936266, year = {2025}, author = {Denton, TT and Carter, GT and Goddard, M and Weiss, J and Weeks, DL and Weydt, P and Russo, EB and Weiss, MD}, title = {Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.}, journal = {Muscle & nerve}, volume = {72}, number = {1}, pages = {7-14}, doi = {10.1002/mus.28359}, pmid = {39936266}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Animals ; *Cannabinoids/therapeutic use/pharmacology ; *Endocannabinoids/metabolism/therapeutic use ; Mice ; }, abstract = {A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1 [G93A] mouse model of ALS. The use of CEs in SOD1 [G93A] murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.}, } @article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The antioxidant role of aromatic plant extracts in managing neurodegenerative diseases: A comprehensive review.}, journal = {Brain research bulletin}, volume = {222}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/pharmacology/therapeutic use ; *Plant Extracts/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Animals ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, } @article {pmid39940644, year = {2025}, author = {Lee, AJB and Bi, S and Ridgeway, E and Al-Hussaini, I and Deshpande, S and Krueger, A and Khatri, A and Tsui, D and Deng, J and Mitchell, CS}, title = {Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940644}, issn = {1422-0067}, support = {P30 AG066511/AG/NIA NIH HHS/United States ; R35GM152245/NH/NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; R35 GM152245/GM/NIGMS NIH HHS/United States ; T32 EB025816/EB/NIBIB NIH HHS/United States ; U19 AG065169/AG/NIA NIH HHS/United States ; R01 AG070937/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/therapy/genetics/pathology/drug therapy/physiopathology ; Animals ; *Homeostasis ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Progression ; Computer Simulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.}, } @article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; alpha-Synuclein/metabolism ; *Protein Multimerization ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, } @article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/drug therapy ; *Vitamins/therapeutic use/pharmacology ; Animals ; Parkinson Disease/prevention & control ; Dietary Supplements ; Neuroprotective Agents/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, } @article {pmid39946662, year = {2025}, author = {Cordts, I and Fuetterer, C and Wachinger, A and von Heynitz, R and Kessler, T and Freigang, M and Quinten, AL and Bjelica, B and Brakemeier, S and Hobbiebrunken, E and Hagenacker, T and Petri, S and Koch, JC and Hahn, A and Lingor, P and Deschauer, M and Günther, R and Weiler, M and Haller, B and Feneberg, E}, title = {Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen.}, journal = {Neurology}, volume = {104}, number = {5}, pages = {e213371}, pmid = {39946662}, issn = {1526-632X}, mesh = {Humans ; Female ; Male ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Adult ; Retrospective Studies ; *Oligonucleotides/therapeutic use ; Middle Aged ; *Muscular Atrophy, Spinal/drug therapy/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.

METHODS: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.

RESULTS: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (Δ HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; Δ RULM, 0.9 [IQR 0.4-1.3], p < 0.001; Δ ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (Δ HFMSE ≤ 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.

DISCUSSION: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.}, } @article {pmid33961562, year = {2022}, author = {Martins, AS and Gromicho, M and Pinto, S and de Carvalho, M and Madeira, SC}, title = {Learning Prognostic Models Using Disease Progression Patterns: Predicting the Need for Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis.}, journal = {IEEE/ACM transactions on computational biology and bioinformatics}, volume = {19}, number = {5}, pages = {2572-2583}, doi = {10.1109/TCBB.2021.3078362}, pmid = {33961562}, issn = {1557-9964}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Disease Progression ; Humans ; *Neurodegenerative Diseases/complications ; *Noninvasive Ventilation/adverse effects ; Prognosis ; Quality of Life ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {Amyotrophic Lateral Sclerosis is a devastating neurodegenerative disease causing rapid degeneration of motor neurons and usually leading to death by respiratory failure. Since there is no cure, treatment's goal is to improve symptoms and prolong survival. Non-invasive Ventilation (NIV) is an effective treatment, leading to extended life expectancy and improved quality of life. In this scenario, it is paramount to predict its need in order to allow preventive or timely administration. In this work, we propose to use itemset mining together with sequential pattern mining to unravel disease presentation patterns together with disease progression patterns by analysing, respectively, static data collected at diagnosis and longitudinal data from patient follow-up. The goal is to use these static and temporal patterns as features in prognostic models, enabling to take disease progression into account in predictions and promoting model interpretability. As case study, we predict the need for NIV within 90, 180 and 365 days (short, mid and long-term predictions). The learnt prognostic models are promising. Pattern evaluation through growth rate suggests bulbar function and phrenic nerve response amplitude, additionally to respiratory function, are significant features towards determining patient evolution. This confirms clinical knowledge regarding relevant biomarkers of disease progression towards respiratory insufficiency.}, } @article {pmid33964142, year = {2021}, author = {Bosanac, T and Hughes, RO and Engber, T and Devraj, R and Brearley, A and Danker, K and Young, K and Kopatz, J and Hermann, M and Berthemy, A and Boyce, S and Bentley, J and Krauss, R}, title = {Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy.}, journal = {Brain : a journal of neurology}, volume = {144}, number = {10}, pages = {3226-3238}, pmid = {33964142}, issn = {1460-2156}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/toxicity ; Armadillo Domain Proteins/*antagonists & inhibitors/deficiency/genetics ; Axons/*drug effects/metabolism ; Cells, Cultured ; Cytoskeletal Proteins/*antagonists & inhibitors/deficiency/genetics ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Mice ; Mice, Knockout ; Paclitaxel/*toxicity ; Peripheral Nervous System Diseases/*chemically induced/*drug therapy/genetics/metabolism ; Thiazoles/pharmacology/*therapeutic use ; }, abstract = {Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.}, } @article {pmid33968923, year = {2021}, author = {Barbosa, M and Gomes, C and Sequeira, C and Gonçalves-Ribeiro, J and Pina, CC and Carvalho, LA and Moreira, R and Vaz, SH and Vaz, AR and Brites, D}, title = {Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {634355}, pmid = {33968923}, issn = {2296-634X}, abstract = {Reactive astrocytes in Amyotrophic Lateral Sclerosis (ALS) change their molecular expression pattern and release toxic factors that contribute to neurodegeneration and microglial activation. We and others identified a dysregulated inflammatory miRNA profile in ALS patients and in mice models suggesting that they represent potential targets for therapeutic intervention. Such cellular miRNAs are known to be released into the secretome and to be carried by small extracellular vesicles (sEVs), which may be harmful to recipient cells. Thus, ALS astrocyte secretome may disrupt cell homeostasis and impact on ALS pathogenesis. Previously, we identified a specific aberrant signature in the cortical brain of symptomatic SOD1-G93A (mSOD1) mice, as well as in astrocytes isolated from the same region of 7-day-old mSOD1 mice, with upregulated S100B/HMGB1/Cx43/vimentin and downregulated GFAP. The presence of downregulated miR-146a on both cases suggests that it can be a promising target for modulation in ALS. Here, we upregulated miR-146a with pre-miR-146a, and tested glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS) for their immunoregulatory properties. VS was more effective in restoring astrocytic miR-146a, GFAP, S100B, HMGB1, Cx43, and vimentin levels than GUDCA, which only recovered Cx43 and vimentin mRNA. The miR-146a inhibitor generated typical ALS aberrancies in wild type astrocytes that were abolished by VS. Similarly, pre-miR-146a transfection into the mSOD1 astrocytes abrogated aberrant markers and intracellular Ca[2+] overload. Such treatment counteracted miR-146a depletion in sEVs and led to secretome-mediated miR-146a enhancement in NSC-34-motor neurons (MNs) and N9-microglia. Secretome from mSOD1 astrocytes increased early/late apoptosis and FGFR3 mRNA in MNs and microglia, but not when derived from pre-miR-146a or VS-treated cells. These last strategies prevented the impairment of axonal transport and synaptic dynamics by the pathological secretome, while also averted microglia activation through either secretome, or their isolated sEVs. Proteomic analysis of the target cells indicated that pre-miR-146a regulates mitochondria and inflammation via paracrine signaling. We demonstrate that replenishment of miR-146a in mSOD1 cortical astrocytes with pre-miR-146a or by VS abrogates their phenotypic aberrancies and paracrine deleterious consequences to MNs and microglia. These results propose miR-146a as a new causal and emerging therapeutic target for astrocyte pathogenic processes in ALS.}, } @article {pmid33973643, year = {2021}, author = {Patel, GN and Gudur, R and Gudur, A and Oswal, RM and Kanethkar, S}, title = {Clinicopathological Evaluation of Acute Leukemias in a Tertiary Care Hospital: A Cross-Sectional Study.}, journal = {Turk patoloji dergisi}, volume = {37}, number = {2}, pages = {145-153}, pmid = {33973643}, issn = {1309-5730}, mesh = {Adolescent ; Adult ; Aged ; Biomarkers, Tumor/analysis/genetics ; Bone Marrow Examination ; Child ; Clinical Decision-Making ; Cross-Sectional Studies ; Cytogenetic Analysis ; Female ; Flow Cytometry ; Humans ; Leukemia, Myeloid, Acute/*diagnosis/genetics/pathology/therapy ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/genetics/pathology/therapy ; Predictive Value of Tests ; Prognosis ; Tertiary Care Centers ; Young Adult ; }, abstract = {OBJECTIVE: Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are clinically and biologically diverse phenotypic diseases amongst hematological malignancies. The current study objectives were to diagnose and classify cases of AL as per revised 4th edition of WHO 2016 classification of AL's and study their clinicopathological profiles.

MATERIAL AND METHOD: This cross-sectional, observational study included 68 patients, diagnosed with AL were recruited. Diagnosis was based on peripheral blood smear examination, bone marrow aspiration, flowcytometry, and cytogenetic and molecular studies.

RESULTS: Sixty-eight cases of AL were diagnosed in a period of 2 years, where 25 cases were of ALL and 43 cases were of AML. In the subclassification of AML as per WHO 2016, 20 cases were of AML, RGA, 21 cases were of AML, NOS, and 2 cases were of AML, MRC. In AML, RGA, APL with PML-RARA positive cases were 10 out of 20 cases, AML with (8;21) RUNX1-RUNX1T1 were 7/20 cases; there were two cases of AML with mutated NPM1 gene and one case of AML with biallelic mutation of CEBPA. In AML, NOS subcategory AML with maturation was more common with 9/21cases. In subcategory of ALL, B-ALL was more common than T-ALL. B-ALL, NOS was more common than B-ALL, RGA and we had 1 case of NK cell Leukemia.

CONCLUSION: The application of revised 4th edition WHO 2016 classification confers uniformity in reporting acute leukemia cases that aids in the treatment by using targeted therapies and helps in the prediction of prognosis. The WHO classification for acute leukemias is very objective, therapy oriented and the need of the hour.}, } @article {pmid33974963, year = {2021}, author = {Tadokoro, K and Yamashita, T and Shang, J and Ohta, Y and Nomura, E and Morihara, R and Omote, Y and Takemoto, M and Abe, K}, title = {Switching the Proteolytic System from the Ubiquitin-Proteasome System to Autophagy in the Spinal Cord of an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Neuroscience}, volume = {466}, number = {}, pages = {47-57}, doi = {10.1016/j.neuroscience.2021.04.034}, pmid = {33974963}, issn = {1873-7544}, mesh = {Adaptor Proteins, Signal Transducing ; *Amyotrophic Lateral Sclerosis ; Animals ; Apoptosis Regulatory Proteins ; Autophagy ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Transgenic ; Proteasome Endopeptidase Complex ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Ubiquitin/metabolism ; }, abstract = {The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.}, } @article {pmid33976351, year = {2021}, author = {Lee, HS and Kang, HS and Kim, SM and Kim, CH and Yang, SH and Han, MH and Chung, CK}, title = {Treatment strategy to maximize the treatment outcome of spinal dural arteriovenous fistula after initial endovascular embolization attempt at diagnostic angiography.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {10004}, pmid = {33976351}, issn = {2045-2322}, mesh = {Aged ; Angiography ; Central Nervous System Vascular Malformations/diagnostic imaging/*therapy ; Endovascular Procedures/*statistics & numerical data ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {Initial attempt of endovascular treatment (EVT) for spinal dural arteriovenous fistula (SDAVF) is preferred because of concurrent diagnosis and treatment. However, outcomes following further treatment with initial EVT are not well studied. We retrospectively reviewed 71 patients with SDAVF to evaluate treatment outcomes of SDAVF after an initial EVT attempt. Pretreatment and posttreatment functional states were assessed by the Aminoff-Logue scale (ALS). In the case of incomplete occlusion or recurrence, overall outcomes after further treatments were compared. Of the 71 patients, 56 underwent initial EVT. Complete occlusion was achieved by initial EVT in 37 of 56 patients (66.1%). Multiple feeders were more frequently observed in patients with incomplete occlusion than complete occlusion after initial EVT (73.7% vs. 27%, P < 0.001). Among 19 patients with incomplete occlusion upon initial EVT, 14 underwent additional surgery, 13 of whom (92.9%) obtained improved or stationary functional outcomes. Functional improvement was not observed in patients who had repeated EVT or follow-up without further treatment. Recurrence was observed in 8 of 37 patients with complete occlusion upon initial EVT. Additional surgery achieved improved functional outcomes in cases of incomplete occlusion of SDAVF after the initial EVT attempt or recurrence rather than repeated EVT or follow-up.}, } @article {pmid33982658, year = {2022}, author = {Kursun, O and Karatas, H and Bariskaner, H and Ozturk, S}, title = {Arachidonic Acid Metabolites in Neurologic Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {21}, number = {2}, pages = {150-159}, doi = {10.2174/1871527320666210512013648}, pmid = {33982658}, issn = {1996-3181}, mesh = {Alzheimer Disease/metabolism ; Animals ; Arachidonic Acid/*metabolism ; Docosahexaenoic Acids/metabolism ; Humans ; Inflammation/metabolism ; Neurodegenerative Diseases/*metabolism ; Parkinson Disease/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVE: Arachidonic acid (ARA) is essential for the fluidity, selective permeability, and flexibility of the cell membrane. It is an important factor for the function of all cells, particularly in the nervous system, immune system, and vascular endothelium. ARA is the second most common polyunsaturated fatty acid in the phospholipids of the nerve cell membrane after docosahexaenoic acid. ARA metabolites have many kinds of physiologic roles. The major action of ARA metabolites is the promotion of the acute inflammatory response, mediated by the production of pro-inflammatory mediators such as PGE2 and PGI2, followed by the formation of lipid mediators, which have pro-resolving effects. Another important action of ARA derivatives, especially COX, is the regulation of vascular reactivity through PGs and TXA2. There is significant involvement of ARA metabolites in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and neuropsychiatric disorders. ARA derivatives also make an important contribution to acute stroke, global ischemia, subarachnoid hemorrhage, and anticoagulation-related hemorrhagic transformation.

CONCLUSION: In this review, we have discussed experimental and human study results of neurologic disorders related to ARA and its metabolites in line with treatment options.}, } @article {pmid33993457, year = {2021}, author = {Mahoney, CJ and Ahmed, RM and Huynh, W and Tu, S and Rohrer, JD and Bedlack, RS and Hardiman, O and Kiernan, MC}, title = {Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {CNS drugs}, volume = {35}, number = {5}, pages = {483-505}, pmid = {33993457}, issn = {1179-1934}, support = {MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/physiopathology/*therapy ; Cognitive Dysfunction/etiology/physiopathology/*therapy ; Disease Progression ; Humans ; Outcome Assessment, Health Care ; Research Design ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.}, } @article {pmid33994932, year = {2021}, author = {Xie, Y and Luo, X and He, H and Tang, M}, title = {Novel Insight Into the Role of Immune Dysregulation in Amyotrophic Lateral Sclerosis Based on Bioinformatic Analysis.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {657465}, pmid = {33994932}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. The causative pathogenic mechanisms in ALS remain unclear, limiting the development of treatment strategies. Neuroinflammation and immune dysregulation were involved in the disease onset and progression of several neurodegenerative disorders, including ALS. In this study, we carried out a bioinformatic analysis using publicly available datasets from Gene Expression Omnibus (GEO) to investigate the role of immune cells and genes alterations in ALS. Single-sample gene set enrichment analysis revealed that the infiltration of multiple types of immune cells, including macrophages, type-1/17 T helper cells, and activated CD4 + /CD8 + T cells, was higher in ALS patients than in controls. Weighted gene correlation network analysis identified immune genes associated with ALS. The Gene Ontology analysis revealed that receptor and cytokine activities were the most highly enriched terms. Pathway analysis showed that these genes were enriched not only in immune-related pathways, such as cytokine-cytokine receptor interaction, but also in PI3K-AKT and MAPK signaling pathways. Nineteen immune-related genes (C3AR1, CCR1, CCR5, CD86, CYBB, FCGR2B, FCGR3A, HCK, ITGB2, PTPRC, TLR1, TLR2, TLR7, TLR8, TYROBP, VCAM1, CD14, CTSS, and FCER1G) were identified as hub genes based on least absolute shrinkage and selection operator analysis. This gene signature could differentiate ALS patients from non-neurological controls (p < 0.001) and predict disease occurrence (AUC = 0.829 in training set; AUC = 0.862 in test set). In conclusion, our study provides potential biomarkers of ALS for disease diagnosis and therapeutic monitoring.}, } @article {pmid33996012, year = {2021}, author = {Häfliger, J and Livingstone, K and Daniliuc, CG and Gilmour, R}, title = {Difluorination of α-(bromomethyl)styrenes via I(I)/I(III) catalysis: facile access to electrophilic linchpins for drug discovery.}, journal = {Chemical science}, volume = {12}, number = {17}, pages = {6148-6152}, pmid = {33996012}, issn = {2041-6520}, abstract = {Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.}, } @article {pmid34000059, year = {2021}, author = {Horvath, CM and Brill, AK and Baty, F and Brutsche, MH}, title = {Efficacy of non-invasive intelligent volume assured pressure support (iVAPS) and pressure support ventilation (PSV) in clinical practice.}, journal = {Swiss medical weekly}, volume = {151}, number = {}, pages = {w20506}, doi = {10.4414/smw.2021.20506}, pmid = {34000059}, issn = {1424-3997}, mesh = {Humans ; Lung ; *Noninvasive Ventilation ; Positive-Pressure Respiration ; *Pulmonary Disease, Chronic Obstructive/therapy ; Respiration ; *Respiratory Insufficiency/therapy ; Retrospective Studies ; }, abstract = {AIMS OF THE STUDY: Noninvasive ventilation (NIV) is a well-established treatment option for hypercapnic respiratory failure; however, the best mode of ventilation remains unknown. The aim of this retrospective study was to compare patients’ adherence to NIV using either pressure support ventilation (PSV) or intelligent volume-assured pressure support (iVAPS).

PATIENTS AND METHODS: In this retrospective cohort study, we assessed in- and outpatients suffering from hypercapnic respiratory failure of various aetiologies (chronic obstructive pulmonary disease [COPD], obese COPD [body mass index >30 kg/m2], obesity hypoventilation syndrome and other diseases such as amyotrophic lateral sclerosis or interstitial lung disease) after NIV initiation with PSV or iVAPS. Adherence to treatment was compared between these modes using the Wilcoxon test. Within-group differences were tested using linear regression models. Mortality and emergency hospital readmission rates were modelled using Kaplan-Meier estimates and Cox proportional hazards models.

RESULTS: Adherence to treatment was similar in both groups throughout the observation period &ndash; after 6 weeks: PSV 363 min/night (interquartile range [IQR] 200&ndash;448), iVAPS 369 min/night (IQR 310&ndash;468) (p = 0.619); after 1 year: PSV 423 (323&ndash;500), iVAPS 429 (298&ndash;475) (p = 0.901); at the last follow up: PSV 481 (395&ndash;586), iVAPS 426 (391&ndash;565) (p = 0.284). NIV reduced PaCO2 significantly compared with baseline at all follow-ups: PSV &minus;1.29/&minus;1.49/&minus;1.49 kPa, iVAPS &minus;1.47/&minus;1.23/&minus;1.24 kPa, p <0.001 each, PSV vs iVAPS: p = 0.250, 0.756 and 0.352, respectively. Median survival time (PSV 5.06 years, iVAPS median not reached; p = 0.800) and time to first readmission (PSV 3.6 years, iVAPS 7.33 years, p = 0.200) did not differ between groups. Obese COPD patients had a longer time to hospital readmission than lean COPD patients (3.8 vs 1.5 years, hazard ratio (HR) 0.39, 95% confidence interval [CI] 0.16&ndash;0. 74; p = 0.007). Good adherence (>4 h/night and >80% nightly usage) was associated with a lower mortality rate (HR 0.34, 95% CI 0.15&ndash;0.77; p = 0.010).

CONCLUSION: In a real-world setting of a mixed population with hypercapnic respiratory failure, iVAPS and PSV seem to be similarly effective in improving gas exchange and demonstrate excellent adherence to treatment. A longer survival was noted in NIV-adherent patients. Randomised controlled studies are necessary to identify patients who might benefit more from hybrid ventilation modes.}, } @article {pmid34002641, year = {2022}, author = {, }, title = {ALSUntangled #61: melatonin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {157-160}, doi = {10.1080/21678421.2021.1927103}, pmid = {34002641}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/complications/drug therapy ; Humans ; *Melatonin/therapeutic use ; Retrospective Studies ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (ALS). Here we review melatonin. We show that it has plausible mechanisms, some positive (and some negative) pre-clinical studies, two cases in which cocktails of supplements including melatonin were associated with recovery of lost motor function, and a very small, flawed retrospective study suggesting that patients in the PRO-ACT database who reported taking melatonin progressed more slowly and lived longer compared to those who were not taking it. Melatonin appears safe, but an optimal dose and route of administration for ALS have not been determined. Based on all this, we support a pilot trial of melatonin in people with ALS but we cannot yet recommend it as a treatment.}, } @article {pmid34004234, year = {2021}, author = {Wu, HT and Yu, Y and Li, XX and Lang, XY and Gu, RZ and Fan, SR and Fang, X and Bai, JP and Lan, R and Qin, XY}, title = {Edaravone attenuates H2O2 or glutamate-induced toxicity in hippocampal neurons and improves AlCl3/D-galactose induced cognitive impairment in mice.}, journal = {Neurotoxicology}, volume = {85}, number = {}, pages = {68-78}, doi = {10.1016/j.neuro.2021.05.005}, pmid = {34004234}, issn = {1872-9711}, mesh = {Aluminum Chloride/*toxicity ; Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cognitive Dysfunction/chemically induced/metabolism/*prevention & control ; Dose-Response Relationship, Drug ; Edaravone/pharmacology/*therapeutic use ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Galactose/*toxicity ; Glutamic Acid/*toxicity ; Hippocampus/drug effects/metabolism ; Hydrogen Peroxide/*toxicity ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Edaravone (Eda) is a free radical scavenger used in clinical trials for the treatment of ischemic stroke and amyotrophic lateral sclerosis. However, how Eda exerts its neuroprotective effects remains to be elucidated. We investigated the neuroprotective effects of Eda in cultured hippocampal neurons and in a mouse model of AlCl3/D-galactose-induced cognitive impairment. Eda protected hippocampal neurons by eliminating H2O2 or glutamate-induced toxicity, leading to decreased cell viability and neurite shortening. Consistently, Eda restored impaired levels of BDNF, FGF2 and their associated signaling axes (including TrkB, p-Akt and Bcl-2) to attenuate neuronal death. In a mouse model of chemically-induced cognitive impairment, Eda restored the levels of BDNF, FGF2 and TrkB/Akt signaling axis to attenuate neuronal apoptosis, thereby ameliorating cognitive impairment. Meanwhile, the pro-inflammation was eliminated due to the restoration of pro-inflammatory factors such as TNF-α, IL-6, IL-1β, and NOS2. In summary, Eda is an effective drug for protecting neurons from neurotoxic injury. BDNF, FGF2, and their regulated pathways may be potential therapeutic targets for neuroprotection.}, } @article {pmid34008857, year = {2021}, author = {Oskarsson, B and Mauricio, EA and Shah, JS and Li, Z and Rogawski, MA}, title = {Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {64}, number = {2}, pages = {215-219}, doi = {10.1002/mus.27328}, pmid = {34008857}, issn = {1097-4598}, support = {FYC-IIS-M001-1015//Eisai/ ; 17-002396//Mayo Foundation for Medical Education and Research/ ; //University of California, Davis/ ; //Mayo Clinic/ ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/diagnosis/*drug therapy ; Cortical Excitability/*drug effects/physiology ; Double-Blind Method ; Evoked Potentials, Motor/drug effects/physiology ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/*drug effects/physiology ; Nitriles ; Pilot Projects ; Pyridones/*administration & dosage/blood ; Receptors, AMPA/*antagonists & inhibitors/physiology ; Transcranial Magnetic Stimulation/methods ; }, abstract = {INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS.

METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured.

RESULTS: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure.

DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.}, } @article {pmid34010004, year = {2021}, author = {Ediriweera, GR and Chen, L and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Non-Viral Vector-Mediated Gene Therapy for ALS: Challenges and Future Perspectives.}, journal = {Molecular pharmaceutics}, volume = {18}, number = {6}, pages = {2142-2160}, doi = {10.1021/acs.molpharmaceut.1c00297}, pmid = {34010004}, issn = {1543-8392}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*therapy ; Animals ; CRISPR-Cas Systems/genetics ; Cells, Cultured ; Clinical Trials, Phase III as Topic ; Disease Models, Animal ; Gene Transfer Techniques/*adverse effects/trends ; Genetic Therapy/adverse effects/*methods/trends ; Genetic Vectors/*administration & dosage/adverse effects ; Humans ; Nanoparticles/administration & dosage ; Primary Cell Culture ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, for which no effective treatment is yet available to either slow or terminate it. Recent advances in gene therapy renew hope for developing an effective approach to control this disease. Non-viral vectors, such as lipid- and polymer-based nanoparticles, cationic polymers, and exosomes, can effectively transfer genes into primary neurons. The resulting gene expression can be long-term, stable, and without immunological complications, which is essential for the effective management of neurological disorders. This Review will first describe the current research and clinical stage of novel therapies for ALS. It will then touch on the journey of non-viral vector use in ALS, subsequently highlighting the application of non-viral vector-mediated gene therapy. The bottlenecks in the translation of non-viral vectors for ALS treatment are also discussed, including the biological barriers of systemic administration and the issues of "when, where, and how much?" for effective gene delivery. The prospect of employing emerging techniques, such as CRISPR-Cas9 gene editing, stem cell methodology, and low-intensity focused ultrasound for fueling the transport of non-viral vectors to the central nervous system for personalized gene therapy, is briefly discussed in the context of ALS. Despite the challenging road that lies ahead, with the current expansion in interest and technological advancement in non-viral vector-delivered gene therapy for ALS, we hold hope that the field is headed toward a positive future.}, } @article {pmid34012311, year = {2021}, author = {Soldatov, VO and Kukharsky, MS and Belykh, AE and Sobolev, AM and Deykin, AV}, title = {Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms.}, journal = {Eye and brain}, volume = {13}, number = {}, pages = {131-146}, pmid = {34012311}, issn = {1179-2744}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in a gradual loss of motor neuron function. Although ophthalmic complaints are not presently considered a classic symptom of ALS, retinal changes such as thinning, axonal degeneration and inclusion bodies have been found in many patients. Retinal abnormalities observed in postmortem human tissues and animal models are similar to spinal cord changes in ALS. These findings are not dramatically unexpected because retina shares an ontogenetic relationship with the brain, and many genes are associated both with neurodegeneration and retinal diseases. Experimental studies have demonstrated that ALS affects many "vulnerable points" of the retina. Aggregate deposition, impaired nuclear protein import, endoplasmic reticulum stress, glutamate excitotoxicity, vascular regression, and mitochondrial dysfunction are factors suspected as being the main cause of motor neuron damage in ALS. Herein, we show that all of these pathways can affect retinal cells in the same way as motor neurons. Furthermore, we suppose that understanding the patterns of neuro-ophthalmic interaction in ALS can help in the diagnosis and treatment of this disease.}, } @article {pmid34014000, year = {2022}, author = {Palese, F and Gigli, GL and Manganotti, P and Passadore, P and Rana, M and Verriello, L}, title = {The diagnostic, therapeutic and assistance pathway for amyotrophic lateral sclerosis in a north-eastern Italian region: satisfaction of patients and their caregivers.}, journal = {Health & social care in the community}, volume = {30}, number = {1}, pages = {124-132}, doi = {10.1111/hsc.13379}, pmid = {34014000}, issn = {1365-2524}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Caregivers ; Humans ; Patient Satisfaction ; Personal Satisfaction ; Surveys and Questionnaires ; }, abstract = {In order to evaluate the users' satisfaction degree for the diagnostic, therapeutic and assistance services for amyotrophic lateral sclerosis (ALS) in the Italian region Friuli-Venezia Giulia (FVG), a self-compiled anonymous multiple-choice questionnaire was administered to ALS patients and their caregivers. The questionnaire explored 41 different issues covering the following areas: (a) access to diagnostic pathway and communication among patients, families and health professionals; (b) quality of disease monitoring and effectiveness of interventions aimed at mitigating ALS symptoms; (c) easiness of access to assistive devices (e.g. wheelchair, ankle-foot-orthosis) and home assistance; (d) patient' choices sharing and health professionals empathy. The same issues were proposed both to patients and carers, appropriately adapting the questions, during the period between June and December 2019. The answers were categorised according to criticality level. Median with interquartile range of the numeric variables and percentages of the categorical variables and of the answers to questions were calculated. The mean percentage of satisfied users was 72.8%, considering all the areas. Pain treatment and easiness of access to ambulance transport were the most positive aspects (95.7% and 92.5% of satisfied respondents, respectively), while information about possible enrolment in clinical trials and about possible registration to the regional ALS association were the most critical issues (30.9% and 43.4% of satisfied users). Although the satisfaction level of ALS patients and their caregivers for the services provided resulted generally good, there were some areas that have to be improved. For this purpose, enhancement of multidisciplinary collaboration, sharing of points of view from users and different practitioners and rising awareness among healthcare professionals through clinical audits could be useful. Further research is needed to identify a wider range of users' unexplored unmet needs.}, } @article {pmid34016561, year = {2021}, author = {Babu, S and Hightower, BG and Chan, J and Zürcher, NR and Kivisäkk, P and Tseng, CJ and Sanders, DL and Robichaud, A and Banno, H and Evora, A and Ashokkumar, A and Pothier, L and Paganoni, S and Chew, S and Dojillo, J and Matsuda, K and Gudesblatt, M and Berry, JD and Cudkowicz, ME and Hooker, JM and Atassi, N}, title = {Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial.}, journal = {NeuroImage. Clinical}, volume = {30}, number = {}, pages = {102672}, pmid = {34016561}, issn = {2213-1582}, support = {S10 OD023517/OD/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Biomarkers ; Cohort Studies ; Humans ; Pyridines ; Indolizines ; Pyrazoles ; }, abstract = {Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by [[11]C]PBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks. In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12-24 weeks and (b) serum NfL over 36-40 weeks. The secondary safety and tolerability endpoints were collected through Week 40. The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (-0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (-1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60-80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events. The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12-24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36-40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.}, } @article {pmid34020673, year = {2021}, author = {Zeman, M and Czarnecki, M and Chmielik, E and Idasiak, A and Skałba, W and Strączyński, M and Paul, PJ and Czarniecka, A}, title = {The assessment of risk factors for long-term survival outcome in ypN0 patients with rectal cancer after neoadjuvant therapy and radical anterior resection.}, journal = {World journal of surgical oncology}, volume = {19}, number = {1}, pages = {154}, pmid = {34020673}, issn = {1477-7819}, mesh = {Disease-Free Survival ; Humans ; *Neoadjuvant Therapy ; Neoplasm Recurrence, Local/epidemiology/therapy ; Neoplasm Staging ; Prognosis ; *Rectal Neoplasms/pathology/surgery ; Retrospective Studies ; Risk Factors ; }, abstract = {BACKGROUND: The main negative prognostic factors in patients with rectal cancer after radical treatment include regional lymph node involvement, lymphovascular invasion, and perineural invasion. However, some patients still develop cancer recurrence despite the absence of the above risk factors. The aim of the study was to assess clinicopathological factors influencing long-term oncologic outcomes in ypN0M0 rectal cancer patients after neoadjuvant therapy and radical anterior resection.

METHODS: A retrospective survival analysis was performed on a group of 195 patients. We assessed clinicopathological factors which included tumor regression grade, number of lymph nodes in the specimen, Charlson comorbidity index (CCI), and colorectal anastomotic leakage (AL).

RESULTS: In the univariate analysis, AL and CCI > 3 had a significant negative impact on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). After the division of ALs into early and late ALs, it was found that only patients with late ALs had a significantly worse survival. The multivariate Cox regression analysis showed that CCI > 3 was a significant adverse risk factor for DFS (HR 5.78, 95% CI 2.15-15.51, p < 0.001), DSS (HR 7.25, 95% CI 2.25-23.39, p < 0.001), and OS (HR 3.9, 95% CI 1.72-8.85, p = 0.001). Similarly, late ALs had a significant negative impact on the risk of DFS (HR 5.05, 95% CI 1.97-12.93, p < 0.001), DSS (HR 10.84, 95% CI 3.44-34.18, p < 0.001), and OS (HR 4.3, 95% CI 1.94-9.53, p < 0.001).

CONCLUSIONS: Late AL and CCI > 3 are the factors that may have an impact on long-term oncologic outcomes. The impact of lymph node yield on understaging was not demonstrated.}, } @article {pmid34024773, year = {2021}, author = {Nash, Y and Sitty, M}, title = {Non-Motor Symptoms of Amyotrophic Lateral Sclerosis: A Multi-Faceted Disorder.}, journal = {Journal of neuromuscular diseases}, volume = {8}, number = {4}, pages = {699-713}, doi = {10.3233/JND-210632}, pmid = {34024773}, issn = {2214-3602}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis ; Biomarkers ; Disease Progression ; Humans ; Quality of Life ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor pathways. A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms as well, which can have a significant impact on patients' quality of life. These symptoms could also, in turn, provide useful information as biomarkers for disease progression, and can shed insight on ALS mechanisms. Here we aim to review a wide range of non-motor symptoms of ALS, with emphasis on their importance to research and clinical treatment of patients.}, } @article {pmid34025132, year = {2021}, author = {Nam, SM and Choi, JH and Choi, SH and Cho, HJ and Cho, YJ and Rhim, H and Kim, HC and Cho, IH and Kim, DG and Nah, SY}, title = {Ginseng gintonin alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis through lysophosphatidic acid 1 receptor.}, journal = {Journal of ginseng research}, volume = {45}, number = {3}, pages = {390-400}, pmid = {34025132}, issn = {1226-8453}, abstract = {BACKGROUND: We recently showed that gintonin, an active ginseng ingredient, exhibits antibrain neurodegenerative disease effects including multiple target mechanisms such as antioxidative stress and antiinflammation via the lysophosphatidic acid (LPA) receptors. Amyotrophic lateral sclerosis (ALS) is a spinal disease characterized by neurodegenerative changes in motor neurons with subsequent skeletal muscle paralysis and death. However, pathophysiological mechanisms of ALS are still elusive, and therapeutic drugs have not yet been developed. We investigate the putative alleviating effects of gintonin in ALS.

METHODS: The G93A-SOD1 transgenic mouse ALS model was used. Gintonin (50 or 100 mg/kg/day, p.o.) administration started from week seven. We performed histological analyses, immunoblot assays, and behavioral tests.

RESULTS: Gintonin extended mouse survival and relieved motor dysfunctions. Histological analyses of spinal cords revealed that gintonin increased the survival of motor neurons, expression of brain-derived neurotrophic factors, choline acetyltransferase, NeuN, and Nissl bodies compared with the vehicle control. Gintonin attenuated elevated spinal NAD(P) quinone oxidoreductase 1 expression and decreased oxidative stress-related ferritin, ionized calcium-binding adapter molecule 1-immunoreactive microglia, S100β-immunoreactive astrocyte, and Olig2-immunoreactive oligodendrocytes compared with the control vehicle. Interestingly, we found that the spinal LPA1 receptor level was decreased, whereas gintonin treatment restored decreased LPA1 receptor expression levels in the G93A-SOD1 transgenic mouse, thereby attenuating neurological symptoms and histological deficits.

CONCLUSION: Gintonin-mediated symptomatic improvements of ALS might be associated with the attenuations of neuronal loss and oxidative stress via the spinal LPA1 receptor regulations. The present results suggest that the spinal LPA1 receptor is engaged in ALS, and gintonin may be useful for relieving ALS symptoms.}, } @article {pmid34027769, year = {2022}, author = {Pagnini, F and Phillips, D and Haulman, A and Bankert, M and Simmons, Z and Langer, E}, title = {An online non-meditative mindfulness intervention for people with ALS and their caregivers: a randomized controlled trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {116-127}, doi = {10.1080/21678421.2021.1928707}, pmid = {34027769}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Caregivers/psychology ; Depression/etiology/psychology/therapy ; Humans ; *Mindfulness ; Quality of Life/psychology ; }, abstract = {Objectives: Mindfulness-based interventions seem to be effective in promoting QOL of ALS patients and caregivers, but most require substantial time. In the Langerian approach, mindfulness can be easily promoted with mental tasks and short lectures. This study aims to explore the impact of an ALS-specific online Langerian mindfulness training program on QOL of ALS patients. Methods: We developed and tested with an Randomized Controlled Trial (RCT) a 5-week active learning mindfulness program. Participants were recruited from the ALS clinic at Penn State Health and online and were randomly assigned to either the mindfulness group or a wait-list control group. The primary outcome was the patient's QOL after the treatment. 3 and 6-month follow-ups, together with anxiety, depression, care burden, and physical function, assessed at all times for both patients and caregivers, were explored as secondary outcomes. Results: 47 ALS patients and 27 caregivers were recruited. Among the ALS patients, the experimental group reported higher levels of QOL at the end of the treatment (d = 0.54). Moreover, they showed lower values of depression, anxiety, and negative emotions, compared to the controls, over time. The caregivers from the mindfulness group reported lower scores of care burden, depression, and anxiety, with higher values of energy and emotional well-being over time. Conclusions: This small RCT provides preliminary evidence that this intervention leads to an increase of QOL and a reduction in psychological comorbidities in ALS patients and caregivers. Given the relatively short time commitment, it may be easily implemented by the ALS community.}, } @article {pmid34032759, year = {2021}, author = {Kakimoto, A and Ishizaki, M and Ueyama, H and Maeda, Y and Ueda, M}, title = {Renal function in amyotrophic lateral sclerosis patients on long-term treatment with edaravone.}, journal = {Medicine}, volume = {100}, number = {21}, pages = {e26127}, pmid = {34032759}, issn = {1536-5964}, mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/*drug therapy/*physiopathology ; Cystatin C/blood ; Drug Administration Schedule ; Edaravone/*administration & dosage/adverse effects ; Female ; Free Radical Scavengers/*administration & dosage/adverse effects ; Glomerular Filtration Rate/*drug effects ; Humans ; Kidney/*physiopathology ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {Edaravone, a free radical-scavenger, was approved in Japan for the treatment of amyotrophic lateral sclerosis (ALS). However, the effect of the drug on renal function in ALS patients remains unclear. This study aimed to investigate renal function in ALS patients on long-term treatment with edaravone by measuring the serum estimated glomerular filtration rate based on cystatin C (eGFR-CysC).In a retrospective study, the data of ALS patients who were treated with over 10 cycles of intravenous edaravone treatment and were evaluated by eGFR-CysC before and after 10 cycles of treatment between July 2015 and June 2018 were analyzed. Then, the results were compared with those of a control ALS group that had never been treated with edaravone.There were 11 patients with ALS who received over 10 cycles of intravenous edaravone treatment. The mean interval between the first and final eGFR-CysC measurements was 18.7 ± 7.9 months. Three patients (27.3%) had >20 mL/min/1.73 m2 decrease in serum eGFR-CysC. However, no patients discontinued edaravone treatment because of renal dysfunction. The average variation rate of eGFR-CysC was not different between the long-term edaravone group (0.29 ± 1.07) and the control group (-0.34 ± 0.40).This retrospective, single-center analysis showed no clinical exacerbation of renal function in ALS patients who received long-term treatment with edaravone.}, } @article {pmid34035826, year = {2021}, author = {Zhao, Q and Zheng, B and Feng, P and Li, X}, title = {A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6694698}, pmid = {34035826}, issn = {1741-427X}, abstract = {BACKGROUND: Butylphthalide (NBP), approved by the China National Medical Products Administration (NMPA) for the treatment of ischemic stroke (IS), showed pleiotropic potentials against central nervous system (CNS) diseases, including neuroprotection and cognitive deficits improvement. However, the effects and corresponding modes of action were not fully explored. This study was designed to investigate the potential of NBP against IS-associated CNS diseases based on network pharmacology (NP) and molecular docking (MD).

METHODS: IS was inputted as the index disease to retrieve the "associated diseases" in DisGeNET. Three-database-based IS genes were obtained and integrated (DisGeNET, Malacards, and OMIM). Then, IS-associated genes were identified by combining these genes. Meanwhile, PubMed references and online databases were applied to identify NBP target genes. The IS-related disease-disease association (DDA) network and NBP-disease regulation network were constructed and analyzed in Cytoscape. In silico MD and references were used to validate the binding affinity of NBP with critical targets and the potential of NBP against certain IS-related CNS disease regulation.

RESULTS: 175 NBP target genes were obtained, while 312 IS-related disease genes were identified. 36 NBP target genes were predicted to be associated with IS-related CNS diseases, including Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), amyotrophic lateral sclerosis (ALS), and dementia. Six target genes (i.e., GRIN1, PTGIS, PTGES, ADRA1A, CDK5, and SULT1E1) indicating disease specificity index (DSI) >0.5 showed certain to good degree binding affinity with NBP, ranging from -9.2 to -6.7 kcal/mol. And the binding modes may be mainly related to hydrogen bonds and hydrophobic "bonds." Further literature validations inferred that these critical NBP targets had a tight association with AD, epilepsy, ALS, and depression.

CONCLUSIONS: Our study proposed a drug-target-disease integrated method to predict the drug repurposing potentials to associated diseases by application of NP and MD, which could be an attractive alternative to facilitate the development of CNS disease therapies. NBP may be promising and showed potentials to be repurposed for treatments for AD, epilepsy, ALS, and depression, and further investigations are warranted to be carefully designed and conducted.}, } @article {pmid34040085, year = {2021}, author = {Tungtur, SK and Wilkins, HM and Rogers, RS and Badawi, Y and Sage, JM and Agbas, A and Jawdat, O and Barohn, RJ and Swerdlow, RH and Nishimune, H}, title = {Oxaloacetate treatment preserves motor function in SOD1[G93A] mice and normalizes select neuroinflammation-related parameters in the spinal cord.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {11051}, pmid = {34040085}, issn = {2045-2322}, support = {P20 RR016475/RR/NCRR NIH HHS/United States ; R01 AG051470/AG/NIA NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; P20 GM104936/GM/NIGMS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; R01 NS078214/NS/NINDS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Disease Models, Animal ; Inflammation/drug therapy/metabolism ; Longevity/drug effects ; Mice ; Motor Activity/*drug effects ; Motor Neurons/drug effects/metabolism ; Oxaloacetic Acid/*pharmacology/therapeutic use ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism ; Spinal Cord/*drug effects/metabolism ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) remains a devastating motor neuron disease with limited treatment options. Oxaloacetate treatment has a neuroprotective effect in rodent models of seizure and neurodegeneration. Therefore, we treated the ALS model superoxide dismutase 1 (SOD1) [G93A] mice with oxaloacetate and evaluated their neuromuscular function and lifespan. Treatment with oxaloacetate beginning in the presymptomatic stage significantly improved neuromuscular strength measured during the symptomatic stage in the injected mice compared to the non-treated group. Oxaloacetate treatment starting in the symptomatic stage significantly delayed limb paralysis compared with the non-treated group. For lifespan analysis, oxaloacetate treatment did not show a statistically significant positive effect, but the treatment did not shorten the lifespan. Mechanistically, SOD1[G93A] mice showed increased levels of tumor necrosis factor-α (TNFα) and peroxisome proliferative activated receptor gamma coactivator 1α (PGC-1α) mRNAs in the spinal cord. However, oxaloacetate treatment reverted these abnormal levels to that of wild-type mice. Similarly, the altered expression level of total NF-κB protein returned to that of wild-type mice with oxaloacetate treatment. These results suggest that the beneficial effects of oxaloacetate treatment in SOD1[G93A] mice may reflect the effects on neuroinflammation or bioenergetic stress.}, } @article {pmid34053435, year = {2021}, author = {van der Smissen, D and Rietjens, JAC and van Gemert-Pijnen, L and van Dulmen, S and van der Heide, A and Korfage, IJ}, title = {Information needs of patients with chronic diseases and their relatives for web-based advance care planning: a qualitative interview study.}, journal = {BMC palliative care}, volume = {20}, number = {1}, pages = {77}, pmid = {34053435}, issn = {1472-684X}, mesh = {Adult ; Female ; Humans ; Male ; *Advance Care Planning ; Chronic Disease ; Internet ; Qualitative Research ; *Quality of Life ; Adult Children ; }, abstract = {BACKGROUND: Advance care planning (ACP) enables persons to identify preferences for future treatment and care, and to discuss, record and review these preferences. However, the uptake of ACP among patients with chronic diseases is relatively low. Web-based ACP programs can support patients and their relatives in ACP. However, information needs of patients and their relatives for ACP are unknown. The aim of this study is to explore information needs of patients with chronic disease and their relatives for web-based ACP.

METHODS: We conducted semi-structured interviews with patients with chronic diseases and relatives at their home or at the study center. In three cases, the patient and relative were paired since they preferred to be interviewed together. We asked about information they would search for when to start with ACP, where they would search for information, what search terms they would use on the Internet, and what content and information they would consider important on an ACP website. The interviewer asked participants to clarify their responses during the interview. We used thematic analysis to analyze the interviewees' responses.

RESULTS: We interviewed nine patients with different chronic diseases including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD) and kidney diseases, and seven relatives, namely partners or (adult) children. The interviewees were aged 24 to 80 years, nine were female and seven were male. Both patients with a chronic disease and relatives mentioned comparable information needs. Many interviewees indicated they would use the Internet to search for information about ACP. Mentioned search terms were "advance care planning", "treatment plan", "disease trajectory" and names of patient associations. Information needs concerned their disease trajectory and quality of life, medical treatment decisions, practical support in arranging care, the concept of ACP and guidance in ACP, communication of treatment and care preferences, peer support of others with chronic diseases, and information for relatives. Many appreciated encouragement of their healthcare providers to take a pro-active role in ACP.

CONCLUSIONS: We conclude that information needs for ACP included guidance in ACP, support in making decisions about medical treatment, and practical support in arranging care. We recommend adapting web-based ACP information to the information needs of patients and their relatives to increase its findability, uptake and usefulness.}, } @article {pmid34054547, year = {2021}, author = {Garcia-Gil, M and Camici, M and Allegrini, S and Pesi, R and Tozzi, MG}, title = {Metabolic Aspects of Adenosine Functions in the Brain.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {672182}, pmid = {34054547}, issn = {1663-9812}, abstract = {Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5'-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington's disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.}, } @article {pmid34062930, year = {2021}, author = {La Cognata, V and Morello, G and Cavallaro, S}, title = {Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {34062930}, issn = {1422-0067}, support = {CTN01_00177_817708//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Biomarkers/metabolism ; Computational Biology ; *Genomics ; Humans ; *Metabolomics ; Neurodegenerative Diseases/*genetics/pathology ; Parkinson Disease/genetics/pathology ; Precision Medicine ; *Proteomics ; }, abstract = {Molecular and clinical heterogeneity is increasingly recognized as a common characteristic of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. This heterogeneity makes difficult the development of early diagnosis and effective treatment approaches, as well as the design and testing of new drugs. As such, the stratification of patients into meaningful disease subgroups, with clinical and biological relevance, may improve disease management and the development of effective treatments. To this end, omics technologies-such as genomics, transcriptomics, proteomics and metabolomics-are contributing to offer a more comprehensive view of molecular pathways underlying the development of NDs, helping to differentiate subtypes of patients based on their specific molecular signatures. In this article, we discuss how omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches, bringing us closer to the goal of personalized medicine in neurology.}, } @article {pmid34065874, year = {2021}, author = {Stoccoro, A and Smith, AR and Baldacci, F and Del Gamba, C and Lo Gerfo, A and Ceravolo, R and Lunnon, K and Migliore, L and Coppedè, F}, title = {Mitochondrial D-Loop Region Methylation and Copy Number in Peripheral Blood DNA of Parkinson's Disease Patients.}, journal = {Genes}, volume = {12}, number = {5}, pages = {}, pmid = {34065874}, issn = {2073-4425}, mesh = {Aged ; Aged, 80 and over ; Biomarkers/blood ; *DNA Methylation ; DNA, Mitochondrial/*genetics ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease/blood/*genetics ; }, abstract = {Altered mitochondrial DNA (mtDNA) methylation has been detected in several human pathologies, although little attention has been given to neurodegenerative diseases. Recently, altered methylation levels of the mitochondrial displacement loop (D-loop) region, which regulates mtDNA replication, were observed in peripheral blood cells of Alzheimer's disease and amyotrophic lateral sclerosis patients. However, nothing is yet known about D-loop region methylation levels in peripheral blood of Parkinson's disease (PD) patients. In the current study, we investigated D-loop methylation levels and mtDNA copy number in peripheral blood of 30 PD patients and 30 age- and sex-matched control subjects. DNA methylation analyses have been performed by means of methylation-sensitive high-resolution melting (MS-HRM) and pyrosequencing techniques, while mtDNA copy number was analyzed by quantitative PCR. MS-HRM and pyrosequencing analyses provided very similar D-loop methylation levels in PD patients and control subjects, and no differences between the two groups have been observed. Treatment with L-dopa and duration of the disease had no effect on D-loop methylation levels in PD patients. Additionally, mtDNA copy number did not differ between PD patients and control subjects. Current results suggest that D-loop methylation levels are not altered in peripheral blood of PD patients nor influenced by dopaminergic treatment.}, } @article {pmid34067277, year = {2021}, author = {Soll, M and Goldshtein, H and Rotkopf, R and Russek-Blum, N and Gross, Z}, title = {A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {6}, pages = {}, pmid = {34067277}, issn = {2076-3921}, support = {2026143//Israel Science Foundation/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson's disease, Alzheimer's disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole, 1-Fe. In this study we used the SOD1 G93R mutant zebrafish ALS model to assess whether 1-Fe, as a potent catalytic antioxidant, displays any therapeutic merits in vivo. Our results show that 1-Fe caused a substantial increase in mutant zebrafish locomotor activity (up to 30%), bringing the locomotive abilities of the mutant treated group close to that of the wild type untreated group (50% more than the mutated untreated group). Furthermore, 1-Fe did not affect WT larvae locomotor activity, suggesting that 1-Fe enhances locomotor ability by targeting mechanisms underlying SOD1 ALS specifically. These results may pave the way for future development of 1-Fe as a viable treatment for ALS.}, } @article {pmid34071187, year = {2021}, author = {Dharmadasa, T}, title = {Cortical Excitability across the ALS Clinical Motor Phenotypes.}, journal = {Brain sciences}, volume = {11}, number = {6}, pages = {}, pmid = {34071187}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.}, } @article {pmid34073630, year = {2021}, author = {Malacarne, C and Galbiati, M and Giagnorio, E and Cavalcante, P and Salerno, F and Andreetta, F and Cagnoli, C and Taiana, M and Nizzardo, M and Corti, S and Pensato, V and Venerando, A and Gellera, C and Fenu, S and Pareyson, D and Masson, R and Maggi, L and Dalla Bella, E and Lauria, G and Mantegazza, R and Bernasconi, P and Poletti, A and Bonanno, S and Marcuzzo, S}, title = {Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34073630}, issn = {1422-0067}, support = {2015-2020//Italian Ministry of Health/ ; 2015-0023//FRRB TRANS-ALS/ ; 2017-1886//CARIPLO/ ; GGP14039 AND GGP19128//FONDAZIONE TELETHON/ ; ALS-HSPB8, ALS-GRANULOPATHY, MLOPATHY, TARGET-RAN//FONDAZIONE ARISLA/ ; 2015LFPNMN, 2017 F2A2C5//PRIN-PROGETTI DI RICERCA DI INTARESSE NAZIONALE/ ; PROGETTO DIPARTIMENTI DI ECCELLENZA//ITALIAN MINISTRY OF UNIVERSITY AND RESEARCH/ ; }, mesh = {Amino Acid Substitution ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; *Bulbo-Spinal Atrophy, X-Linked/genetics/metabolism ; Humans ; Mice ; Mice, Transgenic ; *MicroRNAs/genetics/metabolism ; *Mutation, Missense ; *Superoxide Dismutase/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients' sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.}, } @article {pmid34075522, year = {2021}, author = {Minj, E and Upadhayay, S and Mehan, S}, title = {Nrf2/HO-1 Signaling Activator Acetyl-11-keto-beta Boswellic Acid (AKBA)-Mediated Neuroprotection in Methyl Mercury-Induced Experimental Model of ALS.}, journal = {Neurochemical research}, volume = {46}, number = {11}, pages = {2867-2884}, pmid = {34075522}, issn = {1573-6903}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*metabolism/prevention & control ; Animals ; Female ; Heme Oxygenase (Decyclizing)/*metabolism ; Male ; Methylmercury Compounds/*toxicity ; NF-E2-Related Factor 2/*metabolism ; Neuroprotection/*drug effects/physiology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects/physiology ; Triterpenes/pharmacology/*therapeutic use ; }, abstract = {Methylmercury (MeHg) is a potent neurotoxin that causes neurotoxicity and neuronal cell death. MeHg exposure also leads to oligodendrocyte destruction, glial cell overactivation, and demyelination of motor neurons in the motor cortex and spinal cord. As a result, MeHg plays an important role in the progression of amyotrophic lateral sclerosis (ALS)-like neurocomplications. ALS is a fatal neurodegenerative disorder in which neuroinflammation is the leading cause of further CNS demyelination. Nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway was thought to be a potential target for neuroprotection in ALS. Acetyl-11-keto-beta-boswellic acid (AKBA) is a multi-component pentacyclic triterpenoid mixture derived from Boswellia serrata with anti-inflammatory and antioxidant properties. The research aimed to investigate whether AKBA, as a Nrf2 / HO-1 activator, can provide protection against ALS. Thus, we explored the role of AKBA on the Nrf2/HO-1 signaling pathway in a MeHg-induced experimental ALS model. In this study, ALS was induced in Wistar rats by oral gavage of MeHg 5 mg/kg for 21 days. An open field test, force swim test, and grip strength were performed to observe experimental rats' motor coordination behaviors. In contrast, a morris water maze was performed for learning and memory. Administration of AKBA 50 mg/kg and AKBA 100 mg/kg continued from day 22 to 42. Neurochemical parameters were evaluated in the rat's brain homogenate. In the meantime, post-treatment with AKBA significantly improved behavioral, neurochemical, and gross pathological characteristics in the brain of rats by increasing the amount of Nrf2/HO-1 in brain tissue. Collectively, our findings indicated that AKBA could potentially avoid demyelination and encourage remyelination.}, } @article {pmid34075589, year = {2021}, author = {Milligan, C and Atassi, N and Babu, S and Barohn, RJ and Caress, JB and Cudkowicz, ME and Evora, A and Hawkins, GA and Wosiski-Kuhn, M and Macklin, EA and Shefner, JM and Simmons, Z and Bowser, RP and Ladha, SS}, title = {Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.}, journal = {Muscle & nerve}, volume = {64}, number = {3}, pages = {309-320}, pmid = {34075589}, issn = {1097-4598}, support = {UL1 TR001420/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/*drug therapy ; Anti-Inflammatory Agents/*adverse effects/therapeutic use ; Antibodies, Monoclonal, Humanized/*adverse effects/therapeutic use ; Biomarkers/blood/cerebrospinal fluid ; C-Reactive Protein/*metabolism ; Cytokines/blood/cerebrospinal fluid/*metabolism ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION/AIMS: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.

METHODS: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp[358] Ala polymorphism of the interleukin 6 receptor (IL-6R) gene.

RESULTS: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P = .01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups.

DISCUSSION: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp[358] Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.}, } @article {pmid34084973, year = {2021}, author = {Sadanandan, N and Lee, JY and Garbuzova-Davis, S}, title = {Extracellular vesicle-based therapy for amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {7}, number = {1}, pages = {23-28}, pmid = {34084973}, issn = {2455-4626}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as a neurodegenerative disorder characterized by the rapid progression of motor neuron loss in the brain and spinal cord. Unfortunately, treatment options for ALS are limited, and therefore, novel therapies that prevent further motor neuron degeneration are of dire need. In ALS, the infiltration of pathological elements from the blood to the central nervous system (CNS) compartment that spur motor neuron damage may be prevented via restoration of the impaired blood-CNS-barrier. Transplantation of human bone marrow endothelial progenitor cells (hBM-EPCs) demonstrated therapeutic promise in a mouse model of ALS due to their capacity to mitigate the altered blood-CNS-barrier by restoring endothelial cell (EC) integrity. Remarkably, the hBM-EPCs can release angiogenic factors that endogenously ameliorate impaired ECs. In addition, these cells may produce extracellular vesicles (EVs) that carry a wide range of vesicular factors, which aid in alleviating EC damage. In an in vitro study, hBM-EPC-derived EVs were effectively uptaken by the mouse brain endothelial cells (mBECs) and cell damage was significantly attenuated. Interestingly, the incorporation of EVs into mBECs was inhibited via β1 integrin hindrance. This review explores preclinical studies of the therapeutic potential of hBM-EPCs, specifically via hBM-EPC-derived EVs, for the repair of the damaged blood-CNS-barrier in ALS as a novel treatment approach.}, } @article {pmid34092572, year = {2021}, author = {Okita, Y and Narita, Y}, title = {[Significance of Quality of Life Evaluation for Glioma Patients].}, journal = {No shinkei geka. Neurological surgery}, volume = {49}, number = {3}, pages = {660-664}, doi = {10.11477/mf.1436204440}, pmid = {34092572}, issn = {0301-2603}, mesh = {*Glioma/therapy ; Humans ; *Quality of Life ; }, abstract = {Typically, overall and progression-free survival are used as endpoints in clinical tri-als investigating gliomas, while health-related quality of life(HRQOL)plays a key role in cancer research and may be useful for individual patient care. Previous studies have shown that HRQOL parameters can serve as independent prognostic factors for survival in patients with cancer, while recent studies have highlighted the usefulness of HRQOL in information management and decision-making in cancer treatment. However, a few studies have shown differences between patients' and physicians' perceptions of cancer treatment. In the future, physicians will be expected to recog-nize the importance of the QOL evaluation tool, not only in clinical trials, but also in general practice for gliomas, considering the characteristics of patients with brain tu-mors. In this study, we reviewed the methods of major HRQOL evaluation and sum-marized the first clinical trials incorporating QOL in glioma treatment.}, } @article {pmid34099897, year = {2021}, author = {Moujalled, D and Strasser, A and Liddell, JR}, title = {Molecular mechanisms of cell death in neurological diseases.}, journal = {Cell death and differentiation}, volume = {28}, number = {7}, pages = {2029-2044}, pmid = {34099897}, issn = {1476-5403}, support = {101671/WT_/Wellcome Trust/United Kingdom ; 1020363//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 101671/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Autophagy ; Brain/pathology/*physiopathology ; Humans ; Neurodegenerative Diseases/pathology/*physiopathology/therapy ; Neurons/*pathology ; *Regulated Cell Death ; Signal Transduction ; }, abstract = {Tightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.}, } @article {pmid34101918, year = {2022}, author = {Shaat, MA and Bakry, NS and Elshafie, AM and Talaat, DM}, title = {Intranasal versus sublingual route of dexmedetomidine sedation in paediatric dentistry: A randomized controlled clinical trial.}, journal = {International journal of paediatric dentistry}, volume = {32}, number = {2}, pages = {232-239}, doi = {10.1111/ipd.12848}, pmid = {34101918}, issn = {1365-263X}, mesh = {Administration, Intranasal ; Child ; Procedural Sedation ; *Dexmedetomidine ; Humans ; Hypnotics and Sedatives ; Pediatric Dentistry ; }, abstract = {BACKGROUND: Many children experience dental anxiety during dental treatment. Conscious sedation is used to alleviate anxiety and enhance a child's cooperation.

AIM: This study aimed to compare the efficacy of intranasal versus sublingual dexmedetomidine.

DESIGN: Forty-two healthy, uncooperative children participated in the study. They were divided randomly into two groups: In the first visit, Group I received intranasal dexmedetomidine and group II received sublingual dexmedetomidine, whereas at the second visit, the alternate route was implemented in a crossover design. The child's acceptance of drug administration method was assessed using a 4-point rating scale. Time until optimum sedation was measured. Anxiety during local anesthesia administration was scored using Venham's rating scale. Postoperative response was recorded through Vernon et al's questionnaire.

RESULTS: The sublingual dexmedetomidine route was better accepted than the intranasal route (P=0.01), while the latter acted faster (P>0.001). No significant difference in anxiety scores was found between groups at baseline (P=0.84) or during local anesthetic administration (P=0.44). No negative effect was recorded by the parents who answered the Modified Vernon et al questionnaire 24 hour after the dental visit compared to before the dental visit (P=1.00).

CONCLUSIONS: Both routes prevented the increase in anxiety scores equally during local anesthesia and do not have negative effect on postoperative behavior of children. However, the sublingual route showed better acceptance with longer onset time of action than the intranasal route.}, } @article {pmid34102977, year = {2021}, author = {Kulkarni, NP and Vaidya, B and Narula, AS and Sharma, SS}, title = {Neuroprotective Potential of Caffeic Acid Phenethyl Ester (CAPE) in CNS Disorders: Mechanistic and Therapeutic Insights.}, journal = {Current neuropharmacology}, volume = {19}, number = {9}, pages = {1401-1415}, pmid = {34102977}, issn = {1875-6190}, support = {2019-2020-NPLC-SSSHARMA//Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India/ ; }, mesh = {Aged ; Anti-Inflammatory Agents ; Antioxidants/pharmacology/therapeutic use ; *Caffeic Acids/pharmacology/therapeutic use ; Humans ; *Phenylethyl Alcohol/analogs & derivatives/pharmacology/therapeutic use ; }, abstract = {Neurological disorders like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, traumatic brain injury (TBI), depression, and anxiety are responsible for thousands of deaths worldwide every year. With the increase in life expectancy, there has been a rise in the prevalence of these disorders. Age is one of the major risk factors for these neurological disorders, and with the aged population set to rise to 1.25 billion by 2050, there is a growing concern to look for new therapeutic molecules to treat age-related diseases. Caffeic acid phenethyl ester (CAPE) is a molecule obtained from a number of botanical sources, such as the bark of conifer trees as well as propolis which is extracted from beehives. Though CAPE remains relatively unexplored in human trials, it possesses antioxidant, anti-inflammatory, antimitogenic, and anti-cancer activities, as shown by preclinical studies. Apart from this, it also exhibits tremendous potential for the treatment of neurological disorders through the modulation of multiple molecular pathways and attenuation of behavioural deficits. In the present article, we have reviewed the therapeutic potential of CAPE and its mechanisms in the treatment of neurological disorders.}, } @article {pmid34111668, year = {2021}, author = {Matsuo, T and Adachi-Tominari, K and Sano, O and Kamei, T and Nogami, M and Ogi, K and Okano, H and Yano, M}, title = {Involvement of ferroptosis in human motor neuron cell death.}, journal = {Biochemical and biophysical research communications}, volume = {566}, number = {}, pages = {24-29}, doi = {10.1016/j.bbrc.2021.05.095}, pmid = {34111668}, issn = {1090-2104}, mesh = {Antioxidants/pharmacology ; *Cell Death/drug effects ; Cell Line ; Enzyme Inhibitors/pharmacology ; *Ferroptosis/drug effects ; Humans ; Motor Neurons/*cytology/drug effects ; Phospholipid Hydroperoxide Glutathione Peroxidase/antagonists & inhibitors ; }, abstract = {Ferroptosis was recently defined as a novel type of programmed cell death depending on iron and lipid peroxidation. It is biologically different from other types of cell death such as apoptosis. While the involvement of ferroptosis in cancer, patient and animal model have been intensely studied, ferroptosis in human motor neuron model is still clearly unknown. Here we carefully assessed ferroptosis using human iPS cell-derived motor neuron (hiMNs). We found that almost all hiMNs died by the treatment of glutathione peroxidase 4 (GPX4) inhibitors. Importantly, the cell death was rescued by one antioxidant, vitamin E acetate, iron chelators and lipid peroxidase inhibitors with high dynamic ranges. Finally, these data clearly indicated that ferroptosis constitutively occurs in hiMNs, suggesting the possibility that it might play a biologically and pathologically important roles in motor neuron death such as motor neuron disease (MND)/Amyotrophic lateral sclerosis (ALS).}, } @article {pmid34112310, year = {2021}, author = {Wang, X and Huang, S and Xia, Z and Yao, S and Xia, H}, title = {[Application progress of ultrasound monitoring of diaphragm function in clinic].}, journal = {Zhonghua wei zhong bing ji jiu yi xue}, volume = {33}, number = {5}, pages = {638-640}, doi = {10.3760/cma.j.cn121430-20200824-00591}, pmid = {34112310}, issn = {2095-4352}, mesh = {Airway Extubation ; Critical Care ; *Diaphragm/diagnostic imaging ; Humans ; *Respiration, Artificial ; Ultrasonography ; }, abstract = {In recent years, point of care ultrasound (POCUS) has developed rapidly in the fields of anesthesia and critical care. POCUS is widely used in clinic to monitor the function of human tissues and organs such as the heart, lungs, and diaphragm due to its visual, non-invasive, portable, and repeatable characters at the bedside. Diaphragm is an important structure to maintain respiratory function. Diaphragm paralysis or dysfunction can cause a significant decrease in inspiratory function. The patient's diaphragm function can be assessed through monitoring diaphragm thickness and activity by POCUS, and combined with other clinical indicators, the patient's recovery of respiratory function can be comprehensively evaluated, and rapidly identify the pathological conditions, such as diaphragm paralysis, diaphragm atrophy, diaphragmatic hypoplasia and amyotrophic lateral sclerosis. Dynamic evaluation of the process from diaphragmatic dysfunction to recovery can provide guidance for weaning and extubation, and real-time feedback on the treatment effect. This article reviews the ultrasound evaluation methods and clinical applications to the diaphragm, in order to guide clinicians to use relevant indicators to comprehensively evaluate the structure and function of the diaphragm, and then diagnose and treat diaphragm dysfunction, which may help making clinical decision.}, } @article {pmid34114267, year = {2021}, author = {Essendoubi, M and Alsamad, F and Noël, P and Meunier, M and Scandolera, A and Sandré, J and Manfait, M and Gobinet, C and Reynaud, R and Piot, O}, title = {Combining Raman imaging and MCR-ALS analysis for monitoring retinol permeation in human skin.}, journal = {Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)}, volume = {27}, number = {6}, pages = {1100-1109}, doi = {10.1111/srt.13069}, pmid = {34114267}, issn = {1600-0846}, mesh = {Humans ; Least-Squares Analysis ; Multivariate Analysis ; *Skin/diagnostic imaging ; Spectrum Analysis, Raman ; *Vitamin A ; }, abstract = {BACKGROUND: Monitoring the transcutaneous permeation of exogenous molecules using conventional techniques generally requires long pre-analytical preparation or labelling of samples. However, Raman spectroscopy is a label-free and non-destructive method which provides spatial distribution of tracked actives in skin. The aim of our study was to prove the interest of Raman imaging coupled with multivariate curve resolution alternating least square (MCR-ALS) analysis in monitoring retinol penetration into frozen and living human skin.

MATERIALS AND METHODS: After topical treatment of skin samples by free or encapsulated retinol, thin cross sections were analysed by Raman imaging (up to 100 µm depth). Mann-Whitney test was used to identify retinol spectroscopic markers in skin. MCR-ALS was used to estimate retinol contribution in Raman spectral images. Heat maps were constructed to compare the distribution of free and encapsulated retinol in skin models.

RESULTS: We identified the bands at 1158, 1196 and 1591 cm[-1] as specific features for monitoring retinol in skin. Moreover, our MCR-ALS results showed an improvement of retinol penetration (up to 30 µm depth) with the encapsulated form as well as storage reservoir formation in stratum corneum, for each skin model. Finally, greater retinol penetration into living skin was observed.

CONCLUSION: This study shows a proof of concept for the evaluation of retinol penetration in skin using Raman imaging coupled with MCR-ALS. This concept needs to be validated on more subjects to include inter-individual variability but also other factors affecting skin permeation (age, sex, pH, etc). Our study can be extended to other actives.}, } @article {pmid34115761, year = {2021}, author = {Sofela, S and Sahloul, S and Song, YA}, title = {Biophysical analysis of drug efficacy on C. elegans models for neurodegenerative and neuromuscular diseases.}, journal = {PloS one}, volume = {16}, number = {6}, pages = {e0246496}, pmid = {34115761}, issn = {1932-6203}, mesh = {*Caenorhabditis elegans/drug effects ; Animals ; *Disease Models, Animal ; *Neuromuscular Diseases/drug therapy/genetics ; Drug Evaluation, Preclinical/methods ; Neurodegenerative Diseases/drug therapy ; Muscular Dystrophy, Duchenne/drug therapy/genetics/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; Humans ; Parkinson Disease/drug therapy ; }, abstract = {Caenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping with the focus on morphological-descriptive traits not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical biophysical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with a fluorescence assay to evaluate the efficacy of various drugs currently used in treatment of neurodegenerative and neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson's Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neurodegenerative and neuromuscular diseases when combined with a fluorescence assay in a two-dimensional analysis approach.}, } @article {pmid34118305, year = {2021}, author = {Yang, S and Yang, H and Luo, Y and Deng, X and Zhou, Y and Hu, B}, title = {Long non-coding RNAs in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {148}, number = {}, pages = {105096}, doi = {10.1016/j.neuint.2021.105096}, pmid = {34118305}, issn = {1872-9754}, mesh = {Animals ; Biomarkers ; Humans ; Neurodegenerative Diseases/diagnosis/*genetics/therapy ; RNA, Long Noncoding/drug effects/*genetics ; }, abstract = {Neurodegenerative diseases are gradually becoming the main burden of society. The morbidity and mortality caused by neurodegenerative diseases remain significant health-care concerns. For most neurodegenerative diseases, there are no effective treatments. Over the past few decades, in a quest to exploit efficacious disease-modifying therapies for the treatment of neurodegenerative diseases, disease mechanisms, reliable biomarkers and therapeutic targets have become a research priority. At present, lncRNA is an area with potential research value. In this article, we first summarize some of the existing results of research into lncRNAs, including origin, molecular characteristics, location types, and functional types. We then introduce the possible functions of lncRNAs in different neurodegenerative diseases. Furthermore, some lncRNAs which show promise as biomarkers or potential therapeutic targets are systematically summarized.}, } @article {pmid34118929, year = {2021}, author = {Milani, M and Mammarella, E and Rossi, S and Miele, C and Lattante, S and Sabatelli, M and Cozzolino, M and D'Ambrosi, N and Apolloni, S}, title = {Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {18}, number = {1}, pages = {132}, pmid = {34118929}, issn = {1742-2094}, support = {SpliceALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/genetics/metabolism ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Fibroblasts/drug effects/metabolism ; Fibrosis/drug therapy/prevention & control ; Humans ; Inflammation/drug therapy/prevention & control ; Mice ; Mutation ; NF-kappa B/metabolism ; Niclosamide/*pharmacology/*therapeutic use ; RNA-Binding Protein FUS/genetics ; S100 Calcium-Binding Protein A4/*antagonists & inhibitors/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {BACKGROUND: An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.

METHODS: Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.

RESULTS: We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.

CONCLUSION: Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.}, } @article {pmid34121923, year = {2021}, author = {Soar, J and Böttiger, BW and Carli, P and Couper, K and Deakin, CD and Djärv, T and Lott, C and Olasveengen, T and Paal, P and Pellis, T and Perkins, GD and Sandroni, C and Nolan, JP}, title = {[Adult advanced life support].}, journal = {Notfall & rettungsmedizin}, volume = {24}, number = {4}, pages = {406-446}, pmid = {34121923}, issn = {1434-6222}, abstract = {These European Resuscitation Council Advanced Life Support guidelines are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. This section provides guidelines on the prevention of and ALS treatments for both in-hospital cardiac arrest and out-of-hospital cardiac arrest.}, } @article {pmid34122112, year = {2021}, author = {Zhu, FD and Hu, YJ and Yu, L and Zhou, XG and Wu, JM and Tang, Y and Qin, DL and Fan, QZ and Wu, AG}, title = {Nanoparticles: A Hope for the Treatment of Inflammation in CNS.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {683935}, pmid = {34122112}, issn = {1663-9812}, abstract = {Neuroinflammation, an inflammatory response within the central nervous system (CNS), is a main hallmark of common neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others. The over-activated microglia release pro-inflammatory cytokines, which induces neuronal death and accelerates neurodegeneration. Therefore, inhibition of microglia over-activation and microglia-mediated neuroinflammation has been a promising strategy for the treatment of neurodegenerative diseases. Many drugs have shown promising therapeutic effects on microglia and inflammation. However, the blood-brain barrier (BBB)-a natural barrier preventing brain tissue from contact with harmful plasma components-seriously hinders drug delivery to the microglial cells in CNS. As an emerging useful therapeutic tool in CNS-related diseases, nanoparticles (NPs) have been widely applied in biomedical fields for use in diagnosis, biosensing and drug delivery. Recently, many NPs have been reported to be useful vehicles for anti-inflammatory drugs across the BBB to inhibit the over-activation of microglia and neuroinflammation. Therefore, NPs with good biodegradability and biocompatibility have the potential to be developed as an effective and minimally invasive carrier to help other drugs cross the BBB or as a therapeutic agent for the treatment of neuroinflammation-mediated neurodegenerative diseases. In this review, we summarized various nanoparticles applied in CNS, and their mechanisms and effects in the modulation of inflammation responses in neurodegenerative diseases, providing insights and suggestions for the use of NPs in the treatment of neuroinflammation-related neurodegenerative diseases.}, } @article {pmid34125534, year = {2021}, author = {P, P and Justin, A and Ananda Kumar, TD and Chinaswamy, M and Kumar, BRP}, title = {Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {13}, pages = {2261-2272}, doi = {10.1021/acschemneuro.1c00085}, pmid = {34125534}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; PPAR gamma ; *Parkinson Disease/drug therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Quality of Life ; *Thiazolidinediones ; }, abstract = {Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects. Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.}, } @article {pmid34130902, year = {2021}, author = {Cullell, N and Cárcel-Márquez, J and Gallego-Fábrega, C and Muiño, E and Llucià-Carol, L and Lledós, M and Amaut, KEU and Krupinski, J and Fernández-Cadenas, I}, title = {Sleep/wake cycle alterations as a cause of neurodegenerative diseases: A Mendelian randomization study.}, journal = {Neurobiology of aging}, volume = {106}, number = {}, pages = {320.e1-320.e12}, doi = {10.1016/j.neurobiolaging.2021.05.008}, pmid = {34130902}, issn = {1558-1497}, mesh = {Alzheimer Disease ; Amyotrophic Lateral Sclerosis ; Female ; *Genome-Wide Association Study ; Humans ; Male ; Mendelian Randomization Analysis/*methods ; Neurodegenerative Diseases/*etiology/*genetics/physiopathology/psychology ; Parkinson Disease ; Risk ; Sleep/*physiology ; Sleepiness/*physiology ; Wakefulness/*physiology ; }, abstract = {Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N = 17,996), AD (N = 21,235) and ALS (N = 40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p = 8.47×10[-09] and 95%CI:-7.28 to -4.44, p = 5.87×10[-16], respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p = 0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p = 0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS.}, } @article {pmid34131680, year = {2021}, author = {Zubair, A and Waheed, S and Shuja, F}, title = {Psychological impact of cadaveric dissection on first-year medical students.}, journal = {The journal of the Royal College of Physicians of Edinburgh}, volume = {51}, number = {2}, pages = {173-176}, doi = {10.4997/JRCPE.2021.419}, pmid = {34131680}, issn = {2042-8189}, mesh = {Anxiety/etiology ; Cadaver ; Cross-Sectional Studies ; Dissection ; Humans ; Pakistan ; Stress, Psychological/etiology ; *Students, Medical ; }, abstract = {BACKGROUND: This cross-sectional study was carried out to ascertain if first-time cadaver dissections can cause acute stress disorder (ASD) in medical students, and if death anxiety and gender play a role in the development of these symptoms.

METHODS: A total of 135 first-year medical students at the Services Institute of Medical Sciences and King Edward Medical University, Lahore, Pakistan, who had recently conducted their first ever cadaver dissection filled out three scales: the Impact of Event Scale-Revised (IES-R), the Appraisal of Life Scale (Revised) (ALS-R) and Death Anxiety Inventory. The results were then calculated via SPSS v.23. Any students with a history of psychiatric treatment or disorder were not included in the study.

RESULTS: Scores on the IES-R showed that the sample suffered from symptoms of ASD (mean = 36.15, standard deviation = 15.99). Multilinear regression showed that death anxiety did not predict any variance on the scores for IES-R, whereas higher scores on the ALS-R threat domain scale predicted higher scores on the IES-R. Death anxiety had little to no impact on the scores for IES-R.

CONCLUSIONS: Results showed that students who perceived the dissection situation as threatening and anxiety inducing were more likely to test positively for ASD symptoms. A major limitation of the study was that it did not measure whether these symptoms reduced with repeated exposure to cadaver dissection or how symptoms changed over time.}, } @article {pmid34138412, year = {2022}, author = {De Nicola, AF and Meyer, M and Garay, L and Kruse, MS and Schumacher, M and Guennoun, R and Gonzalez Deniselle, MC}, title = {Progesterone and Allopregnanolone Neuroprotective Effects in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Cellular and molecular neurobiology}, volume = {42}, number = {1}, pages = {23-40}, pmid = {34138412}, issn = {1573-6830}, support = {PIP 112 20120100016//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; 20020100100062//Universidad de Buenos Aires/ ; 2002010010008//Universidad de Buenos Aires/ ; PICT2012-0009//Ministry of Science and Technology/ ; PICT 2019 3292//Ministry of Science and Technology/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; Disease Models, Animal ; Mice ; Motor Neurons ; *Neuroprotective Agents/metabolism/pharmacology/therapeutic use ; Pregnanolone/metabolism/pharmacology/therapeutic use ; Progesterone/metabolism/pharmacology/therapeutic use ; Spinal Cord/metabolism ; }, abstract = {Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.}, } @article {pmid34138531, year = {2021}, author = {Santur, K and Reinartz, E and Lien, Y and Tusche, M and Altendorf, T and Sevenich, M and Tamgüney, G and Mohrlüder, J and Willbold, D}, title = {Ligand-Induced Stabilization of the Native Human Superoxide Dismutase 1.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {13}, pages = {2520-2528}, doi = {10.1021/acschemneuro.1c00253}, pmid = {34138531}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Ligands ; Motor Neurons ; Mutation/genetics ; *Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {A common characteristic of familial (fALS) and sporadic amyotrophic lateral sclerosis (sALS) is the accumulation of aberrant proteinaceous species in the motor neurons and spinal cord of ALS patients-including aggregates of the human superoxide dismutase 1 (hSOD1). hSOD1 is an enzyme that occurs as a stable dimeric protein with several post-translational modifications such as the formation of an intramolecular disulfide bond and the acquisition of metal cofactors that are essential for enzyme activity and further contribute to protein stability. Some mutations and/or destabilizing factors promote hSOD1 misfolding, causing neuronal death. Aggregates containing misfolded wild-type hSOD1 have been found in the spinal cords of sALS as well as in non-hSOD1 fALS patients, leading to the hypothesis that hSOD1 misfolding is a common part of the ALS pathomechanism. Therefore, stabilizing the native conformation of SOD1 may be a promising approach to prevent the formation of toxic hSOD1 species and thus ALS pathogenesis. Here, we present the 16-mer peptide S1VL-21 that interferes with hSOD1 aggregation. S1VL-21 was identified by phage display selection with the native conformation of hSOD1 as a target. Several methods such as microscale thermophoresis (MST) measurements, aggregation assays, and cell viability assays revealed that S1VL-21 has a micromolar binding affinity to native hSOD1 and considerably reduces the formation of hSOD1 aggregates. This present work therefore provides the first important data on a potential lead compound for hSOD1-related drug development for ALS therapy.}, } @article {pmid34139704, year = {2021}, author = {Parra-Cantu, C and Zaldivar-Ruenes, A and Martinez-Vazquez, M and Martinez, HR}, title = {Prevalence of Gastrointestinal Symptoms, Severity of Dysphagia, and Their Correlation with Severity of Amyotrophic Lateral Sclerosis in a Mexican Cohort.}, journal = {Neuro-degenerative diseases}, volume = {21}, number = {1-2}, pages = {42-47}, doi = {10.1159/000517613}, pmid = {34139704}, issn = {1660-2862}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Deglutition Disorders/diagnosis/epidemiology/etiology ; Disease Progression ; Humans ; Prevalence ; Quality of Life ; Severity of Illness Index ; }, abstract = {OBJECTIVES: Our study aimed to identify the prevalence and severity of gastrointestinal (GI) symptoms and dysphagia in patients with amyotrophic lateral sclerosis (ALS) and to assess whether a correlation exists between these symptoms and the severity of ALS progression.

METHODS: The presence and severity of GI symptoms and dysphagia were identified by means of the Gastrointestinal Symptom Rating Scale (GSRS) and the Functional Outcome Swallowing Scale (FOSS). The Revised ALS Functional Rating Scale (ALSFRS-R) was utilized to determine the severity of ALS. Analysis of data was performed with Spearman correlations in semi-qualitative variables of clinical scales. ALSFRS-R scores were divided into 2 categories: those with mild to moderate ALS (≥40-30 points) and patients with moderate to advanced ALS (29-≤20 points).

RESULTS: We studied 43 patients with definite ALS. The most frequent GI symptoms were constipation (60.5%), rectal tenesmus (57.5%), hard stools (55.0%), and borborygmus (42.5%). The moderate to advanced ALS stage was correlated with constipation (r = 0.334; p = 0.028), acid regurgitation (r = 0.384; p = 0.013), eructation (r = 0.334; p = 0.032), rectal tenesmus (r = 0.498; p = 0.001), and functional dysphagia (r = 0.656; p = <0.001).

CONCLUSIONS: Early detection of these GI symptoms can guide timely therapeutic decisions to avoid weight loss, a predictor for worse prognosis. This study highlights the relevance of the detection of these symptoms in ALS patients who score ≤29 points in the ALSFRS-R scale to establish an appropriate treatment, prevent systemic complications, provide more comfort, and improve quality of life.}, } @article {pmid34145880, year = {2021}, author = {Matthews, DC and Mao, X and Dowd, K and Tsakanikas, D and Jiang, CS and Meuser, C and Andrews, RD and Lukic, AS and Lee, J and Hampilos, N and Shafiian, N and Sano, M and David Mozley, P and Fillit, H and McEwen, BS and Shungu, DC and Pereira, AC}, title = {Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease.}, journal = {Brain : a journal of neurology}, volume = {144}, number = {12}, pages = {3742-3755}, pmid = {34145880}, issn = {1460-2156}, support = {R01 AG063819/AG/NIA NIH HHS/United States ; K76 AG054772/AG/NIA NIH HHS/United States ; R01 MH075895/MH/NIMH NIH HHS/United States ; UL1 TR001866/TR/NCATS NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R01 AG064020/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy/metabolism ; Brain/*drug effects/metabolism ; Double-Blind Method ; Female ; Glucose/*metabolism ; Humans ; Male ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Riluzole/*therapeutic use ; }, abstract = {Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer's disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of ageing and Alzheimer's disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer's disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer's disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, 50 participants who met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary end points were baseline to 6 months changes in (i) cerebral glucose metabolism as measured with fluorodeoxyglucose-PET in prespecified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal); and (ii) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer's disease biomarker and predictor of disease progression, declined significantly less in several prespecified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated participants in comparison to the placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group × visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and provide a rationale for more powered, longer duration studies of riluzole as a potential intervention for Alzheimer's disease.}, } @article {pmid34153344, year = {2021}, author = {De Marchi, F and Munitic, I and Amedei, A and Berry, JD and Feldman, EL and Aronica, E and Nardo, G and Van Weehaeghe, D and Niccolai, E and Prtenjaca, N and Sakowski, SA and Bendotti, C and Mazzini, L}, title = {Interplay between immunity and amyotrophic lateral sclerosis: Clinical impact.}, journal = {Neuroscience and biobehavioral reviews}, volume = {127}, number = {}, pages = {958-978}, pmid = {34153344}, issn = {1873-7528}, support = {R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Immune System ; *Neurodegenerative Diseases ; Positron-Emission Tomography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease. Despite decades of research and many new insights into disease biology over the 150 years since the disease was first described, causative pathogenic mechanisms in ALS remain poorly understood, especially in sporadic cases. Our understanding of the role of the immune system in ALS pathophysiology, however, is rapidly expanding. The aim of this manuscript is to summarize the recent advances regarding the immune system involvement in ALS, with particular attention to clinical translation. We focus on the potential pathophysiologic mechanism of the immune system in ALS, discussing local and systemic factors (blood, cerebrospinal fluid, and microbiota) that influence ALS onset and progression in animal models and people. We also explore the potential of Positron Emission Tomography to detect neuroinflammation in vivo, and discuss ongoing clinical trials of therapies targeting the immune system. With validation in human patients, new evidence in this emerging field will serve to identify novel therapeutic targets and provide realistic hope for personalized treatment strategies.}, } @article {pmid34156104, year = {2021}, author = {Serruya, MD and Rosenwasser, RH}, title = {An artificial nervous system to treat chronic stroke.}, journal = {Artificial organs}, volume = {45}, number = {8}, pages = {804-812}, doi = {10.1111/aor.13998}, pmid = {34156104}, issn = {1525-1594}, mesh = {Animals ; Brain-Computer Interfaces ; Chronic Disease ; Humans ; Nerve Transfer ; Neurofeedback ; Neuronal Plasticity ; Prostheses and Implants ; Recovery of Function ; Stroke Rehabilitation/*methods ; Wearable Electronic Devices ; }, abstract = {Despite remarkable advances in the treatment of numerous medical conditions, neurological disease and injury remains an outstanding challenge and cause of disability worldwide. The decreased regenerative capacity and extreme complexity and heterogeneity of nervous tissue, in particular the brain, and the fact that the brain remains the least understood organ, have hampered our ability to provide definitive treatments for prevalent conditions such as stroke. Stroke is the second-leading cause of death worldwide, and the nervous system is intimately involved in other prevalent conditions including ischemic heart disease, diabetes mellitus, and hypertension. Advances in neuromodulation, electroceuticals, microsurgical techniques, optogenetics, brain-computer interfaces, and autologous constructs offer potential solutions to address the otherwise permanent neurological deficits of stroke and other conditions. Here we review these various approaches to build an "artificial nervous system" that could restore function and independence in people living with these conditions. We focus on stroke both because it is the leading cause of neurological disability worldwide and because we anticipate that advances in the reversal of stroke-related deficits will have ripple effects benefiting people with other neurological conditions including spinal cord injury, traumatic brain injury, ALS, and muscular dystrophy.}, } @article {pmid34158851, year = {2021}, author = {Li, X and Chen, C and Zhan, X and Li, B and Zhang, Z and Li, S and Xie, Y and Song, X and Shen, Y and Liu, J and Liu, P and Liu, GP and Yang, X}, title = {R13 preserves motor performance in SOD1[G93A] mice by improving mitochondrial function.}, journal = {Theranostics}, volume = {11}, number = {15}, pages = {7294-7307}, pmid = {34158851}, issn = {1838-7640}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/enzymology/genetics/physiopathology ; Animals ; Central Nervous System/*enzymology ; Flavones/*pharmacology ; Humans ; Mice ; Mice, Transgenic ; *Mitochondria/enzymology/genetics ; *Motor Activity/drug effects/genetics ; *Superoxide Dismutase/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS. Methods: In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1[G93A] mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1. Results: Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1[G93A] mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1[G93A] mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1. Conclusions: These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.}, } @article {pmid34160014, year = {2021}, author = {Wall, JM and Basu, A and Zunica, ERM and Dubuisson, OS and Pergola, K and Broussard, JP and Kirwan, JP and Axelrod, CL and Johnson, AE}, title = {CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases.}, journal = {Disease models & mechanisms}, volume = {14}, number = {7}, pages = {}, pmid = {34160014}, issn = {1754-8411}, support = {K99 NS100988/NS/NINDS NIH HHS/United States ; R00 NS100988/NS/NINDS NIH HHS/United States ; R35 GM138116/GM/NIGMS NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Animals ; CRISPR-Cas Systems/genetics ; Cell Cycle Proteins/genetics/metabolism ; Disease Models, Animal ; *Drosophila ; Female ; Humans ; Male ; Mutation/genetics ; Valosin Containing Protein/genetics/metabolism ; }, abstract = {Mutations in Valosin Containing Protein (VCP) are associated with several degenerative diseases, including multisystem proteinopathy (MSP-1) and amyotrophic lateral sclerosis. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. A deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. Our models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including nuclear morphology defects and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models generated in this study will be useful for studying the etiology of individual VCP patient mutations and testing potential genetic and/or pharmacological therapies.}, } @article {pmid34169068, year = {2021}, author = {Ding, Q and Chaplin, J and Morris, MJ and Hilliard, MA and Wolvetang, E and Ng, DCH and Noakes, PG}, title = {TDP-43 Mutation Affects Stress Granule Dynamics in Differentiated NSC-34 Motoneuron-Like Cells.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {611601}, pmid = {34169068}, issn = {2296-634X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is characterized by degeneration of motor neurons in the brain and spinal cord. Cytoplasmic inclusions of TDP-43 are frequently reported in motor neurons of ALS patients. TDP-43 has also been shown to associate with stress granules (SGs), a complex of proteins and mRNAs formed in response to stress stimuli that temporarily sequester mRNA translation. The effect of pathogenic TDP-43 mutations within glycine-rich regions (where the majority of ALS-causing TDP-43 mutations occur) on SG dynamics in motor neurons is poorly understood. To address this issue, we generated murine NSC-34 cell lines that stably over-express wild type TDP-43 (TDP-43 [W T]) or mutant forms (ALS-causing TDP-43 mutations TDP-43 [A315T] or TDP-43 [M337V]). We then differentiated these NSC-34 lines into motoneuron-like cells and evaluated SG formation and disassembly kinetics in response to oxidative or osmotic stress treatment. Wild type and mutant TDP-43 appeared to be largely retained in the nucleus following exposure to arsenite-induced oxidative stress. Upon arsenite removal, mutant TDP-43 clearly accumulated within HuR positive SGs in the cytoplasm, whereas TDP-43 [W T] remained mostly within the nucleus. 24 h following arsenite removal, all SGs were disassembled in both wild type and mutant TDP-43 expressing cells. By contrast, we observed significant differences in the dynamics of mutant TDP-43 association with SGs in response to hyperosmotic stress. Specifically, in response to sorbitol treatment, TDP-43 [W T] remained in the nucleus, whereas mutant TDP-43 relocalized to HuR positive SGs in the cytoplasm following exposure to sorbitol stress, resulting in a significant increase in TDP-43 SG numbers. These SGs remained assembled for 24 h following removal of sorbitol. Our data reveal that under certain stress conditions the rates of SG formation and disassembly is modulated by TDP-43 mutations associated with ALS, and suggest that this may be an early event in the seeding of insoluble cytoplasmic inclusions observed in ALS.}, } @article {pmid34175843, year = {2021}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.}, journal = {Neuroimmunomodulation}, volume = {28}, number = {4}, pages = {204-212}, doi = {10.1159/000516926}, pmid = {34175843}, issn = {1423-0216}, mesh = {*Amyotrophic Lateral Sclerosis ; Animals ; Humans ; Motor Neurons ; Neuroglia ; Spinal Cord ; Superoxide Dismutase ; }, abstract = {ALS is a human neurodegenerative disorder that induces a progressive paralysis of voluntary muscles due to motor neuron loss. The causes are unknown, and there is no curative treatment available. Mitochondrial dysfunction is a hallmark of ALS pathology; however, it is currently unknown whether it is a cause or a consequence of disease progression. Recent evidence indicates that glial mitochondrial function changes to cope with energy demands and critically influences neuronal death and disease progression. Aberrant glial cells detected in the spinal cord of diseased animals are characterized by increased proliferation rate and reduced mitochondrial bioenergetics. These features can be compared with cancer cell behavior of adapting to nutrient microenvironment by altering energy metabolism, a concept known as metabolic reprogramming. We focus on data that suggest that aberrant glial cells in ALS undergo metabolic reprogramming and profound changes in glial mitochondrial activity, which are associated with motor neuron death in ALS. This review article emphasizes on the association between metabolic reprogramming and glial reactivity, bringing new paradigms from the area of cancer research into neurodegenerative diseases. Targeting glial mitochondrial function and metabolic reprogramming may result in promising therapeutic strategies for ALS.}, } @article {pmid34179015, year = {2021}, author = {Desole, C and Gallo, S and Vitacolonna, A and Montarolo, F and Bertolotto, A and Vivien, D and Comoglio, P and Crepaldi, T}, title = {HGF and MET: From Brain Development to Neurological Disorders.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {683609}, pmid = {34179015}, issn = {2296-634X}, abstract = {Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, encoded by the MET cellular proto-oncogene, are expressed in the nervous system from pre-natal development to adult life, where they are involved in neuronal growth and survival. In this review, we highlight, beyond the neurotrophic action, novel roles of HGF-MET in synaptogenesis during post-natal brain development and the connection between deregulation of MET expression and developmental disorders such as autism spectrum disorder (ASD). On the pharmacology side, HGF-induced MET activation exerts beneficial neuroprotective effects also in adulthood, specifically in neurodegenerative disease, and in preclinical models of cerebral ischemia, spinal cord injuries, and neurological pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). HGF is a key factor preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms. Recent evidence suggests that HGF acts on neural stem cells to enhance neuroregeneration. The possible therapeutic application of HGF and HGF mimetics for the treatment of neurological disorders is discussed.}, } @article {pmid34179845, year = {2021}, author = {Mencattini, A and Spalloni, A and Casti, P and Comes, MC and Di Giuseppe, D and Antonelli, G and D'Orazio, M and Filippi, J and Corsi, F and Isambert, H and Di Natale, C and Longone, P and Martinelli, E}, title = {NeuriTES. Monitoring neurite changes through transfer entropy and semantic segmentation in bright-field time-lapse microscopy.}, journal = {Patterns (New York, N.Y.)}, volume = {2}, number = {6}, pages = {100261}, pmid = {34179845}, issn = {2666-3899}, abstract = {One of the most challenging frontiers in biological systems understanding is fluorescent label-free imaging. We present here the NeuriTES platform that revisits the standard paradigms of video analysis to detect unlabeled objects and adapt to the dynamic evolution of the phenomenon under observation. Object segmentation is reformulated using robust algorithms to assure regular cell detection and transfer entropy measures are used to study the inter-relationship among the parameters related to the evolving system. We applied the NeuriTES platform to the automatic analysis of neurites degeneration in presence of amyotrophic lateral sclerosis (ALS) and to the study of the effects of a chemotherapy drug on living prostate cancer cells (PC3) cultures. Control cells have been considered in both the two cases study. Accuracy values of 93% and of 92% are achieved, respectively. NeuriTES not only represents a tool for investigation in fluorescent label-free images but demonstrates to be adaptable to individual needs.}, } @article {pmid34182195, year = {2021}, author = {Samara, VC and Jerant, P and Gibson, S and Bromberg, M}, title = {Bowel, bladder, and sudomotor symptoms in ALS patients.}, journal = {Journal of the neurological sciences}, volume = {427}, number = {}, pages = {117543}, doi = {10.1016/j.jns.2021.117543}, pmid = {34182195}, issn = {1878-5883}, mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Constipation/epidemiology/etiology ; Humans ; Quality of Life ; *Urinary Bladder, Overactive/diagnosis/epidemiology/etiology ; }, abstract = {OBJECTIVES: To describe prevalence rates of bowel, bladder, and sudomotor symptoms in patients with amyotrophic lateral sclerosis (ALS) in relation to disease onset and progression. Treatment strategies and efficacies were also assessed.

METHODS: A pilot patient cohort revealed increased incidences of bowel/bladder and sudomotor symptoms. Questionnaires derived from formal bowel and bladder survey instruments were administered to a second cohort of patients during multidisciplinary ALS clinic visits.

RESULTS: The pilot cohort of 30 patients reported an increase in bowel symptoms from 17% prior to 70% after the diagnosis of ALS, and an increase in urinary symptoms from 24% to 76%. In the second cohort of 66 patients an increase in constipation from 33% prior to 64.7% after the diagnosis of ALS was reported. 25.4% of patients reported bowel urgency initially, which increased to 33.3% over time. Constipation was most commonly treated with docusate, dietary fiber supplementation, fluid/exercise, and polyethylene glycol. In the second cohort the prevalence of overactive bladder symptoms increased from 3.1% prior to 25.0% after the diagnosis of ALS. Urinary symptoms are most commonly treated with catheters and oxybutynin. A sudomotor survey found stinging eyes in 17.2% of patients, oily/greasy skin in 14.1% of patients, and flaking of the skin in 29.7% of patients.

CONCLUSIONS: Bowel and bladder symptoms are common in the ALS population and respond to treatment. Sudomotor symptoms are also common. Inquiring about these symptoms at clinic visits and initiating treatment can significantly improve the patients' quality of life.}, } @article {pmid34182408, year = {2021}, author = {van den Boom, M and Miller, KJ and Gregg, NM and Ojeda Valencia, G and Lee, KH and Richner, TJ and Ramsey, NF and Worrell, GA and Hermes, D}, title = {Typical somatomotor physiology of the hand is preserved in a patient with an amputated arm: An ECoG case study.}, journal = {NeuroImage. Clinical}, volume = {31}, number = {}, pages = {102728}, pmid = {34182408}, issn = {2213-1582}, support = {KL2 TR002379/TR/NCATS NIH HHS/United States ; R01 MH122258/MH/NIMH NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R01 MH111417/MH/NIMH NIH HHS/United States ; R01 NS092882/NS/NINDS NIH HHS/United States ; }, mesh = {*Arm ; Electrocorticography ; Electroencephalography ; Hand ; Humans ; *Motor Cortex ; Movement ; }, abstract = {Electrophysiological signals in the human motor system may change in different ways after deafferentation, with some studies emphasizing reorganization while others propose retained physiology. Understanding whether motor electrophysiology is retained over longer periods of time can be invaluable for patients with paralysis (e.g. ALS or brainstem stroke) when signals from sensorimotor areas may be used for communication or control over neural prosthetic devices. In addition, a maintained electrophysiology can potentially benefit the treatment of phantom limb pains through prolonged use of these signals in a brain-machine interface (BCI). Here, we were presented with the unique opportunity to investigate the physiology of the sensorimotor cortex in a patient with an amputated arm using electrocorticographic (ECoG) measurements. While implanted with an ECoG grid for clinical evaluation of electrical stimulation for phantom limb pain, the patient performed attempted finger movements with the contralateral (lost) hand and executed finger movements with the ipsilateral (healthy) hand. The electrophysiology of the sensorimotor cortex contralateral to the amputated hand remained very similar to that of hand movement in healthy people, with a spatially focused increase of high-frequency band (65-175 Hz; HFB) power over the hand region and a distributed decrease in low-frequency band (15-28 Hz; LFB) power. The representation of the three different fingers (thumb, index and little) remained intact and HFB patterns could be decoded using support vector learning at single-trial classification accuracies of >90%, based on the first 1-3 s of the HFB response. These results indicate that hand representations are largely retained in the motor cortex. The intact physiological response of the amputated hand, the high distinguishability of the fingers and fast temporal peak are encouraging for neural prosthetic devices that target the sensorimotor cortex.}, } @article {pmid34183988, year = {2021}, author = {Pervin, Z and Stephen, JM}, title = {Effect of alcohol on the central nervous system to develop neurological disorder: pathophysiological and lifestyle modulation can be potential therapeutic options for alcohol-induced neurotoxication.}, journal = {AIMS neuroscience}, volume = {8}, number = {3}, pages = {390-413}, pmid = {34183988}, issn = {2373-7972}, abstract = {The central nervous system (CNS) is the major target for adverse effects of alcohol and extensively promotes the development of a significant number of neurological diseases such as stroke, brain tumor, multiple sclerosis (MS), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Excessive alcohol consumption causes severe neuro-immunological changes in the internal organs including irreversible brain injury and it also reacts with the defense mechanism of the blood-brain barrier (BBB) which in turn leads to changes in the configuration of the tight junction of endothelial cells and white matter thickness of the brain. Neuronal injury associated with malnutrition and oxidative stress-related BBB dysfunction may cause neuronal degeneration and demyelination in patients with alcohol use disorder (AUD); however, the underlying mechanism still remains unknown. To address this question, studies need to be performed on the contributing mechanisms of alcohol on pathological relationships of neurodegeneration that cause permanent neuronal damage. Moreover, alcohol-induced molecular changes of white matter with conduction disturbance in neurotransmission are a likely cause of myelin defect or axonal loss which correlates with cognitive dysfunctions in AUD. To extend our current knowledge in developing a neuroprotective environment, we need to explore the pathophysiology of ethanol (EtOH) metabolism and its effect on the CNS. Recent epidemiological studies and experimental animal research have revealed the association between excessive alcohol consumption and neurodegeneration. This review supports an interdisciplinary treatment protocol to protect the nervous system and to improve the cognitive outcomes of patients who suffer from alcohol-related neurodegeneration as well as clarify the pathological involvement of alcohol in causing other major neurological disorders.}, } @article {pmid34187257, year = {2022}, author = {Bedlack, R and Barkhaus, P and Carter, G and Crayle, J and Mcdermott, C and Pattee, G and Polak, M and Salmon, K and Wicks, P}, title = {ALSUntangled #62: vitamin C.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {476-479}, doi = {10.1080/21678421.2021.1946088}, pmid = {34187257}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; *Ascorbic Acid/therapeutic use ; Clinical Trials as Topic ; Dietary Supplements ; Humans ; Treatment Outcome ; *Vitamins/therapeutic use ; }, abstract = {Vitamin C is one of the most common supplements taken by people with ALS. As an antioxidant, it has a plausible mechanism for slowing disease progression and there are some flawed pre-clinical studies and case reports suggesting benefit. However, a small human trial showed no benefit. Given this negative trial, we do not currently advise vitamin C as an ALS treatment.}, } @article {pmid34191081, year = {2022}, author = {Aizawa, H and Kato, H and Oba, K and Kawahara, T and Okubo, Y and Saito, T and Naito, M and Urushitani, M and Tamaoka, A and Nakamagoe, K and Ishii, K and Kanda, T and Katsuno, M and Atsuta, N and Maeda, Y and Nagai, M and Nishiyama, K and Ishiura, H and Toda, T and Kawata, A and Abe, K and Yabe, I and Takahashi-Iwata, I and Sasaki, H and Warita, H and Aoki, M and Sobue, G and Mizusawa, H and Matsuyama, Y and Haga, T and Kwak, S}, title = {Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {269}, number = {2}, pages = {885-896}, pmid = {34191081}, issn = {1432-1459}, support = {CCT-B-2804//Japan Agency for Medical Research and Development/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Nitriles ; Pyridones/adverse effects ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS).

METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment.

RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483).

CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.}, } @article {pmid34193885, year = {2021}, author = {Area-Gomez, E and Larrea, D and Yun, T and Xu, Y and Hupf, J and Zandkarimi, F and Chan, RB and Mitsumoto, H}, title = {Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13562}, pmid = {34193885}, issn = {2045-2322}, support = {R01 AG056387/AG/NIA NIH HHS/United States ; K01 AG045335/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Biomarkers/blood ; Female ; Humans ; *Lipidomics ; Lipids/*blood ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {Motor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.}, } @article {pmid34194298, year = {2021}, author = {Zhu, X and Zhang, Y and Yang, X and Hao, C and Duan, H}, title = {Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {618171}, pmid = {34194298}, issn = {1662-5099}, abstract = {The pathogenesis of neurodegenerative diseases (NDDs) is complex and diverse. Over the decades, our understanding of NDD has been limited to pathological features. However, recent advances in gene sequencing have facilitated elucidation of NDD at a deeper level. Gene editing techniques have uncovered new genetic links to phenotypes, promoted the development of novel treatment strategies and equipped researchers with further means to construct effective cell and animal models. The current review describes the history of evolution of gene editing tools, with the aim of improving overall understanding of this technology, and focuses on the four most common NDD disorders to demonstrate the potential future applications and research directions of gene editing.}, } @article {pmid34202494, year = {2021}, author = {Yang, X and Ji, Y and Wang, W and Zhang, L and Chen, Z and Yu, M and Shen, Y and Ding, F and Gu, X and Sun, H}, title = {Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {7}, pages = {}, pmid = {34202494}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.}, } @article {pmid34207859, year = {2021}, author = {Quessada, C and Bouscary, A and René, F and Valle, C and Ferri, A and Ngo, ST and Loeffler, JP}, title = {Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?.}, journal = {Cells}, volume = {10}, number = {6}, pages = {}, pmid = {34207859}, issn = {2073-4409}, mesh = {Amyotrophic Lateral Sclerosis/*metabolism ; Animals ; Humans ; Male ; Muscle, Skeletal/*metabolism/pathology ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose-fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.}, } @article {pmid34208136, year = {2021}, author = {Sindona, C and Schepici, G and Contestabile, V and Bramanti, P and Mazzon, E}, title = {NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {57}, number = {6}, pages = {}, pmid = {34208136}, issn = {1648-9144}, support = {//Ministero della Salute/ ; }, mesh = {*Coronavirus Infections ; Humans ; *Neurodegenerative Diseases ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {Coronavirus disease 2019 (COVID-19) is a rapidly spreading contagious infectious disease caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that primarily affects the respiratory tract as well as the central nervous system (CNS). SARS-CoV-2 infection occurs through the interaction of the viral protein Spike with the angiotensin II receptor (ACE 2), leading to an increase of angiotensin II and activation of nicotinamide adenine dinucleotide phosphate oxidase2 (NOX2), resulting in the release of both reactive oxygen species (ROS) and inflammatory molecules. The purpose of the review is to explain that SARS-CoV-2 infection can determine neuroinflammation that induces NOX2 activation in microglia. To better understand the role of NOX2 in inflammation, an overview of its involvement in neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) is provided. To write this manuscript, we performed a PubMed search to evaluate the possible relationship of SARS-CoV-2 infection in NOX2 activation in microglia, as well as the role of NOX2 in NDs. Several studies highlighted that NOX2 activation in microglia amplifies neuroinflammation. To date, there is no clinical treatment capable of counteracting its activation, however, NOX2 could be a promising pharmaceutical target useful for both the treatment and prevention of NDs and COVID-19 treatment.}, } @article {pmid34209129, year = {2021}, author = {Post, J and Schaffrath, A and Gering, I and Hartwig, S and Lehr, S and Shah, NJ and Langen, KJ and Willbold, D and Kutzsche, J and Willuweit, A}, title = {Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1[G93A] Transgenic Mice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {13}, pages = {}, pmid = {34209129}, issn = {1422-0067}, support = {20-64-46027//Russian Science Foundation/ ; Technology Transfer Fund//Forschungszentrum Jülich/ ; Portfolio Drug Research//Impuls und Vernetzungs-Fonds der Helmholtzgemeinschaft/ ; }, mesh = {Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy/enzymology/genetics/pathology ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/*enzymology/pathology ; Peptides ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1[G93A] mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1[G93A] mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1[G93A] mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1[G93A] mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1[G93A] mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment.}, } @article {pmid34209688, year = {2021}, author = {Niccolai, E and Di Pilato, V and Nannini, G and Baldi, S and Russo, E and Zucchi, E and Martinelli, I and Menicatti, M and Bartolucci, G and Mandrioli, J and Amedei, A}, title = {The Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity?.}, journal = {Biomedicines}, volume = {9}, number = {7}, pages = {}, pmid = {34209688}, issn = {2227-9059}, support = {RF-2016-02361616//Ministero della Salute/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with an unknown etiology and no effective treatment, and is characterized by large phenotypic heterogeneity, including variable sites, ages of symptom onset and rates of disease progression. Increasing data support the role of the microbiota-immunity axis in the pathogenesis of neurodegenerative diseases. In the present study, we compared the inflammatory and microbiota profile of ALS patients with different clinical characteristics, with healthy family caregivers. Measuring a panel of 30 inflammatory cytokines in serum and fecal samples, we observed a distinct cytokine profile both at the systemic and intestinal level in patients compared to controls and even in patients with different clinical phenotypes and progression rates. The 16S targeted metagenome analysis revealed slight differences in patients compared to controls as well as in patients with slow progression, marked by the reduction of butyrate-producing bacteria and a decrease of the Firmicutes/Bacteroidetes ratio in ALS. Finally, the short chain fatty acid analysis did not show a different distribution among the groups. If confirmed in a larger number of patients, the inflammatory cytokine profile and the microbial composition could be appropriate biomarker candidates for deciphering ALS heterogeneity.}, } @article {pmid34211575, year = {2021}, author = {Lin, M and Hu, X and Chang, S and Chang, Y and Bian, W and Hu, R and Wang, J and Zhu, Q and Qiu, J}, title = {Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6678422}, pmid = {34211575}, issn = {1741-427X}, abstract = {Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.}, } @article {pmid34216082, year = {2021}, author = {Schneider, C and Wassermann, MK and Grether, NB and Fink, GR and Wunderlich, G and Lehmann, HC}, title = {Motor unit number estimation in adult patients with spinal muscular atrophy treated with nusinersen.}, journal = {European journal of neurology}, volume = {28}, number = {9}, pages = {3022-3029}, doi = {10.1111/ene.15005}, pmid = {34216082}, issn = {1468-1331}, mesh = {Adult ; Cross-Sectional Studies ; Humans ; Longitudinal Studies ; *Muscular Atrophy, Spinal/drug therapy ; *Oligonucleotides ; }, abstract = {BACKGROUND AND PURPOSE: The aim was to assess the organization and short-term changes of motor units in adult patients with spinal muscular atrophy (SMA) treated with nusinersen.

METHODS: In this single-centre cross-sectional and longitudinal study 15 adult patients with SMA type 3 were assessed and compared to 15 age-matched healthy controls and nine patients with amyotrophic lateral sclerosis. Moreover, 10 patients with SMA were followed up after 4-8 months. All patients were investigated clinically and by the motor unit number estimation method MScanFit of the abductor pollicis brevis muscle.

RESULTS: The number of motor units (p < 0.001) was significantly lower in patients with SMA compared to healthy controls at study entry. Mean unit amplitude, median amplitude and largest unit (p < 0.001) were significantly increased in patients with SMA. Patients with amyotrophic lateral sclerosis showed a significant reduction of compound muscle action potential (p = 0.005) and number of motor units (p = 0.03) compared to patients with SMA, accompanied by a larger median amplitude (p = 0.03). A prospective analysis identified patients with the ability to walk to improve the number of motor units (p = 0.046) accompanied by a decreased median amplitude (p = 0.03). Electrophysiological measures showed a moderate to strong correlation with clinical scores.

CONCLUSION: Patients with SMA show loss of motor units in distal muscles. MScanFit variables indicate that compound muscle action potential amplitudes are maintained by collateral sprouting. Prospective analyses suggest that milder affected adult patients with SMA preferentially benefit from nusinersen treatment through recovery of smaller motor units. Correlations with clinical scores underline the potential of MScanFit as a surrogate marker.}, } @article {pmid34217018, year = {2021}, author = {Tolkovsky, A and Kipervasser, S and Fainmesser, Y and Alcalay, Y and Gadoth, A}, title = {A paraneoplastic syndrome misdiagnosed as ALS: What are the red flags? A case report and review of the literature.}, journal = {Journal of neuroimmunology}, volume = {358}, number = {}, pages = {577635}, doi = {10.1016/j.jneuroim.2021.577635}, pmid = {34217018}, issn = {1872-8421}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/blood/*cerebrospinal fluid/*diagnosis ; *Diagnostic Errors ; Humans ; Male ; Paraneoplastic Syndromes, Nervous System/blood/*cerebrospinal fluid/*diagnosis ; }, abstract = {Background Paraneoplastic motor neuron disease (PMND) is a rare, non-classical form of paraneoplastic neurological syndrome (PNS). Anti-Hu and anti-CV2/CRMP5 PNS are mostly associated with small-cell lung cancer (SCLC) and consist of highly variable clinical syndromes, including sensory neuronopathy, cerebellar ataxia and/or limbic encephalitis. However, substantial motor impairment is uncommon, particularly when no sensory dysfunction co-exists. Case A 72-year-old man with a recent diagnosis of amyotrophic lateral sclerosis (ALS) was referred to our department of neurology for evaluation. The patient sub-acutely developed progressive neurological dysfunction including erectile dysfunction, behavioral changes, limb weakness, dysphagia, anorexia, as well as worsening stridor that necessitated tracheostomy due to bilateral vocal cord paralysis (BVCP). Neurological examination revealed motor weakness of upper and lower motor neuron origin with autonomic and cognitive dysfunction. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis, elevated protein, presence of oligoclonal bands (OCB), and neuronal antibody testing was positive for anti-Hu and anti-CV2/CRMP5. Based on these findings a diagnosis of a PNS was made. Evaluation for malignancy was negative, and immunosuppressive/immunomodulatory treatment was initiated but had little effect during fifteen months of follow-up. Conclusions Although PMND is very rare, in an atypical presentation, especially with features that are not usually present in ALS such as autonomic dysfunction, sensory disturbance or cognitive decline, this etiology should be in the differential diagnosis.}, } @article {pmid34218510, year = {2021}, author = {Laforest, M and Soufiane, B and Patterson, EL and Vargas, JJ and Boggess, SL and Houston, LC and Trigiano, RN and Brosnan, JT}, title = {Differential expression of genes associated with non-target site resistance in Poa annua with target site resistance to acetolactate synthase inhibitors.}, journal = {Pest management science}, volume = {77}, number = {11}, pages = {4993-5000}, pmid = {34218510}, issn = {1526-4998}, support = {//University of Tennessee Office of AgResearch/ ; //USDA-NACA/ ; }, mesh = {*Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; Plant Proteins/genetics ; *Poa ; }, abstract = {BACKGROUND: Poa annua is a pervasive grassy, self-pollinating, weed that has evolved resistance to 10 different herbicide modes-of-action, third most of all weed species. We investigated constitutive overexpression of genes associated with non-target site resistance (NTSR) in POAAN-R3 and the response of those genes when treated with trifloxysulfuron despite the biotype having a known target site mutation in acetolactate synthase (ALS).

RESULTS: Despite having an ALS target site mutation, POAAN-R3 still had a transcriptomic response to herbicide application that differed from a susceptible biotype. We observed differential expression of genes associated with transmembrane transport and oxidation-reduction activities, with differences being most pronounced prior to herbicide treatment.

CONCLUSIONS: In the P. annua biotype we studied with confirmed target site resistance to ALS inhibitors, we also observed constitutive expression of genes regulating transmembrane transport, as well as differential expression of genes associated with oxidative stress after treatment with trifloxysulfuron. This accumulation of mechanisms, in addition to the manifestation of target site resistance, could potentially increase the chance of survival when plants are challenged by different modes of action.}, } @article {pmid34220504, year = {2021}, author = {Islam, MS and Quispe, C and Hossain, R and Islam, MT and Al-Harrasi, A and Al-Rawahi, A and Martorell, M and Mamurova, A and Seilkhan, A and Altybaeva, N and Abdullayeva, B and Docea, AO and Calina, D and Sharifi-Rad, J}, title = {Neuropharmacological Effects of Quercetin: A Literature-Based Review.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {665031}, pmid = {34220504}, issn = {1663-9812}, abstract = {Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer's disease, Amyloid β peptide, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.}, } @article {pmid34223387, year = {2021}, author = {Charlton, K and McClelland, G and Millican, K and Haworth, D and Aitken-Fell, P and Norton, M}, title = {The impact of introducing real time feedback on ventilation rate and tidal volume by ambulance clinicians in the North East in cardiac arrest simulations.}, journal = {Resuscitation plus}, volume = {6}, number = {}, pages = {100130}, pmid = {34223387}, issn = {2666-5204}, abstract = {BACKGROUND: Research suggests rescuers deliver ventilations outside of recommendations during out of hospital cardiac arrest (OHCA), which can be deleterious to survival. We aimed to determine if ambulance clinician compliance with ventilation recommendations could be improved using the Zoll Accuvent real time ventilation feedback device (VFD).

METHODS: Participants simulated a two-minute cardiac arrest scenario using a mannequin and defibrillator without ventilation feedback. Eligible for inclusion were all clinicians aged ≥18 years who perform cardiopulmonary resuscitation (CPR) as part of their role, who had completed an internal advanced life support (ALS) refresher. Following familiarisation of a few minutes with the VFD, participants repeated the two-minute scenario with ventilation feedback. Ventilation rate and volume and CPR quality were recorded. Primary outcome was % difference in ventilation compliance with and without feedback. Secondary outcomes were differences between paramedic and non-paramedic clinicians and compliance with chest compression guidelines.

RESULTS: One hundred and six participants completed the study. Median ventilation rate without feedback was 10 (IQR 8-14, range 4-30) compared to 9 (IQR 9-9, range 6-17) with feedback; median tidal volume without feedback was 630 mls (IQR 518-725, range 201-1114) compared to 546 mls (IQR 531-560, range 490-750) with feedback. Proportion of clinicians ≥50% compliant with European Resuscitation Council ventilation recommendations were significantly greater with ventilation feedback compared to without, 91% vs. 9%, (McNemars test p = <0.0001). Paramedics out performed non-paramedic clinicians with and without feedback and compression quality was not compromised by using the VFD.

CONCLUSIONS: Ambulance clinician baseline ventilation quality was frequently outside of recommendations, but a VFD can ensure treatment is within evidence-based recommendations. Further research is required to validate the use of the VFD in true clinical practice and to evaluate the relationship between improved ventilation quality during OHCA and patient outcomes.}, } @article {pmid34225938, year = {2021}, author = {Ahmed, RM and Steyn, F and Dupuis, L}, title = {Hypothalamus and weight loss in amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {180}, number = {}, pages = {327-338}, doi = {10.1016/B978-0-12-820107-7.00020-3}, pmid = {34225938}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Hypothalamus ; Weight Loss ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder. While initially pathophysiology was thought to be restricted to motor deficits, it is increasingly recognized that patients develop prominent changes in weight and eating behavior that result from and mediate the underlying neurodegenerative process. These changes include alterations in metabolism, lipid levels, and insulin resistance. Emerging research suggests that these alterations may be mediated through changes in the hypothalamic function, with atrophy of the hypothalamus shown in both ALS patients and also presymptomatic genetic at-risk patients. This chapter reviews the evidence for hypothalamic involvement in ALS, including melanocortin pathways and potential treatment targets.}, } @article {pmid34233722, year = {2021}, author = {Nakajima, T and Sankai, Y and Takata, S and Kobayashi, Y and Ando, Y and Nakagawa, M and Saito, T and Saito, K and Ishida, C and Tamaoka, A and Saotome, T and Ikai, T and Endo, H and Ishii, K and Morita, M and Maeno, T and Komai, K and Ikeda, T and Ishikawa, Y and Maeshima, S and Aoki, M and Ito, M and Mima, T and Miura, T and Matsuda, J and Kawaguchi, Y and Hayashi, T and Shingu, M and Kawamoto, H}, title = {Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001).}, journal = {Orphanet journal of rare diseases}, volume = {16}, number = {1}, pages = {304}, pmid = {34233722}, issn = {1750-1172}, mesh = {Cross-Over Studies ; Exercise Therapy ; Humans ; Lower Extremity ; *Neuromuscular Diseases ; *Wearable Electronic Devices ; }, abstract = {BACKGROUND: Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients.

RESULTS: We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667-19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied.

CONCLUSIONS: HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases.

TRIAL REGISTRATION: JMACTR, JMA-IIA00156.}, } @article {pmid34237390, year = {2021}, author = {Tang, W and Li, Y and Li, Y and Wang, Q}, title = {Caveolin-1, a novel player in cognitive decline.}, journal = {Neuroscience and biobehavioral reviews}, volume = {129}, number = {}, pages = {95-106}, doi = {10.1016/j.neubiorev.2021.06.044}, pmid = {34237390}, issn = {1873-7528}, mesh = {Caveolae/metabolism ; *Caveolin 1/metabolism ; *Cognitive Dysfunction/metabolism ; Humans ; Oxidative Stress ; Quality of Life ; }, abstract = {Cognitive decline (CD), which related to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and diabetes mellitus, is a growing health concern that has a great impact on the patients' quality of life. Although extensive efforts, the mechanisms of CD are still far from being clarified, not to mention the effective treatment and prevention strategies. Caveolin-1 (Cav-1), a trans-membrane protein, is a major component of the caveolae structure and scaffolding proteins. Recently, ample evidence depicts a strong correlation between Cav-1 and CD, however, the specific role of Cav-1 in CD has not been clearly examined and how they might be connected have yet to be identified. This review seeks to provide a comprehensive overview about how Cav-1 modulates pathogeneses of CD-associated diseases. In summary, Cav-1 can promote structural and functional plasticity of neurons, improve neurogenesis, relieve mitochondrial dysfunction, inhibit inflammation and suppress oxidative stress, which have shed light on the idea that Cav-1 may be an efficacious therapeutic target to treat CD.}, } @article {pmid34238153, year = {2022}, author = {Mannan, A and Singh, TG and Singh, V and Garg, N and Kaur, A and Singh, M}, title = {Insights into the Mechanism of the Therapeutic Potential of Herbal Monoamine Oxidase Inhibitors in Neurological Diseases.}, journal = {Current drug targets}, volume = {23}, number = {3}, pages = {286-310}, doi = {10.2174/1389450122666210707120256}, pmid = {34238153}, issn = {1873-5592}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; }, abstract = {Monoamine oxidase (MAO) is an enzyme that catalyzes the deamination of monoamines and other proteins. MAO's hyperactivation results in the massive generation of reactive oxygen species, which leads to a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and depression-like disorders. Although synthetic MAO inhibitors are clinically available, they are associated with side effects such as hepatotoxicity, cheese reaction, hypertensive crisis, and so on, necessitating the investigation of alternative MAO inhibitors from a natural source with a safe profile. Herbal medications have a significant impact on the prevention of many diseases; additionally, they have fewer side effects and serve as a precursor for drug development. This review discusses the potential of herbal MAO inhibitors as well as their associated mechanism of action, with an aim to foster future research on herbal MAO inhibitors as a potential treatment for neurological diseases.}, } @article {pmid34248499, year = {2021}, author = {Molnar-Kasza, A and Hinteregger, B and Neddens, J and Rabl, R and Flunkert, S and Hutter-Paier, B}, title = {Evaluation of Neuropathological Features in the SOD1-G93A Low Copy Number Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {681868}, pmid = {34248499}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) still depicts an incurable and devastating disease. Drug development efforts are mostly based on superoxide dismutase 1 gene (SOD1)-G93A mice that present a very strong and early phenotype, allowing only a short time window for intervention. An alternative mouse model is available, that is based on the same founder line but has a reduced SOD1-G93A copy number, resulting in a weaker and delayed phenotype. To be able to use these SOD1-G93A/low mice for drug testing, we performed a characterization of ALS-typical pathologies. All analyses were performed compared to non-transgenic (ntg) littermates of the same sex and age. In vivo analysis of SOD1-G93A/low mice was performed by weekly body weight measurements, analysis of the survival rate, and measurement of the muscle strength of 24-30 weeks old female and male SOD1-G93A/low mice. Immunofluorescent labeling of SOD1, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba1) protein was performed in the cervical, thoracic, and lumbar ventral horn of the spinal cord of 24-30 weeks old male and female SOD1-G93A/low mice. The musculus gastrocnemius of male SOD1-G93A/low mice was labeled with fluorophore-conjugated α-bungarotoxin and antibodies against phosphorylated neurofilaments. Fluorescent labeling was detected and quantified by macro-based image analysis. Although SOD1 protein levels were highly increased in both sexes and all age groups, levels strongly peaked in 30 weeks old male SOD1-G93A/low mice. Astrocytosis and activated microglia in the spinal cord ventral horn and phosphorylated neurofilaments in the motor unit of the musculus gastrocnemius progressively increased, while muscle strength progressively decreased in male SOD1-G93A/low mice. In female SOD1-G93A/low mice, only activated microglia increased progressively, while muscle strength was constantly reduced starting at 26 weeks. These differences result in a shorter survival time of male SOD1-G93A/low mice of about 3 weeks compared to female animals. The results suggest that male SOD1-G93A/low mice present a stronger pathology and are, therefore, better suitable to evaluate the efficacy of new drugs against ALS as most pathological features are developing progressively paralleled by a survival time that allows treatment to start before symptom onset.}, } @article {pmid34248597, year = {2021}, author = {Asadi, MR and Sadat Moslehian, M and Sabaie, H and Jalaiei, A and Ghafouri-Fard, S and Taheri, M and Rezazadeh, M}, title = {Stress Granules and Neurodegenerative Disorders: A Scoping Review.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {650740}, pmid = {34248597}, issn = {1663-4365}, abstract = {Cytoplasmic ribonucleoproteins called stress granules (SGs) are considered as one of the main cellular solutions against stress. Their temporary presence ends with stress relief. Any factor such as chronic stress or mutations in the structure of the components of SGs that lead to their permanent presence can affect their interactions with pathological aggregations and increase the degenerative effects. SGs involved in RNA mechanisms are important factors in the pathophysiology of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and Alzheimer's diseases (AD). Although many studies have been performed in the field of SGs and neurodegenerative disorders, so far, no systematic studies have been executed in this field. The purpose of this study is to provide a comprehensive perspective of all studies about the role of SGs in the pathogenesis of neurodegenerative disorders with a focus on the protein ingredients of these granules. This scoping review is based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted until December 2020. Publications were screened independently by two reviewers and quantitative and qualitative analysis was performed on the extracted data. Bioinformatics analysis was used to plot the network and predict interprotein interactions. In addition, GO analysis was performed. A total of 48 articles were identified that comply the inclusion criteria. Most studies on neurodegenerative diseases have been conducted on ALS, AD, and FTD using human post mortem tissues. Human derived cell line studies have been used only in ALS. A total 29 genes of protein components of SGs have been studied, the most important of which are TDP-43, TIA-1, PABP-1. Bioinformatics studies have predicted 15 proteins to interact with the protein components of SGs, which may be the constituents of SGs. Understanding the interactions between SGs and pathological aggregations in neurodegenerative diseases can provide new targets for treatment of these disorders.}, } @article {pmid34251911, year = {2022}, author = {Brooks, BR and Pioro, EP and Beaulieu, D and Taylor, AA and Schactman, M and Keymer, M and Agnese, W and Perdrizet, J and Apple, S and Ennist, DL}, title = {Evidence for generalizability of edaravone efficacy using a novel machine learning risk-based subgroup analysis tool.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {49-57}, doi = {10.1080/21678421.2021.1927102}, pmid = {34251911}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Edaravone/therapeutic use ; Machine Learning ; Vital Capacity ; }, abstract = {Introduction: The edaravone development program for amyotrophic lateral sclerosis (ALS) included trials MCI186-16 (Study 16) and MCI186-19 (Study 19). A cohort enrichment strategy was based on a Study 16 post hoc analysis and applied to Study 19 to elucidate a treatment effect in that study. To determine whether the Study 19 results could be generalized to a broader ALS population, we used a machine learning (ML) model to create a novel risk-based subgroup analysis tool. Methods: A validated ML model was used to rank order all Study 16 participants by predicted time to 50% expected vital capacity. Subjects were stratified into nearest-neighbor risk-based subgroups that were systematically expanded to include the entire Study 16 population. For each subgroup, a statistical analysis generated heat maps that revealed statistically significant effect sizes. Results: A broad region of the Study 16 heat map with significant effect sizes was identified, including up to 70% of the trial population. Incorporating participants identified in the cohort enrichment strategy yielded a broad group comprising 76% of the original participants with a statistically significant treatment effect. This broad group spanned the full range of the functional score progression observed in Study 16. Conclusions: This analysis, applying predictions derived using an ML model to a novel methodology for subgroup identification, ascertained a statistically significant edaravone treatment effect in a cohort of participants with broader disease characteristics than the Study 19 inclusion criteria. This novel methodology may assist clinical interpretation of study results and potentially inform efficient future clinical trial design strategies.}, } @article {pmid34260979, year = {2021}, author = {Sancho, J and Ferrer, S and Burés, E and Luis Díaz, J and Torrecilla, T and Signes-Costa, J and Servera, E}, title = {Effect of one-year dextromethorphan/quinidine treatment on management of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Respiratory medicine}, volume = {186}, number = {}, pages = {106536}, doi = {10.1016/j.rmed.2021.106536}, pmid = {34260979}, issn = {1532-3064}, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*complications ; Dextromethorphan/*administration & dosage ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Prospective Studies ; Quinidine/*administration & dosage ; Respiratory Insufficiency/*drug therapy/*etiology ; Time Factors ; Treatment Outcome ; }, abstract = {UNLABELLED: Treatment with Dextromethorphan/Quinidine (DM/Q) has demonstrated benefit on pseudobulbar affect and bulbar function in amyotrophic lateral sclerosis (ALS). The aim of this study was to assess whether DM/Q could provide long-term improvement in bulbar function and thereby prolong noninvasive respiratory management in ALS.

MATERIALS AND METHODS: This prospective, case-cohort study, recruited ALS patients with bulbar dysfunction. Subjects included were compared with cross-matched historical controls. Cases received DM/Q (20/10 mg twice daily) during one-year follow-up; bulbar dysfunction was evaluated with the Norris scale bulbar subscore (NBS) and bulbar subscale of AlSFRS-R (ALSFRSb).

RESULTS: In total, 21 cases and 20 controls were enrolled, of whom noninvasive respiratory muscle assistance failed in 6 (28.5%) patients in the DM/Q group, compared with 4 patients (20.0%) in the control group (p = 0.645). Time from study onset to failure of respiratory muscle aids was 5.50 + 1.31 months in the DM/Q group and 5.20 + 1.15 months in the control group (p = 0.663). The adjusted OR for the effect of treatment on failure of noninvasive respiratory muscle aids was 2.12 (95%CI 0.23-33.79, p = 0.592). In the DM/Q group an impairment in scores was found in NBS (F = 19.26, p = 0.000) and ALSFRS-Rb (F = 12.71, p = 0.001) across different months of the study.

CONCLUSION: Treatment with DM/Q in ALS is unable to prolong noninvasive respiratory management, and moreover, has no effect on long-term deterioration of bulbar function. Notwithstanding the results on bulbar function, DM/Q was found to improve pseudobulbar affect during one-year follow-up.}, } @article {pmid34266598, year = {2021}, author = {Ahmed, RM and Halliday, G and Hodges, JR}, title = {Hypothalamic symptoms of frontotemporal dementia disorders.}, journal = {Handbook of clinical neurology}, volume = {182}, number = {}, pages = {269-280}, doi = {10.1016/B978-0-12-819973-2.00019-8}, pmid = {34266598}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis ; Cognition ; Disease Progression ; Feeding Behavior ; *Frontotemporal Dementia ; Humans ; Hypothalamus ; }, abstract = {Frontotemporal dementia (FTD) has traditionally been regarded as a disease of cognition and behavior, but emerging evidence suggests that the disease also affects body functions including changes in eating behavior and metabolism, autonomic function, sleep behavior, and sexual function. Central to these changes are potentially complex neural networks involving the hypothalamus, with hypothalamic atrophy shown in behavioral variant FTD. The physiological changes found in FTD are reviewed and the key neural networks and neuroendocrine changes mediating these changes in function discussed, including the ability to use these changes as biomarkers to aid in disease diagnosis, monitoring disease progression, and as potential treatment targets.}, } @article {pmid34269182, year = {2022}, author = {Panes, JD and Wendt, A and Ramirez-Molina, O and Castro, PA and Fuentealba, J}, title = {Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure.}, journal = {Neural regeneration research}, volume = {17}, number = {2}, pages = {237-245}, pmid = {34269182}, issn = {1673-5374}, abstract = {The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.}, } @article {pmid34283400, year = {2021}, author = {Betancor, M and Moreno-Martínez, L and López-Pérez, Ó and Otero, A and Hernaiz, A and Barrio, T and Badiola, JJ and Osta, R and Bolea, R and Martín-Burriel, I}, title = {Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease.}, journal = {Molecular neurobiology}, volume = {58}, number = {10}, pages = {5312-5326}, pmid = {34283400}, issn = {1559-1182}, support = {POCTEFA 2014-2020//European Regional Development Fund/ ; }, mesh = {Animals ; Brain/*drug effects/pathology ; *Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pilot Projects ; Prion Diseases/*drug therapy/*genetics/pathology ; Sheep ; Tetanus Toxin/*administration & dosage ; }, abstract = {The non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrP[C]) into an abnormal and misfolded isoform known as PrP[Sc]. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease or Alzheimer's disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrP[C], were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.}, } @article {pmid34290621, year = {2021}, author = {Kiriaev, L and Perry, BD and Mahns, DA and Shortland, PJ and Redwan, A and Morley, JW and Head, SI}, title = {Minocycline Treatment Reduces Mass and Force Output From Fast-Twitch Mouse Muscles and Inhibits Myosin Production in C2C12 Myotubes.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {696039}, pmid = {34290621}, issn = {1664-042X}, abstract = {Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 μg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions.}, } @article {pmid34293378, year = {2021}, author = {Aslani, M and Mortazavi-Jahromi, SS and Mirshafiey, A}, title = {Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology.}, journal = {Immunology letters}, volume = {238}, number = {}, pages = {1-20}, doi = {10.1016/j.imlet.2021.07.004}, pmid = {34293378}, issn = {1879-0542}, mesh = {Animals ; *Biomarkers ; Diagnosis, Differential ; Disease Management ; Disease Susceptibility ; *Gene Expression Regulation ; Humans ; MicroRNAs/*genetics ; Neuroimmunomodulation/genetics/immunology ; Neuroinflammatory Diseases/diagnosis/*etiology/*metabolism/therapy ; *RNA Interference ; Signal Transduction ; }, abstract = {Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.}, } @article {pmid34293864, year = {2021}, author = {Baggio, C and Kulinich, A and Dennys, CN and Rodrigo, R and Meyer, K and Ethell, I and Pellecchia, M}, title = {NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.}, journal = {Journal of medicinal chemistry}, volume = {64}, number = {15}, pages = {11229-11246}, pmid = {34293864}, issn = {1520-4804}, support = {P20 CA242620/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 CA168517/CA/NCI NIH HHS/United States ; R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acids/chemistry/*pharmacology ; Amyotrophic Lateral Sclerosis/*drug therapy/metabolism ; Animals ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; *Drug Design ; Fluorenes/chemistry/*pharmacology ; High-Throughput Screening Assays ; Humans ; Ligands ; Magnetic Resonance Spectroscopy ; Mice ; Mice, Transgenic ; Models, Molecular ; Molecular Structure ; Receptor, EphA4/*agonists/metabolism ; Structure-Activity Relationship ; Thermodynamics ; }, abstract = {In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Together with preliminary in vivo pharmacology studies, the data form a strong foundation for the translation of these agents for the treatment of ALS and potentially other human diseases.}, } @article {pmid34295897, year = {2021}, author = {Sykova, E and Cizkova, D and Kubinova, S}, title = {Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {695900}, pmid = {34295897}, issn = {2296-634X}, abstract = {Preclinical and clinical studies with various stem cells, their secretomes, and extracellular vesicles (EVs) indicate their use as a promising strategy for the treatment of various diseases and tissue defects, including neurodegenerative diseases such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). Autologous and allogenic mesenchymal stem cells (MSCs) are so far the best candidates for use in regenerative medicine. Here we review the effects of the implantation of MSCs (progenitors of mesodermal origin) in animal models of SCI and ALS and in clinical studies. MSCs possess multilineage differentiation potential and are easily expandable in vitro. These cells, obtained from bone marrow (BM), adipose tissue, Wharton jelly, or even other tissues, have immunomodulatory and paracrine potential, releasing a number of cytokines and factors which inhibit the proliferation of T cells, B cells, and natural killer cells and modify dendritic cell activity. They are hypoimmunogenic, migrate toward lesion sites, induce better regeneration, preserve perineuronal nets, and stimulate neural plasticity. There is a wide use of MSC systemic application or MSCs seeded on scaffolds and tissue bridges made from various synthetic and natural biomaterials, including human decellularized extracellular matrix (ECM) or nanofibers. The positive effects of MSC implantation have been recorded in animals with SCI lesions and ALS. Moreover, promising effects of autologous as well as allogenic MSCs for the treatment of SCI and ALS were demonstrated in recent clinical studies.}, } @article {pmid34295920, year = {2021}, author = {Paß, T and Wiesner, RJ and Pla-Martín, D}, title = {Selective Neuron Vulnerability in Common and Rare Diseases-Mitochondria in the Focus.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {676187}, pmid = {34295920}, issn = {2296-889X}, abstract = {Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca[2+] handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as in rare neurological disorders, including Huntington's disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.}, } @article {pmid34307464, year = {2021}, author = {Yang, C and Qi, Y and Sun, Z}, title = {The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases.}, journal = {Frontiers in molecular biosciences}, volume = {8}, number = {}, pages = {711710}, pmid = {34307464}, issn = {2296-889X}, abstract = {The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.}, } @article {pmid34310733, year = {2022}, author = {Makizodila, BAM and van de Wijdeven, JHE and de Soet, JJ and van Selms, MKA and Volgenant, CMC}, title = {Oral hygiene in patients with motor neuron disease requires attention: A cross-sectional survey study.}, journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}, volume = {42}, number = {1}, pages = {9-14}, pmid = {34310733}, issn = {1754-4505}, mesh = {*Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; Humans ; *Motor Neuron Disease ; Oral Hygiene ; Quality of Life ; }, abstract = {AIMS: Motor Neuron Disease (MND) is a progressive neurodegenerative neuromuscular disease, which can progressively impair arm-hand function. Needs and barriers of MND patients and their caregivers in performing oral hygiene were studied.

METHODS: An online survey was sent to 706 MND patients. The questions of the survey included self-reliance, self-reported oral health, and oral hygiene. The oral health-related quality of life (GOHAI-NL) and the subjective well-being (ALSAQ-5) were also measured.

RESULTS: A total of 259 patients responded (36.7%), of which 71.9% stated not to be informed about the importance of maintaining good oral health by their MND treatment team. Moreover, 40.4% would like to receive help concerning oral hygiene from a dental professional. 19.8% were not satisfied about oral care as conducted by themselves or their caregivers. Patients who do not ask for support with their daily oral care had a significantly worse oral health-related quality of life compared to patients who do ask for support.

CONCLUSIONS: The support for daily oral hygiene of MND patients and their barriers to requesting support needs more attention from both MND-treatment teams and general dental professionals.}, } @article {pmid34311486, year = {2022}, author = {Elliesen, R and Glaesmer, H and Koranyi, S and Mehnert-Theuerkauf, A}, title = {[Death Wishes in Patients with Advanced Cancer: An Explorative Analysis of Psychotherapeutic Treatment Transcripts].}, journal = {Psychotherapie, Psychosomatik, medizinische Psychologie}, volume = {72}, number = {1}, pages = {18-25}, doi = {10.1055/a-1499-8082}, pmid = {34311486}, issn = {1439-1058}, mesh = {Humans ; *Neoplasms/therapy ; Pain ; }, abstract = {Todeswünsche bei Patienten mit einer fortgeschrittenen Krebserkrankung sind bereits seit längerem Gegenstand der psychoonkologischen Forschung. Auch wenn es inzwischen einige Ansätze gibt, die sich mit der Konzeptualisierung und Beschreibung von Todeswünschen befassen, fehlt es bislang an einem in der klinischen Praxis gut anwendbaren Konzept und dazugehörigen Erhebungsinstrumenten. Ziel der Studie ist deshalb die phänomenologische Beschreibung von Todeswünschen bei Patienten mit fortgeschrittenem Krebs. Dafür wurden N=228 transkribierte Psychotherapiegespräche von 76 Patienten im Rahmen der randomisiert-kontrollierten Psychotherapiestudie Managing Cancer and Living Meaningfully (CALM) hinsichtlich des Themas Todeswunsch explorativ analysiert. Von den untersuchten 76 Patienten berichteten 16 (21%) explizit von Todeswünschen. Mithilfe ihrer Beschreibungen konnten zwei Dimensionen identifiziert werden: (1) Gründe für Todeswünsche mit sieben Unterkategorien (Vermeidung von Schmerz und Leid, Kontrolle und Selbstbestimmung erhalten, körperlicher Abbau und Begrenzungen im Alltag, Angst vor Siechtum, Leben nicht mehr lebenswert, Gefühl der Lebensvollendung und alles getan zu haben, fehlende Zukunftsperspektiven) sowie (2) der Grad des mit dem Todeswunsch verbundenen Handlungsdrucks. Die Ergebnisse stimmen mit existierenden Theorien zu Todeswünschen bei Patienten mit einer fortgeschrittenen Krebserkrankung größtenteils überein. Als zusammengehörige Dimensionen des Phänomens Todeswunsch wurden sie jedoch bisher noch nicht beschrieben. Vor allem für die klinische Praxis scheint dies sehr sinnvoll zu sein, da die Gründe in der Therapie größtenteils bearbeitbar sein dürften und der Grad des Handlungsdrucks Aufschluss über die Notwendigkeit einer Intervention geben kann.Death wishes in patients with advanced cancer is a research topic of high interest in psycho-oncologic research. Despite existing concepts describing death wishes, there is a lack of clinically applicable concepts and appropriate instruments. The objective of this study was the phenomenological description of death wishes in patients with advanced cancer. For this purpose, we qualitatively explored N=228 transcribed psychotherapeutic treatment sessions of 76 patients derived from an RCT evaluating the efficacy of Managing Cancer and Living Meaningfully (CALM) psychotherapeutic intervention. Sixteen out of the 76 patients explicitly reported death wishes (21%). Two dimensions were identified: (1) reasons for a death wish with seven subcategories (avoidance of pain and suffering, maintaining control and self-determination, physical deterioration and limitations in everyday life, fear of infirmity, life not longer worth living, feeling of life completion and having done everything, lack of future perspectives) and (2) the degree of pressure to act associated with the death wish. These results are consistent with existing theories regarding death wishes in patients with advanced cancer. However, they have not yet been described as interrelated dimensions of the phenomenon of the death wish.}, } @article {pmid34321067, year = {2021}, author = {Freigang, M and Steinacker, P and Wurster, CD and Schreiber-Katz, O and Osmanovic, A and Petri, S and Koch, JC and Rostásy, K and Falkenburger, B and Ludolph, AC and Otto, M and Hermann, A and Günther, R}, title = {Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy.}, journal = {Orphanet journal of rare diseases}, volume = {16}, number = {1}, pages = {330}, pmid = {34321067}, issn = {1750-1172}, mesh = {Adult ; Child ; Hexosaminidases ; Humans ; *Muscular Atrophy, Spinal/drug therapy ; *Oligonucleotides ; Prospective Studies ; }, abstract = {BACKGROUND: Studies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen.

METHODS: In this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.

RESULTS: CHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.

CONCLUSIONS: CHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.}, } @article {pmid34322776, year = {2021}, author = {Fadel, IM and Ragab, MH and Eid, OM and Helmy, NA and El-Bassyouni, HT and Mazen, I}, title = {IGF1R, IGFALS, and IGFBP3 gene copy number variations in a group of non-syndromic Egyptian short children.}, journal = {Journal, genetic engineering & biotechnology}, volume = {19}, number = {1}, pages = {109}, pmid = {34322776}, issn = {2090-5920}, abstract = {BACKGROUND: Insulin-like growth factor-1 (IGF-1) is required for normal intrauterine and postnatal growth, and this action is mediated through IGF1 receptor (IGF1R). IGF1R copy number variants (CNVs) can cause pre- and postnatal growth restriction, affecting an individual's height. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to detect CNVs in IGF1R, IGFALS, and IGFBP3 genes in the diagnostic workup of short stature for 40 Egyptian children with short stature.

RESULTS: We detected a heterozygous deletion of IGF1R (exons 4 through 21) in 1 out of the 40 studied children (2.5%). Meanwhile, we did not detect any CNVs in either IGFALS or IGFBP3.

CONCLUSION: The diagnostic workup of short stature using MLPA for CNVs of IGF1R and other recognized height-related genes, such as SHOX and GH, in non-syndromic short stature children can be a fast and inexpensive diagnostic tool to recognize a subcategory of patients in which growth hormone treatment can be considered.}, } @article {pmid34335276, year = {2021}, author = {Wang, X and Zhang, JB and He, KJ and Wang, F and Liu, CF}, title = {Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {713963}, pmid = {34335276}, issn = {1663-9812}, abstract = {Neurodegenerative disease (NDD), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by the progressive loss of neurons which leads to the decline of motor and/or cognitive function. Currently, the prevalence of NDD is rapidly increasing in the aging population. However, valid drugs or treatment for NDD are still lacking. The clinical heterogeneity and complex pathogenesis of NDD pose a great challenge for the development of disease-modifying therapies. Numerous animal models have been generated to mimic the pathological conditions of these diseases for drug discovery. Among them, zebrafish (Danio rerio) models are progressively emerging and becoming a powerful tool for in vivo study of NDD. Extensive use of zebrafish in pharmacology research or drug screening is due to the high conserved evolution and 87% homology to humans. In this review, we summarize the zebrafish models used in NDD studies, and highlight the recent findings on pharmacological targets for NDD treatment. As high-throughput platforms in zebrafish research have rapidly developed in recent years, we also discuss the application prospects of these new technologies in future NDD research.}, } @article {pmid34339943, year = {2021}, author = {Manochkumar, J and Doss, CGP and El-Seedi, HR and Efferth, T and Ramamoorthy, S}, title = {The neuroprotective potential of carotenoids in vitro and in vivo.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {91}, number = {}, pages = {153676}, doi = {10.1016/j.phymed.2021.153676}, pmid = {34339943}, issn = {1618-095X}, mesh = {Antioxidants ; *Carotenoids/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Neuroprotection ; *Neuroprotective Agents/pharmacology ; Oxidative Stress ; }, abstract = {BACKGROUND: Despite advances in research on neurodegenerative diseases, the pathogenesis and treatment response of neurodegenerative diseases remain unclear. Recent studies revealed a significant role of carotenoids to treat neurodegenerative diseases. The aim of this study was to systematically review the neuroprotective potential of carotenoids in vivo and in vitro and the molecular mechanisms and pathological factors contributing to major neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and stroke).

HYPOTHESIS: Carotenoids as therapeutic molecules to target neurodegenerative diseases.

RESULTS: Aggregation of toxic proteins, mitochondrial dysfunction, oxidative stress, the excitotoxic pathway, and neuroinflammation were the major pathological factors contributing to the progression of neurodegenerative diseases. Furthermore, in vitro and in vivo studies supported the beneficiary role of carotenoids, namely lycopene, β-carotene, crocin, crocetin, lutein, fucoxanthin and astaxanthin in alleviating disease progression. These carotenoids provide neuroprotection by inhibition of neuro-inflammation, microglial activation, excitotoxic pathway, modulation of autophagy, attenuation of oxidative damage and activation of defensive antioxidant enzymes. Additionally, studies conducted on humans also demonstrated that dietary intake of carotenoids lowers the risk of neurodegenerative diseases.

CONCLUSION: Carotenoids may be used as drugs to prevent and treat neurodegenerative diseases. Although, the in vitro and in vivo results are encouraging, further well conducted clinical studies on humans are required to conclude about the full potential of neurodegenerative diseases.}, } @article {pmid34357138, year = {2021}, author = {Pikatza-Menoio, O and Elicegui, A and Bengoetxea, X and Naldaiz-Gastesi, N and López de Munain, A and Gerenu, G and Gil-Bea, FJ and Alonso-Martín, S}, title = {The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis.}, journal = {Journal of personalized medicine}, volume = {11}, number = {7}, pages = {}, pmid = {34357138}, issn = {2075-4426}, support = {PI19/00175//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputación Foral de Gipuzkoa/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.}, } @article {pmid34358737, year = {2021}, author = {Martín-Rivada, Á and Barrios, V and Martínez Díaz-Guerra, G and Pozo, J and Martos-Moreno, GÁ and Argente, J}, title = {Adult height and long-term outcomes after rhIGF-1 therapy in two patients with PAPP-A2 deficiency.}, journal = {Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {60-61}, number = {}, pages = {101419}, doi = {10.1016/j.ghir.2021.101419}, pmid = {34358737}, issn = {1532-2238}, mesh = {*Body Height ; Child ; Female ; Follow-Up Studies ; Growth Disorders/*drug therapy/genetics/metabolism/pathology ; Human Growth Hormone/*administration & dosage ; Humans ; Insulin-Like Growth Factor Binding Protein 3/*metabolism ; Insulin-Like Growth Factor I/*metabolism ; Male ; Pregnancy-Associated Plasma Protein-A/*deficiency/genetics ; Prognosis ; Recombinant Proteins/*administration & dosage ; }, abstract = {PAPP-A2 deficiency is a novel syndrome characterized by short stature due to low IGF bioactivity, skeletal abnormalities and decreased bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) for 1 year demonstrated to increase growth velocity and BMD, without reported adverse effects, but data regarding the long-term efficacy and safety of rhIGF-1 administration in this entity has not yet been reported. Two Spanish siblings with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) were treated with rhIGF-1 twice daily for six years. Growth velocity continued to increase and both patients achieved their target height. Free IGF-1 concentrations increased notably after rhIGF-1 administration, with serum IGFBP-3, IGFBP-5 and ALS levels also being higher during treatment. BMD was progressively normalized and an increase in lean mass was also noted during treatment. No episodes of hypoglycemia or any other adverse effects were documented. An increase in the growth of kidney and spleen length was observed in one of the patients.}, } @article {pmid34359358, year = {2021}, author = {Youn, BY and Ko, Y and Moon, S and Lee, J and Ko, SG and Kim, JY}, title = {Digital Biomarkers for Neuromuscular Disorders: A Systematic Scoping Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {34359358}, issn = {2075-4418}, abstract = {Biomarkers play a vital role in clinical care. They enable early diagnosis and treatment by identifying a patient's condition and disease course and act as an outcome measure that accurately evaluates the efficacy of a new treatment or drug. Due to the rapid development of digital technologies, digital biomarkers are expected to grow tremendously. In the era of change, this scoping review was conducted to see which digital biomarkers are progressing in neuromuscular disorders, a diverse and broad-range disease group among the neurological diseases, to discover available evidence for their feasibility and reliability. Thus, a total of 10 studies were examined: 9 observational studies and 1 animal study. Of the observational studies, studies were conducted with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA) patients. Non-peer reviewed poster presentations were not considered, as the articles may lead to erroneous results. The only animal study included in the present review investigated the mice model of ALS for detecting rest disturbances using a non-invasive digital biomarker.}, } @article {pmid34360586, year = {2021}, author = {Tarnacka, B and Jopowicz, A and Maślińska, M}, title = {Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360586}, issn = {1422-0067}, mesh = {Ceruloplasmin/*deficiency ; Copper/*adverse effects ; Humans ; Iron/*adverse effects ; Iron Metabolism Disorders/chemically induced/etiology/*pathology ; Manganese/*adverse effects ; Manganese Poisoning/complications ; Metabolic Diseases/chemically induced/*pathology ; Metalloproteins/metabolism ; Neuroaxonal Dystrophies/chemically induced/*pathology ; Neurodegenerative Diseases/etiology/*pathology ; Oxidative Stress ; }, abstract = {Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.}, } @article {pmid34360808, year = {2021}, author = {Jin, M and Akgün, K and Ziemssen, T and Kipp, M and Günther, R and Hermann, A}, title = {Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34360808}, issn = {1422-0067}, support = {not applicable//Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; n.a.//NOMIS Stiftung/ ; }, mesh = {Amyotrophic Lateral Sclerosis/*immunology/pathology ; Cell Survival/immunology ; Humans ; Induced Pluripotent Stem Cells/*immunology/pathology ; Interleukin-17/*immunology ; Motor Neurons/*immunology/pathology ; RNA-Binding Protein FUS/*immunology ; Th17 Cells/*immunology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.}, } @article {pmid34363869, year = {2021}, author = {Orienti, I and Armida, M and Dobrowolny, G and Pepponi, R and Sollazzini, G and Pezzola, A and Casola, I and Musarò, A and Popoli, P and Potenza, RL}, title = {Fenretinide Beneficial Effects on Amyotrophic Lateral Sclerosis-associated SOD1[G93A] Mutant Protein Toxicity: In Vitro and In Vivo Evidences.}, journal = {Neuroscience}, volume = {473}, number = {}, pages = {1-12}, doi = {10.1016/j.neuroscience.2021.07.033}, pmid = {34363869}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Animals ; Disease Models, Animal ; Female ; *Fenretinide/pharmacology ; Mice ; Mice, Transgenic ; Mutant Proteins ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1[G93A] mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1[G93A] ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1[G93A] mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1[G93A] ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research.}, } @article {pmid34372914, year = {2021}, author = {Xu, X and Shen, D and Gao, Y and Zhou, Q and Ni, Y and Meng, H and Shi, H and Le, W and Chen, S and Chen, S}, title = {A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?.}, journal = {Translational neurodegeneration}, volume = {10}, number = {1}, pages = {29}, pmid = {34372914}, issn = {2047-9158}, mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/*therapy ; Clinical Trials as Topic/*methods ; *Disease Management ; *Disease Progression ; Edaravone/therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Stem Cell Transplantation/methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.}, } @article {pmid34376243, year = {2021}, author = {Pasetto, L and Callegaro, S and Corbelli, A and Fiordaliso, F and Ferrara, D and Brunelli, L and Sestito, G and Pastorelli, R and Bianchi, E and Cretich, M and Chiari, M and Potrich, C and Moglia, C and Corbo, M and Sorarù, G and Lunetta, C and Calvo, A and Chiò, A and Mora, G and Pennuto, M and Quattrone, A and Rinaldi, F and D'Agostino, VG and Basso, M and Bonetto, V}, title = {Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {52}, pmid = {34376243}, issn = {1750-1326}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*blood/*diagnosis ; Animals ; Biomarkers/*blood ; Extracellular Vesicles/*metabolism/*ultrastructure ; Female ; Humans ; Machine Learning ; Male ; Mice ; Microscopy, Electron, Transmission ; Middle Aged ; Proteomics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease's complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell's physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification.

METHODS: We analyzed plasma-derived EVs of ALS patients (n = 106) and controls (n = 96), and SOD1[G93A] and TDP-43[Q331K] mouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis.

RESULTS: Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs.

CONCLUSIONS: Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis.}, } @article {pmid34376973, year = {2021}, author = {Conti, N and Gatti, M and Raschi, E and Diemberger, I and Potena, L}, title = {Evidence and Current Use of Levosimendan in the Treatment of Heart Failure: Filling the Gap.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {3391-3409}, pmid = {34376973}, issn = {1177-8881}, mesh = {Adenosine Triphosphate/metabolism ; Cardiotonic Agents/adverse effects/*pharmacology ; Heart Failure/*drug therapy/physiopathology ; Humans ; Phosphodiesterase 3 Inhibitors/adverse effects/pharmacology ; Simendan/*pharmacology ; Vasodilator Agents/adverse effects/pharmacology ; }, abstract = {Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.}, } @article {pmid34381654, year = {2021}, author = {Murray, NM and Reimer, RJ and Cao, M}, title = {Acute on Chronic Neuromuscular Respiratory Failure in the Intensive Care Unit: Optimization of Triage, Ventilation Modes, and Extubation.}, journal = {Cureus}, volume = {13}, number = {7}, pages = {e16297}, pmid = {34381654}, issn = {2168-8184}, abstract = {Critical care management of acute respiratory failure in patients with neuromuscular disease (NMD) such as amyotrophic lateral sclerosis (ALS) is not standardized and is challenging for many critical care specialists. Progressive hypercapnic respiratory failure and ineffective airway clearance are key issues in this patient population. Often at the time of hospital presentation, patients are already supported by home mechanical ventilatory support with noninvasive ventilation (NIV) and an airway clearance regimen. Prognosis is poor once a patient develops acute respiratory failure requiring intubation and invasive mechanical ventilatory support, commonly leading to tracheostomy or palliative-focused care. We focus on this understudied group of patients with ALS without tracheostomy and incorporate existing data to propose a technical approach to the triage and management of acute respiratory failure, primarily for those who require intubation and mechanical ventilatory support for reversible causes, and also for progression of end-stage disease. Optimizing management in this setting improves both quality and quantity of life. Neuromuscular patients with acute respiratory failure require protocolized and personalized triage and treatment. Here, we describe the technical methods used at our single institution. The triage phase incorporates comprehensive evaluation for new etiologies of hypoxia and hypercapnia, which are not initially presumed to be secondary to progression or end-stage neuromuscular respiratory failure. In select patients, this may involve intubation or advanced adjustments of NIV machines. Next, once the acute etiology(s) is identified and treated, the focus shifts: training and use of mechanical airway clearance to optimize pulmonary function, facilitation of NIV wean or successful extubation to NIV, and transition to a stable regimen for home ventilation. The comprehensive protocol described here incorporates multi-institutional approaches and effectively optimizes acute respiratory failure in patients with neuromuscular pulmonary disease.}, } @article {pmid34382759, year = {2021}, author = {Barrington, CJ and Burruano, M and Carney, C and Choi, J and Januska, J and Lachuk, L and Oskarsson, B and Rodriguez, C and Speicher, L and Tereso, G}, title = {Addressing the role of edaravone in the management of amyotrophic lateral sclerosis and gaps in care and access: expert panel recommendations.}, journal = {The American journal of managed care}, volume = {27}, number = {12 Suppl}, pages = {S231-S237}, doi = {10.37765/ajmc.2021.88732}, pmid = {34382759}, issn = {1936-2692}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone ; Free Radical Scavengers ; Humans ; Managed Care Programs ; Specialization ; United States ; }, abstract = {A virtual key opinion leader (KOL) and payer discussion was held on December 5, 2020. In attendance were 2 KOLs, both specialists in amyotrophic lateral sclerosis (ALS) at leading clinics in the United States, and 6 managed care executives from US regional health plans. The objective of this panel was to share opinions, ideas, and information around the treatment of ALS with edaravone, gaps in management and guidelines, and potential solutions. The panel concluded that coverage criteria for edaravone may need to be reassessed and treatment guidelines could be revisited to include a determination of place in therapy for edaravone.}, } @article {pmid34386317, year = {2021}, author = {Ahsan, A and Liu, M and Zheng, Y and Yan, W and Pan, L and Li, Y and Ma, S and Zhang, X and Cao, M and Wu, Z and Hu, W and Chen, Z and Zhang, X}, title = {Natural compounds modulate the autophagy with potential implication of stroke.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {7}, pages = {1708-1720}, pmid = {34386317}, issn = {2211-3835}, abstract = {Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.}, } @article {pmid34390052, year = {2021}, author = {Wright, AL and Della Gatta, PA and Le, S and Berning, BA and Mehta, P and Jacobs, KR and Gul, H and San Gil, R and Hedl, TJ and Riddell, WR and Watson, O and Keating, SS and Venturato, J and Chung, RS and Atkin, JD and Lee, A and Shi, B and Blizzard, CA and Morsch, M and Walker, AK}, title = {Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.}, journal = {The European journal of neuroscience}, volume = {54}, number = {6}, pages = {6237-6255}, doi = {10.1111/ejn.15422}, pmid = {34390052}, issn = {1460-9568}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Female ; Mice ; Mice, Transgenic ; *Neurodegenerative Diseases ; Riluzole/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.}, } @article {pmid34390468, year = {2021}, author = {Maraschi, A and Gumina, V and Dragotto, J and Colombrita, C and Mompeán, M and Buratti, E and Silani, V and Feligioni, M and Ratti, A}, title = {SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.}, journal = {Molecular neurobiology}, volume = {58}, number = {11}, pages = {5682-5702}, pmid = {34390468}, issn = {1559-1182}, support = {SUMALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; }, mesh = {Cell Line, Tumor ; Cell Nucleus/*chemistry ; Cytoplasm/*chemistry ; DNA-Binding Proteins/analysis/*metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Nerve Tissue Proteins/analysis/*metabolism ; Neuroblastoma ; Peptide Fragments/pharmacology ; Potassium Chloride/pharmacology ; Protein Conformation ; *Protein Processing, Post-Translational ; Protein Transport ; RNA Interference ; RNA Splicing ; RNA, Small Interfering/pharmacology ; Sequence Alignment ; Sequence Homology, Amino Acid ; Stress Granules ; Sumoylation ; }, abstract = {The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.}, } @article {pmid34392765, year = {2022}, author = {Young, C and Pinto, S and Grosskreutz, J and Hardiman, O and Clawson, LL and Cudkowicz, ME and Andrews, JA}, title = {Medical therapies for amyotrophic lateral sclerosis-related respiratory decline: an appraisal of needs, opportunities and obstacles.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {1-2}, pages = {66-75}, doi = {10.1080/21678421.2021.1920981}, pmid = {34392765}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; *COVID-19 ; Humans ; *Noninvasive Ventilation ; Pandemics ; Quality of Life ; *Respiratory Insufficiency/etiology/therapy ; SARS-CoV-2 ; }, abstract = {A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.}, } @article {pmid34396011, year = {2021}, author = {Grauffel, C and Weng, WH and Dudev, T and Lim, C}, title = {Trinuclear Calcium Site in the C2 Domain of PKCα/γ Is Prone to Lithium Attack.}, journal = {ACS omega}, volume = {6}, number = {31}, pages = {20657-20666}, pmid = {34396011}, issn = {2470-1343}, abstract = {Lithium (Li[+]) is the first-line therapy for bipolar disorder and a candidate drug for various diseases such as amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Despite being the captivating subject of many studies, the mechanism of lithium's therapeutic action remains unclear. To date, it has been shown that Li[+] competes with Mg[2+] and Na[+] to normalize the activity of inositol and neurotransmitter-related signaling proteins, respectively. Furthermore, Li[+] may co-bind with Mg[2+]-loaded adenosine or guanosine triphosphate to alter the complex's susceptibility to hydrolysis and mediate cellular signaling. Bipolar disorder patients exhibit abnormally high cytosolic Ca[2+] levels and protein kinase C (PKC) hyperactivity that can be downregulated by long-term Li[+] treatment. However, the possibility that monovalent Li[+] could displace the bulkier divalent Ca[2+] and inhibit PKC activity has not been considered. Here, using density functional theory calculations combined with continuum dielectric methods, we show that Li[+] may displace the native dication from the positively charged trinuclear site in the C2 domain of cytosolic PKCα/γ. This would affect the membrane-docking ability of cytosolic PKCα/γ and reduce the abnormally high membrane-associated active PKCα/γ levels, thus downregulating the PKC hyperactivity found in bipolar patients.}, } @article {pmid34396115, year = {2021}, author = {Harley, J and Hagemann, C and Serio, A and Patani, R}, title = {TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain.}, journal = {Brain communications}, volume = {3}, number = {3}, pages = {fcab166}, pmid = {34396115}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/M02492X/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {RNA binding proteins have been shown to play a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in valosin-containing protein (VCP/p97) cause ALS and exhibit the hallmark nuclear-to-cytoplasmic mislocalization of RNA binding proteins (RBPs). However, the mechanism by which mutations in VCP lead to this mislocalization of RBPs remains incompletely resolved. To address this, we used human-induced pluripotent stem cell-derived motor neurons carrying VCP mutations. We first demonstrate reduced nuclear-to-cytoplasmic ratios of transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS) and splicing factor proline and glutamine rich (SFPQ) in VCP mutant motor neurons. Upon closer analysis, we also find these RBPs are mislocalized to motor neuron neurites themselves. To address the hypothesis that altered function of the D2 ATPase domain of VCP causes RBP mislocalization, we used pharmacological inhibition of this domain in control motor neurons and found this does not recapitulate RBP mislocalization phenotypes. However, D2 domain inhibition in VCP mutant motor neurons was able to robustly reverse mislocalization of both TDP-43 and FUS, in addition to partially relocalizing SFPQ from the neurites. Together these results argue for a gain-of-function of D2 ATPase in VCP mutant human motor neurons driving the mislocalization of TDP-43 and FUS. Our data raise the intriguing possibility of harnessing VCP D2 ATPase inhibitors in the treatment of VCP-related ALS.}, } @article {pmid34400291, year = {2021}, author = {Oli, V and Gupta, R and Kumar, P}, title = {FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders.}, journal = {Journal of chemical neuroanatomy}, volume = {116}, number = {}, pages = {102012}, doi = {10.1016/j.jchemneu.2021.102012}, pmid = {34400291}, issn = {1873-6300}, mesh = {Animals ; Forkhead Box Protein O1/*metabolism ; Forkhead Transcription Factors/metabolism ; Humans ; Neurodegenerative Diseases/*metabolism/pathology ; Neurons/*metabolism/pathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others, are characterized by progressive loss of neuronal cells, which causes memory impairment and cognitive decline. Mounting evidence demonstrated the possible implications of diverse biological processes, namely oxidative stress, mitochondrial dysfunction, aberrant cell cycle re-entry, post-translational modifications, protein aggregation, impaired proteasome dysfunction, autophagy, and many others that cause neuronal cell death. The condition worsens as there is no effective treatment for such diseases due to their complex pathogenesis and mechanism. Mounting evidence demonstrated the role of regulatory transcription factors, such as NFκβ, FoxO, Myc, CREB, and others that regulate the biological processes and diminish the disease progression and pathogenesis. Studies demonstrated that forkhead box O (FoxO) transcription factors had been implicated in the regulation of aging and longevity. Further, the functions of FoxO proteins are regulated by different post-translational modifications (PTMs), namely acetylation, and ubiquitination. Various studies concluded that FoxO proteins exert both neuroprotective and neurotoxic properties depending on their regulation mechanism and activity in the brain. Thus, understanding the nature of FoxO expression and activity in the brain will help develop effective therapeutic strategies. Herein, firstly, we discuss the role of FoxO protein in cell cycle regulation and cell proliferation, followed by the regulation of FoxO proteins through acetylation and ubiquitination. We also briefly explain the activity and expression pattern of FoxO proteins in the neuronal cells and explain the mechanism through which FoxO proteins are rescued from oxidative stress-induced neurotoxicity. Later on, we present a detailed view of the implication of FoxO proteins in neurodegenerative disease and FoxO proteins as an effective therapeutic target.}, } @article {pmid34409288, year = {2021}, author = {Giovannelli, I and Bayatti, N and Brown, A and Wang, D and Mickunas, M and Camu, W and Veyrune, JL and Payan, C and Garlanda, C and Locati, M and Juntas-Morales, R and Pageot, N and Malaspina, A and Andreasson, U and Suehs, C and Saker, S and Masseguin, C and de Vos, J and Zetterberg, H and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Heath, PR and Shaw, PJ and Kirby, J}, title = {Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2.}, journal = {Brain communications}, volume = {3}, number = {3}, pages = {fcab141}, pmid = {34409288}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.}, } @article {pmid34411281, year = {2021}, author = {Cocozza, G and Garofalo, S and Morotti, M and Chece, G and Grimaldi, A and Lecce, M and Scavizzi, F and Menghini, R and Casagrande, V and Federici, M and Raspa, M and Wulff, H and Limatola, C}, title = {The feeding behaviour of Amyotrophic Lateral Sclerosis mouse models is modulated by the Ca[2+] -activated KCa 3.1 channels.}, journal = {British journal of pharmacology}, volume = {178}, number = {24}, pages = {4891-4906}, pmid = {34411281}, issn = {1476-5381}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Disease Models, Animal ; Energy Metabolism ; *Feeding Behavior ; Homeostasis ; Melanocortins ; Mice ; Mice, Transgenic ; Microglia/cytology ; Potassium Channels, Calcium-Activated/*metabolism ; Pyrazoles/pharmacology ; Receptors, Cannabinoid ; Spinal Cord/metabolism ; Superoxide Dismutase-1/metabolism ; Weight Gain ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KCa 3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models.

EXPERIMENTAL APPROACH: hSOD1[G93A] and TDP43[A315T] mice were treated daily with 120 mg·kg[-1] of TRAM-34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1[G93A] and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1[G93A] mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB1 (rimonabant) and μ-opioid receptors (naloxone), respectively.

KEY RESULTS: We found that treatment of hSOD1[G93A] mice with the KCa 3.1 inhibitor TRAM-34 (i), attenuates the pro-inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro-opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis.

CONCLUSION AND IMPLICATIONS: Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa 3.1 to counteract weight loss in ALS.}, } @article {pmid34411491, year = {2021}, author = {Roman, A and Baylor, C and Johnson, L and Barton, M}, title = {Expanding Availability of Speech-Generating Device Evaluation and Treatment to People With Amyotrophic Lateral Sclerosis (pALS) Through Telepractice: Perspectives of pALS and Communication Partners.}, journal = {American journal of speech-language pathology}, volume = {30}, number = {5}, pages = {2098-2114}, doi = {10.1044/2021_AJSLP-20-00334}, pmid = {34411491}, issn = {1558-9110}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Communication ; *Communication Devices for People with Disabilities ; Humans ; Speech ; *Speech-Language Pathology ; }, abstract = {Purpose To examine the experiences of people with ALS (pALS) and their communication partners (cALS) regarding receiving speech-generating device (SGD) evaluation and treatment via telepractice. Method Eight pALS along with a primary cALS participated in telepractice SGD evaluation and treatment with an augmentative and alternative communication (AAC) specialist and representatives from multiple SGD vendors. Participants were interviewed postevaluation and post-SGD training to examine their experiences. Mixed methods data were collected through Likert scale responses and qualitative interviews. Results Telepractice SGD evaluation and training were feasible and resulted in all pALS receiving SGDs they were able to use to communicate. In both Likert rating items and qualitative interviews, participants rated the telepractice experience very highly in terms of giving them access to AAC services via an AAC specialist that they would not have otherwise been able to access, and doing so in a format that was possible given their limitations in mobility, endurance, and caregiver availability. Suggestions for improving the telepractice experience were provided. Conclusions Telepractice should be considered as an option to provide vital SGD services to patients who are geographically remote, mobility impaired, unable to leave their home, experience fatigue with travel, or otherwise would not have access to these specialized services. Telepractice allows patients to preserve their time and energy for the assessment and treatment sessions, resulting in perhaps deeper and more frequent engagement in evaluation and training. Telepractice could serve as an alternative to outpatient, in-person evaluations, or be utilized in conjunction with in-person appointments. Supplemental Material https://doi.org/10.23641/asha.15094257.}, } @article {pmid34411705, year = {2021}, author = {Anzilotti, S and Valsecchi, V and Brancaccio, P and Guida, N and Laudati, G and Tedeschi, V and Petrozziello, T and Frecentese, F and Magli, E and Hassler, B and Cuomo, O and Formisano, L and Secondo, A and Annunziato, L and Pignataro, G}, title = {Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model.}, journal = {Neurobiology of disease}, volume = {159}, number = {}, pages = {105480}, doi = {10.1016/j.nbd.2021.105480}, pmid = {34411705}, issn = {1095-953X}, mesh = {Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology/physiopathology ; Animals ; Astrocytes/drug effects/metabolism/pathology ; Benzodiazepinones/*pharmacology ; Humans ; Mice ; Mice, Transgenic ; Microglia/drug effects/metabolism/pathology ; Motor Neurons/*drug effects/metabolism/pathology ; Neuroinflammatory Diseases/*metabolism/pathology/physiopathology ; Neuroprotective Agents/*pharmacology ; Pyrrolidines/*pharmacology ; Sodium-Calcium Exchanger/*agonists ; Spinal Cord/*drug effects/metabolism/pathology ; Superoxide Dismutase/genetics ; Survival Rate ; }, abstract = {Imbalance in cellular ionic homeostasis is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Sodium-calcium exchanger (NCX) is a membrane antiporter that, operating in a bidirectional way, couples the exchange of Ca[2+] and Na [+] ions in neurons and glial cells, thus controlling the intracellular homeostasis of these ions. Among the three NCX genes, NCX1 and NCX2 are widely expressed within the CNS, while NCX3 is present only in skeletal muscles and at lower levels of expression in selected brain regions. ALS mice showed a reduction in the expression and activity of NCX1 and NCX2 consistent with disease progression, therefore we aimed to investigate their role in ALS pathophysiology. Notably, we demonstrated that the pharmacological activation of NCX1 and NCX2 by the prolonged treatment of SOD1[G93A] mice with the newly synthesized compound neurounina: (1) prevented the reduction in NCX activity observed in spinal cord; (2) preserved motor neurons survival in the ventral spinal horn of SOD1[G93A] mice; (3) prevented the spinal cord accumulation of misfolded SOD1; (4) reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord; (5) improved the lifespan and mitigated motor symptoms of ALS mice. The present study highlights the significant role of NCX1 and NCX2 in the pathophysiology of this neurodegenerative disorder and paves the way for the design of a new pharmacological approach for ALS.}, } @article {pmid34422879, year = {2021}, author = {Milošević, M and Arsić, A and Cvetković, Z and Vučić, V}, title = {Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition.}, journal = {Frontiers in nutrition}, volume = {8}, number = {}, pages = {688086}, pmid = {34422879}, issn = {2296-861X}, abstract = {Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome-brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.}, } @article {pmid34425427, year = {2022}, author = {Tian, M and Morais, CLM and Shen, H and Pang, W and Xu, L and Huang, Q and Martin, FL}, title = {Direct identification and visualisation of real-world contaminating microplastics using Raman spectral mapping with multivariate curve resolution-alternating least squares.}, journal = {Journal of hazardous materials}, volume = {422}, number = {}, pages = {126892}, doi = {10.1016/j.jhazmat.2021.126892}, pmid = {34425427}, issn = {1873-3336}, mesh = {Animals ; Least-Squares Analysis ; *Microplastics ; Multivariate Analysis ; Plastics ; Polyethylene ; *Water Pollutants, Chemical/analysis ; }, abstract = {Microplastics (MPs) contamination is ubiquitous in environmental matrices worldwide. Moreover these pollutants can be ingested by organisms and transported to organs via the circulatory system. Although efficient methods for the analysis of MPs derived from environment matrices and organisms' tissue samples have been developed after special sample pre-treatment, there remains a need for an optimised approach allowing direct identification and visualisation these MPs in real environmental matrices and organismal samples. Herein, we firstly used a multivariate curve resolution-alternating least squares (MCR-ALS) analysis of Raman hyperspectral imaging data to direct identification and visualisation of MPs in a complex serum background. Four common MPs types including polyethylene (PE), polystyrene (PS), polypropylene (PP) and polyethylene terephthalate (PET) were identified and visualised either individually or in mixtures within spiked samples at an 8-μm spatial resolution. Moreover, Raman imaging based on MCR-ALS was successfully applied in fish faeces biological samples and environmental sand samples for in situ MPs identification directly without washing or removal of organic matter. The current results demonstrate Raman imaging based on MCR-ALS as a novel imaging approach for direct identification and visualisation of MPs, through extraction of MPs' chemical spectra within a complicated biological or environmental background whilst eliminating overlapping Raman bands and fluorescence interference.}, } @article {pmid34426623, year = {2021}, author = {Keerie, A and Brown-Wright, H and Kirkland, I and Grierson, A and Alix, JJP and Holscher, C and Mead, RJ}, title = {The GLP-1 receptor agonist, liraglutide, fails to slow disease progression in SOD1[G93A] and TDP-43[Q331K] transgenic mouse models of ALS.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {17027}, pmid = {34426623}, issn = {2045-2322}, support = {SITRAN/APR13/983-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; SITRAN/JUL16/987-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*pathology ; Animals ; Behavior, Animal/drug effects ; Biomarkers/metabolism ; Blood Glucose/metabolism ; Calcium-Binding Proteins/metabolism ; DNA-Binding Proteins/*genetics ; Disease Models, Animal ; *Disease Progression ; Glial Fibrillary Acidic Protein/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Liraglutide/*pharmacology ; Lumbar Vertebrae/drug effects/pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Motor Neurons/drug effects/pathology ; Neuroglia/drug effects/metabolism ; Superoxide Dismutase-1/*genetics ; Mice ; *Glucagon-Like Peptide-1 Receptor Agonists ; }, abstract = {GLP-1 receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer's disease (AD) and Parkinson's disease (PD). There are currently few studies investigating GLP-1 receptor agonists in the treatment of ALS, where these neuroprotective effects may be beneficial. Here we investigate the effects of liraglutide, a GLP-1 receptor agonist, in two well characterised transgenic mouse models of ALS (SOD1[G93A] and TDP-43[Q331K]) to determine if liraglutide could be a potential treatment in ALS patients. Doses of liraglutide previously shown to have efficacy in AD and PD mouse models were used. Behavioural testing was carried out to ascertain the effect of liraglutide on disease progression. Immunohistochemical analysis of tissue was used to determine any neuroprotective effects on the CNS. We found that liraglutide dosed animals showed no significant differences in disease progression when compared to vehicle dosed animals in either the SOD1[G93A] or TDP-43[Q331K] mouse models of ALS. We also observed no changes in motor neuron counts or glial activation in lumbar spinal cords of liraglutide treated mice compared to vehicle dosed mice. Overall, we found no evidence to support clinical evaluation of liraglutide as a potential candidate for the treatment of ALS.}, } @article {pmid34429248, year = {2021}, author = {Kato, Y and Sakamoto, K}, title = {Niclosamide affects intracellular TDP-43 distribution in motor neurons, activates mitophagy, and attenuates morphological changes under stress.}, journal = {Journal of bioscience and bioengineering}, volume = {132}, number = {6}, pages = {640-650}, doi = {10.1016/j.jbiosc.2021.06.015}, pmid = {34429248}, issn = {1347-4421}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; DNA-Binding Proteins/genetics ; Humans ; Mitophagy ; Motor Neurons ; *Niclosamide/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron loss in the brain and spinal cord; however, its etiology is unknown, and no curative treatment exists. TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, is a genetic mutation observed in 2-5% of familial ALS, and TDP is known to be mislocalized in the cytoplasm. This study aimed to identify compounds that inhibited the nuclear to cytoplasmic localization of TDP-43 in human induced pluripotent stem (iPS) cells-derived neurons. TDP-43 transgenic human iPS cells were constructed, differentiated into motor neurons, and then treated with MG-132 and sodium arsenite (stressors) to induce nuclear to cytoplasmic localization of TDP-43. STAT3 inhibitors, such as niclosamide, prevented TDP-43 mislocalization and degraded TDP-43 aggregates, and attenuated morphological changes under stress. Furthermore, niclosamide activated mitophagy via the PINK1-parkin-ubiquitin pathway. These findings suggest niclosamide may be a therapeutic candidate for ALS.}, } @article {pmid34432256, year = {2022}, author = {Shan, L and Martens, GJM and Swaab, DF}, title = {Histamine-4 Receptor: Emerging Target for the Treatment of Neurological Diseases.}, journal = {Current topics in behavioral neurosciences}, volume = {59}, number = {}, pages = {131-145}, pmid = {34432256}, issn = {1866-3370}, mesh = {Animals ; Anti-Inflammatory Agents ; Genome-Wide Association Study ; *Histamine ; Histamine Antagonists/therapeutic use ; Humans ; *Neurodegenerative Diseases ; Receptors, Histamine/genetics ; }, abstract = {A major challenge in the field of the biogenic amine histamine is the search for new-generation histamine receptor specific drugs. Daniel Bovet and Sir James Black received their Nobel Prizes for Medicine for their work on histamine-1 receptor (H1R) and H2R antagonists to treat allergies and gastrointestinal disorders. The first H3R-targeting drug to reach the market was approved for the treatment of the neurological disorder narcolepsy in 2018. The antagonists for the most recently identified histamine receptor, H4R, are currently under clinical evaluation for their potential therapeutic effects on inflammatory diseases such as atopic dermatitis and pruritus. In this chapter, we propose that H4R antagonists are endowed with prominent anti-inflammatory and immune effects, including in the brain. To substantiate this proposition, we combine data from transcriptional analyses of postmortem human neurodegenerative disease brain samples, human genome-wide association studies (GWAS), and translational animal model studies. The results prompt us to suggest the potential involvement of the H4R in various neurodegenerative diseases and how manipulating the H4R may create new therapeutic opportunities in central nervous system diseases.}, } @article {pmid34439576, year = {2021}, author = {Novak, V and Rogelj, B and Župunski, V}, title = {Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439576}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.}, } @article {pmid34439911, year = {2021}, author = {Barp, A and Ferrero, A and Casagrande, S and Morini, R and Zuccarino, R}, title = {Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New.}, journal = {Biomolecules}, volume = {11}, number = {8}, pages = {}, pmid = {34439911}, issn = {2218-273X}, mesh = {Amyotrophic Lateral Sclerosis/*blood ; Animals ; Antibodies/chemistry ; Biomarkers/*blood ; Creatine Kinase/*metabolism ; Disease Progression ; Humans ; Intermediate Filaments/chemistry/metabolism ; Mice ; MicroRNAs/metabolism ; Models, Biological ; Motor Neuron Disease/metabolism ; Muscular Dystrophy, Duchenne/*blood ; Neuromuscular Diseases ; Reproducibility of Results ; }, abstract = {The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less "time-consuming". In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers.}, } @article {pmid34440204, year = {2021}, author = {Obrador, E and Salvador-Palmer, R and López-Blanch, R and Dellinger, RW and Estrela, JM}, title = {NAD[+] Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440204}, issn = {2227-9059}, support = {OTR2018-19337INVES//University of Valencia and Elysium Health Inc./ ; OTR2017-18255INVES//University of Valencia and Elysium Health Inc./ ; }, abstract = {Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD[+]-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD[+] generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.}, } @article {pmid34440645, year = {2021}, author = {Cen, X and Zhang, M and Zhou, M and Ye, L and Xia, H}, title = {Mitophagy Regulates Neurodegenerative Diseases.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440645}, issn = {2073-4409}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Humans ; Mitochondria/metabolism/*pathology ; *Mitophagy ; *Nerve Degeneration ; Neurodegenerative Diseases/metabolism/*pathology ; Neurons/metabolism/*pathology ; Parkinson Disease/metabolism/pathology ; Signal Transduction ; }, abstract = {Mitochondria play an essential role in supplying energy for the health and survival of neurons. Mitophagy is a metabolic process that removes dysfunctional or redundant mitochondria. This process preserves mitochondrial health. However, defective mitophagy triggers the accumulation of damaged mitochondria, causing major neurodegenerative disorders. This review introduces molecular mechanisms and signaling pathways behind mitophagy regulation. Furthermore, we focus on the recent advances in understanding the potential role of mitophagy in the pathogenesis of major neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's, etc.) and aging. The findings will help identify the potential interventions of mitophagy regulation and treatment strategies of neurodegenerative diseases.}, } @article {pmid34440761, year = {2021}, author = {Bonaventura, G and Munafò, A and Bellanca, CM and La Cognata, V and Iemmolo, R and Attaguile, GA and Di Mauro, R and Di Benedetto, G and Cantarella, G and Barcellona, ML and Cavallaro, S and Bernardini, R}, title = {Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?.}, journal = {Cells}, volume = {10}, number = {8}, pages = {}, pmid = {34440761}, issn = {2073-4409}, mesh = {Alzheimer Disease/metabolism/pathology/physiopathology/surgery ; Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology/surgery ; Animals ; Central Nervous System/immunology/metabolism/pathology/*physiopathology ; Humans ; *Nerve Degeneration ; *Nerve Regeneration ; Neural Stem Cells/immunology/metabolism/*transplantation ; Neurodegenerative Diseases/metabolism/pathology/physiopathology/*surgery ; Neuroimmunomodulation ; Parkinson Disease/metabolism/pathology/physiopathology/surgery ; Phenotype ; Recovery of Function ; *Stem Cell Transplantation/adverse effects ; }, abstract = {Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease).}, } @article {pmid34442438, year = {2021}, author = {Lazzarino, G and Mangione, R and Belli, A and Di Pietro, V and Nagy, Z and Barnes, NM and Bruce, L and Ropero, BM and Persson, LI and Manca, B and Saab, MW and Amorini, AM and Tavazzi, B and Lazzarino, G and Logan, A}, title = {ILB[®] Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Journal of personalized medicine}, volume = {11}, number = {8}, pages = {}, pmid = {34442438}, issn = {2075-4426}, abstract = {Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB[®]. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients' clinical conditions, indicating a response to ILB[®] treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes.}, } @article {pmid34443678, year = {2021}, author = {Koike, H and Iguchi, Y and Sahashi, K and Katsuno, M}, title = {Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {16}, pages = {}, pmid = {34443678}, issn = {1420-3049}, support = {20FC1022//The Ministry of Health, Labor and Welfare of Japan/ ; }, mesh = {Amyloid/*metabolism ; Amyloidosis/*physiopathology/*therapy ; Animals ; Humans ; Organ Specificity ; Protein Aggregates ; Schwann Cells/pathology ; }, abstract = {Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer's disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer's disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.}, } @article {pmid34445680, year = {2021}, author = {Martínez-González, L and Gonzalo-Consuegra, C and Gómez-Almería, M and Porras, G and de Lago, E and Martín-Requero, Á and Martínez, A}, title = {Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {16}, pages = {}, pmid = {34445680}, issn = {1422-0067}, support = {B2017/BMD3813 ELA-Madrid//Consejería de Educación, Juventud y Deporte, Comunidad de Madrid/ ; CIBERNED CB18/05/00040//Instituto de Salud Carlos III/ ; CIBERNED CB06/05/0089//Instituto de Salud Carlos III/ ; RTI2018-096100-B-I00//Agencia Estatal de Investigación/ ; PID2019-105600RB-I00//Agencia Estatal de Investigación/ ; RTI2018-0988885-B-I00//Agencia Estatal de Investigación/ ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/*metabolism/physiology ; Disease Models, Animal ; Drug Repositioning ; Glycogen Synthase Kinase 3 beta/*metabolism/physiology ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Motor Neurons/metabolism ; Pharmaceutical Preparations/metabolism ; Phosphorylation ; Protein Kinases/metabolism ; Spinal Cord/metabolism ; Thiadiazoles/*pharmacology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3β inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3β activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43[A315T] mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.}, } @article {pmid34451802, year = {2021}, author = {Houzen, H and Kano, T and Horiuchi, K and Wakita, M and Nagai, A and Yabe, I}, title = {Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {34451802}, issn = {1424-8247}, abstract = {Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2-64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan-Meier analysis, which revealed that the median survival durations were 49 (9-88) and 25 (8-41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS.}, } @article {pmid34452489, year = {2021}, author = {Scialò, C and Celauro, L and Zattoni, M and Tran, TH and Bistaffa, E and Moda, F and Kammerer, R and Buratti, E and Legname, G}, title = {The Cellular Prion Protein Increases the Uptake and Toxicity of TDP-43 Fibrils.}, journal = {Viruses}, volume = {13}, number = {8}, pages = {}, pmid = {34452489}, issn = {1999-4915}, mesh = {Animals ; Biological Transport ; Cell Line ; Cell Survival ; DNA-Binding Proteins/genetics/*metabolism/pharmacology ; Humans ; Mice ; PrPC Proteins/classification/*genetics/*metabolism ; Prion Proteins/genetics/*metabolism ; }, abstract = {Cytoplasmic aggregation of the primarily nuclear TAR DNA-binding protein 43 (TDP-43) affects neurons in most amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases. The cellular prion protein, PrP[C], has been recognized as a common receptor and downstream effector of circulating neurotoxic species of several proteins involved in neurodegeneration. Here, capitalizing on our recently adapted TDP-43 real time quaking induced reaction, we set reproducible protocols to obtain standardized preparations of recombinant TDP-43 fibrils. We then exploited two different cellular systems (human SH-SY5Y and mouse N2a neuroblastoma cells) engineered to express low or high PrP[C] levels to investigate the link between PrP[C] expression on the cell surface and the internalization of TDP-43 fibrils. Fibril uptake was increased in cells overexpressing either human or mouse prion protein. Increased internalization was associated with detrimental consequences in all PrP-overexpressing cell lines but was milder in cells expressing the human form of the prion protein. As described for other amyloids, treatment with TDP-43 fibrils induced a reduction in the accumulation of the misfolded form of PrP[C], PrP[Sc], in cells chronically infected with prions. Our results expand the list of misfolded proteins whose uptake and detrimental effects are mediated by PrP[C], which encompass almost all pathological amyloids involved in neurodegeneration.}, } @article {pmid34457038, year = {2021}, author = {Mora, JS and Bradley, WG and Chaverri, D and Hernández-Barral, M and Mascias, J and Gamez, J and Gargiulo-Monachelli, GM and Moussy, A and Mansfield, CD and Hermine, O and Ludolph, AC}, title = {Long-term survival analysis of masitinib in amyotrophic lateral sclerosis.}, journal = {Therapeutic advances in neurological disorders}, volume = {14}, number = {}, pages = {17562864211030365}, pmid = {34457038}, issn = {1756-2856}, abstract = {BACKGROUND: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001.

METHODS: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity.

RESULTS: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001.

CONCLUSIONS: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).}, } @article {pmid34459327, year = {2022}, author = {Luna, J and Jost, J and Diagana, M and Ait Aissa, L and Tazir, M and Ali Pacha, L and Kacem, I and Gouider, R and Henning, F and Basse, A and Cisse, O and Balogou, AK and Kombate, D and Agbetou, M and Houinato, D and Gnonlonfoun, DD and Millogo, A and Agba, T and Belo, M and Sengxeu, N and Hamidou, B and Preux, PM and Benoit, M and Couratier, P and , }, title = {Clinical management and disease-modifying treatment for amyotrophic lateral sclerosis in African hospital centers: the TROPALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {279-283}, doi = {10.1080/21678421.2021.1961806}, pmid = {34459327}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology ; Hospitals ; Humans ; *Riluzole/therapeutic use ; }, abstract = {Objective: To assess the availability of health workers and medications for clinical management of amyotrophic lateral sclerosis (ALS) in African hospital centers. Availability and affordability analyses of disease-modifying treatments were performed. Methods: A multicenter observational study involving African hospitals was conducted. A standard questionnaire was developed based on the European Federation of the Neurological Societies (EFNS) guidelines. We collected data on multidisciplinary care and availability of medicines. The availability and affordability were evaluated according to the WHO guidelines. Results: Nine hospital centers from eight African countries participated. We observed a low degree of implementation of multidisciplinary care in ALS management. Riluzole was only available in centers from South Africa, Senegal, Tunisia, and Togo. This treatment was unaffordable and the adjusted price was highly variable among countries. The cost of riluzole was partly or fully covered by patients, which implies a substantial economic burden. Conclusion: Our findings strengthen the need to promote multidisciplinary care in the clinical management of ALS in Africa. Disease-modifying medication should be both available and affordable. Local and international collaboration is needed to improve ALS health care access in Africa.}, } @article {pmid34462350, year = {2021}, author = {Krishna, S and Cheng, B and Sharma, DR and Yadav, S and Stempinski, ES and Mamtani, S and Shah, E and Deo, A and Acherjee, T and Thomas, T and Zhang, X and Zhang, J and Iacobas, DA and Ballabh, P}, title = {PPAR-γ activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {36}, pages = {}, pmid = {34462350}, issn = {1091-6490}, support = {P50 HD105352/HD/NICHD NIH HHS/United States ; R01 NS110760/NS/NINDS NIH HHS/United States ; R21 NS102897/NS/NINDS NIH HHS/United States ; }, mesh = {Amino Acid Transport Systems, Acidic/deficiency/metabolism ; Animals ; Animals, Newborn ; Antiporters/deficiency/metabolism ; Cerebral Intraventricular Hemorrhage/*metabolism/pathology ; Disease Models, Animal ; Hereditary Central Nervous System Demyelinating Diseases/metabolism ; Humans ; Infant, Premature ; Microglia/metabolism ; Mitochondrial Diseases/metabolism ; Myelin Proteins/*biosynthesis ; Oligodendroglia/pathology ; PPAR gamma/agonists/*metabolism ; Psychomotor Disorders/metabolism ; Rabbits ; Rosiglitazone/pharmacology ; Sequence Analysis, RNA/methods ; }, abstract = {Intraventricular hemorrhage (IVH) results in periventricular inflammation, hypomyelination of the white matter, and hydrocephalus in premature infants. No effective therapy exists to prevent these disorders. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists reduce inflammation, alleviate free radical generation, and enhance microglial phagocytosis, promoting clearance of debris and red blood cells. We hypothesized that activation of PPAR-γ would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in a preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPAR-γ expression in microglia of both preterm human infants and rabbit kits. The treatment with PPAR-γ agonist or PPAR-γ overexpression by adenovirus delivery further elevated PPAR-γ levels in microglia, reduced proinflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPAR-γ-induced genes for purinergic signaling, cyclic adenosine monophosphate generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-sequencing analyses of microglia revealed PPAR-γ-triggered down-regulation of several proinflammatory genes and transcripts having roles in Parkinson's disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPAR-γ activation enhanced myelination and neurological function in kits with IVH. This also enhanced microglial phagocytosis of red blood cells but did not reduce hydrocephalus. Treatment with PPAR-γ agonist might enhance myelination and neurological recovery in premature infants with IVH.}, } @article {pmid34466357, year = {2021}, author = {Dhindsa, BS and Naga, Y and Saghir, SM and Daid, SGS and Chandan, S and Mashiana, H and Dhaliwal, A and Sidhu, A and Sayles, H and Ramai, D and Bhat, I and Singh, S and McDonough, S and Adler, DG}, title = {Endo-sponge in management of anastomotic colorectal leaks: a systematic review and meta-analysis.}, journal = {Endoscopy international open}, volume = {9}, number = {9}, pages = {E1342-E1349}, pmid = {34466357}, issn = {2364-3722}, abstract = {Background and study aims Following colorectal surgery, anastomotic dehiscence and leak formation has an incidence of 2 % to 7 %. Endo-SPONGE has been applied in the management of anastomatic leaks (ALs) after colorectal surgery. This is the first systematic review and meta analysis to evaluate the efficacy and safety of Endo-SPONGE in the management of colorectal ALs. Patients and methods The primary outcomes assessed were the technical and clinical success of Endo-SPONGE placement in colorectal ALs. The secondary outcomes assessed were the overall adverse events (AEs) and the AE subtypes. Pooled estimates were calculated using random-effects models with 95 % confidence interval (C. I.). The statistical analysis was done using STATA v16.1 software (StataCorp, LLC College Station, Texas, United States). Results The analysis included 17 independent cohort studies with a total of 384 patients. The rate of technical success was 99.86 % (95 % CI: 99.2 %, 100 %; P = 0.00; I [2] = 70.69 %) and the calculated pooled rate of clinical success was 84.99 % (95 % CI: 77.4 %, 91.41 %; P = 0.00; I [2] = 68.02 %). The calculated pooled rate of adverse events was 7.6 % (95 % CI: 3.99 %, 12.21 %; P = 0.03; I [2] = 42.5 %) with recurrent abscess formation and bleeding being the most common AEs. Moderate to substantial heterogeneity was noted in our meta-analysis. Conclusions Endoscopic vacuum therapy appears to be a minimally invasive, safe, and effective treatment modality for patients with a significant colorectal leak without any generalized peritonitis with high clinical and technical success rates and a low rate of adverse events. Further prospective or randomized controlled trials are needed to validate our findings.}, } @article {pmid34466632, year = {2021}, author = {Tavakol-Afshari, J and Boroumand, AR and Farkhad, NK and Adhami Moghadam, A and Sahab-Negah, S and Gorji, A}, title = {Safety and efficacy of bone marrow derived-mesenchymal stem cells transplantation in patients with amyotrophic lateral sclerosis.}, journal = {Regenerative therapy}, volume = {18}, number = {}, pages = {268-274}, pmid = {34466632}, issn = {2352-3204}, abstract = {Stem cell-based treatments have emerged as potentially effective approaches to delay the progression of amyotrophic lateral sclerosis (ALS). This study was designed as a single-center, prospective, and open-label study without a placebo control group to assess the safety and efficacy of concurrent intrathecal (IT) and intravenous (IV) administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS. Autologous BM-MSCs were isolated and expanded under standard conditions. Fifteen patients were neurologically examined before BM-MSCs transplantation (1 × 10 [6] cells/kg BW) to evaluate the rate of pre-treatment disease progression. To assess the safety and efficacy, patients were examined at 1, 3, and 6 months following the treatment with BM-MSCs. Adverse reactions were assessed, and the clinical outcome was determined by the evaluation of the ALS functional rating scale-revised (ALSFRS-R) and forced vital capacity (FVC). No serious adverse reaction was observed after combined IT and IV administration of BM-MSCs. The mean ALSFRS-R and FVC values remained stable during the first 3 months of the treatment. However, a significant reduction in ALSFRS-R and FVC levels was observed in these patients 6 months after BM-MSCs administration. Our study revealed that the concurrent IT and IV application of BM-MSCs in patients with ALS is a safe procedure. Furthermore, our data indicate a temporary delay in the progression of ALS after a single combined IT and IV administration of BM-MSCs. Further studies are required to explore if the repeated applications of BM-MSCs could prolong survival and delay the progression of ALS.}, } @article {pmid34472458, year = {2022}, author = {Martinez, B and Peplow, PV}, title = {MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {728-740}, pmid = {34472458}, issn = {1673-5374}, abstract = {A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals.}, } @article {pmid34472488, year = {2022}, author = {Wei, QQ and Hou, YB and Zhang, LY and Ou, RW and Cao, B and Chen, YP and Shang, HF}, title = {Neutrophil-to-lymphocyte ratio in sporadic amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {17}, number = {4}, pages = {875-880}, pmid = {34472488}, issn = {1673-5374}, abstract = {The neutrophil-to-lymphocyte ratio (NLR) is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases. However, it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis (ALS). To correlate NLR with disease progression and survival in sporadic ALS, 1030 patients with ALS between January 2012 and December 2018 were included in this study. These patients were assigned into three groups according to their NLR values: Group 1 (NLR < 2, n = 544 [52.8%]), Group 2 (NLR = 2-3, n = 314 [30.5%]), and Group 3 (NLR > 3, n = 172 [16.7%]). All patients were followed up until April 2020. Patients in Group 3 had a significantly older onset age, a lower score on the Revised ALS Functional Rating Scale, and rapidly progressing disease conditions. Furthermore, faster disease progression rates were associated with higher NLR values (odds ratio = 1.211, 95% confidence interval [CI]: 1.090-1.346, P < 0.001) after adjusting for other risk factors. Compared with Groups 1 and 2, the survival time in Group 3 was significantly shorter (log-rank P = 0.002). The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters (hazard ratio [HR] = 1.079, 95% CI: 1.016-1.146, P = 0.014). The effects on ALS survival remained significant when adjusted for treatment (HR = 1.074, 95% CI: 1.012-1.141, Ptrend = 0.019) or when considering the stratified NLR value (HR = 1.115, 95% CI: 1.009-1.232, Ptrend = 0.033). Thus, the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS. The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University, China (approval No. 2015 (236)) on December 23, 2015.}, } @article {pmid34476128, year = {2021}, author = {Berry, J and Brooks, B and Genge, A and Heiman-Patterson, T and Appel, S and Benatar, M and Bowser, R and Cudkowicz, M and Gooch, C and Shefner, J and Westra, J and Agnese, W and Merrill, C and Nelson, S and Apple, S}, title = {Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design.}, journal = {Neurology. Clinical practice}, volume = {11}, number = {4}, pages = {e472-e479}, pmid = {34476128}, issn = {2163-0402}, abstract = {OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes.

METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported.

RESULTS: The study is estimated to be completed in 2022 with an interim analysis planned.

CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.}, } @article {pmid34479020, year = {2021}, author = {Nguyen, TT and Dung Nguyen, TT and Vo, TK and Tran, NM and Nguyen, MK and Van Vo, T and Van Vo, G}, title = {Nanotechnology-based drug delivery for central nervous system disorders.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {143}, number = {}, pages = {112117}, doi = {10.1016/j.biopha.2021.112117}, pmid = {34479020}, issn = {1950-6007}, mesh = {Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System Agents/*administration & dosage/chemistry/metabolism ; Central Nervous System Diseases/*drug therapy/metabolism ; *Drug Carriers ; Drug Compounding ; Drug Development ; Drug Discovery ; Humans ; *Nanomedicine ; *Nanoparticles ; Permeability ; Translational Research, Biomedical ; }, abstract = {Drug delivery to central nervous system (CNS) diseases is very challenging since the presence of the innate blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier that impede drug delivery. Among new strategies to overcome these limitations and successfully deliver drugs to the CNS, nanotechnology-based drug delivery platform, offers potential therapeutic approach for the treatment of some common neurological disorders like Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease. This review aimed to highlight advances in research on the development of nano-based therapeutics for their implications in therapy of CNS disorders. The challenges during clinical translation of nanomedicine from bench to bed side is also discussed.}, } @article {pmid34479980, year = {2021}, author = {Garbuzova-Davis, S and Boccio, KJ and Llauget, A and Shell, R and Hailu, S and Mustafa, H and Ehrhart, J and Sanberg, PR and Appel, SH and Borlongan, CV}, title = {Beneficial Effects of Transplanted Human Bone Marrow Endothelial Progenitors on Functional and Cellular Components of Blood-Spinal Cord Barrier in ALS Mice.}, journal = {eNeuro}, volume = {8}, number = {5}, pages = {}, pmid = {34479980}, issn = {2373-2822}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Animals ; Bone Marrow ; Disease Models, Animal ; Endothelial Cells ; Endothelium ; Humans ; Mice ; Mice, Transgenic ; Spinal Cord ; Superoxide Dismutase/genetics ; }, abstract = {Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated versus non-treated mice via Western blotting at four weeks after transplant. Capillary pericyte, basement membrane laminin, and endothelial F-actin magnitudes were determined in cervical/lumbar spinal cord tissues in ALS mice, including controls, by immunohistochemistry and fluorescent staining. Results showed that cell-treated versus media-treated ALS mice substantially increased tight junction protein levels, capillary pericyte coverage, basement membrane laminin immunoexpressions, and endothelial cytoskeletal F-actin fluorescent expressions. The greatest benefits were detected in mice receiving hBM-EPCs versus hBM34+ cells. These study results support treatment with a specific cell type derived from human bone marrow toward BSCB repair in ALS. Thus, hBM-EPCs may be advanced for clinical applications as a cell-specific approach for ALS therapy through restored barrier integrity.}, } @article {pmid34481449, year = {2021}, author = {Alessenko, AV and Gutner, UA and Nebogatikov, VO and Shupik, MA and Ustyugov, AA}, title = {[The role of sphingolipids in pathogenesis of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {121}, number = {8}, pages = {131-140}, doi = {10.17116/jnevro2021121081131}, pmid = {34481449}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Motor Neurons ; *Neurodegenerative Diseases ; Sphingolipids ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by selective degeneration of motor neurons of the spinal cord and motor cortex and brain stem. The key features of the course of this disease are excitotoxicity, oxidative stress, mitochondrial dysfunction, neuro-inflammatory and immune reactions. Recently, the mechanisms of programmed cell death (apoptosis), which may be responsible for the degeneration of motor neurons in this disease, have been intensively studied. In this regard, sphingolipids, which are the most important sources of secondary messengers that transmit cell proliferation, differentiation and apoptosis signals, and are involved in the development of neuroinflammatory and immune responses, are of particular interest in the context of ALS pathogenesis. The review provides information from domestic and foreign authors on the involvement of various sphingolipids (sphingomyelins, ceramides, sphingosine, sphinganin, sphingosine-1-phosphate, galactosylceramides, glucosylceramides, gangliosides) in the development of pro-inflammatory reactions and apoptosis of motor neurons in ALS. The authors discuss the prospects of using new drugs that control the metabolism of sphingolipids for the treatment of ALS.}, } @article {pmid34491837, year = {2021}, author = {Bertozzi, M and Ruffoli, M and Vatta, F and Gazzaneo, M and Raffaele, A and Mencherini, S and Riccipetitoni, G}, title = {The Effectiveness of Abdominal Lymphangioma Laparoscopic Removal in Children: A Single Center Experience.}, journal = {Journal of laparoendoscopic & advanced surgical techniques. Part A}, volume = {31}, number = {12}, pages = {1367-1371}, doi = {10.1089/lap.2021.0323}, pmid = {34491837}, issn = {1557-9034}, mesh = {Child ; *Digestive System Surgical Procedures ; Humans ; Infant ; *Laparoscopy ; *Lymphangioma/surgery ; Magnetic Resonance Imaging ; *Mesocolon ; }, abstract = {Background: Lymphangiomas represent 5% of all benign pediatric tumors. Abdominal lymphangiomas (ALs) are extremely rare. Therapy includes surgery, sclerotherapy, or pharmacological treatment. Laparoscopic resection (LR) has been already described, but mainly as case reports. The aim of this study is to present our series of ALs LR. Materials and Methods: From 2007 to 2020, 10 cases of ALs were electively treated by LR. Patients' age ranged from 4 months to 14 years. Preoperative diagnosis was achieved by ultrasonography and magnetic resonance images. In all cases LR was performed with four trocars: a 10 mm transumbilical trocar for camera and extraction and three 3-5 mm operative trocars. Results: Lymphangiomas arise from mesocolon in 5 giant cases, ileal mesentery in 3 and right adrenal gland in 2. LR was achieved without intraoperative complications and need of conversion in all cases. Two giant cases needed a percutaneous puncture under laparoscopic view to gain working space. A minimal ileal resection by video-assisted procedure was carried out in 2. Median hospital length was 4 days; no recurrence of disease at serial ultrasound examinations was seen at median follow-up of 5.9 years. Discussion: Several approaches have been proposed for AL treatment. The main challenges are the huge dimensions, the difficulty to achieve a complete resection, and the risk of recurrence. In this series, elective LR of ALs resulted as feasible and effective, and we consider it the standard surgical therapy.}, } @article {pmid34492237, year = {2022}, author = {Subbarayan, MS and Joly-Amado, A and Bickford, PC and Nash, KR}, title = {CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases.}, journal = {Pharmacology & therapeutics}, volume = {231}, number = {}, pages = {107989}, doi = {10.1016/j.pharmthera.2021.107989}, pmid = {34492237}, issn = {1879-016X}, support = {IK6 BX004214/BX/BLRD VA/United States ; }, mesh = {CX3C Chemokine Receptor 1/metabolism ; *Chemokine CX3CL1/metabolism ; Humans ; Microglia/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroglia/metabolism ; }, abstract = {Neuroinflammation was initially thought of as a consequence of neurodegenerative disease pathology, but more recently it is becoming clear that it plays a significant role in the development and progression of disease. Thus, neuroinflammation is seen as a realistic and valuable therapeutic target for neurodegeneration. Neuroinflammation can be modulated by neuron-glial signaling through various soluble factors, and one such critical modulator is Fractalkine or C-X3-C Motif Chemokine Ligand 1 (CX3CL1). CX3CL1 is produced in neurons and is a unique chemokine that is initially translated as a transmembrane protein but can be proteolytically processed to generate a soluble chemokine. CX3CL1 has been shown to signal through its sole receptor CX3CR1, which is located on microglial cells within the central nervous system (CNS). Although both the membrane bound and soluble forms of CX3CL1 appear to interact with CX3CR1, they do seem to have different signaling capabilities. It is believed that the predominant function of CX3CL1 within the CNS is to reduce the proinflammatory response and many studies have shown neuroprotective effects. However, in some cases CX3CL1 appears to be promoting neurodegeneration. This review focusses on presenting a comprehensive overview of the complex nature of CX3CL1/CX3CR1 signaling in neurodegeneration and how it may present as a therapeutic in some neurodegenerative diseases but not others. The role of CX3CL1/CXCR1 is reviewed in the context of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ischemia, retinopathies, spinal cord and neuropathic pain, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy.}, } @article {pmid34496365, year = {2022}, author = {Mohammadi, A and Hosseinzadeh Colagar, A and Khorshidian, A and Amini, SM}, title = {The Functional Roles of Curcumin on Astrocytes in Neurodegenerative Diseases.}, journal = {Neuroimmunomodulation}, volume = {29}, number = {1}, pages = {4-14}, doi = {10.1159/000517901}, pmid = {34496365}, issn = {1423-0216}, mesh = {Animals ; Astrocytes ; Brain ; *Curcumin/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; Neurons ; }, abstract = {Progressive abnormality and loss of axons and neurons in the central nervous system (CNS) cause neurodegenerative diseases (NDs). Protein misfolding and its collection are the most important pathological features of NDs. Astrocytes are the most plentiful cells in the mammalian CNS (about 20-40% of the human brain) and have several central functions in the maintenance of the health and correct function of the CNS. Astrocytes have an essential role in the preservation of brain homeostasis, and it is not surprising that these multifunctional cells have been implicated in the onset and progression of several NDs. Thus, they become an exciting target for the study of NDs. Over almost 15 years, it was revealed that curcumin has several therapeutic effects in a wide variety of diseases' treatment. Curcumin is a valuable ingredient present in turmeric spice and has several essential roles, including those which are anticarcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic, and anti-infectious. Furthermore, curcumin can suppress inflammation; promote angiogenesis; and treat diabetes, pulmonary problems, and neurological dysfunction. Here, we review the effects of curcumin on astrocytes in NDs, with a focus on Alzheimer's disease, Parkinson's disease, multiple scleroses, Huntington's disease, and amyotrophic lateral sclerosis.}, } @article {pmid34502460, year = {2021}, author = {Fernández-Beltrán, LC and Godoy-Corchuelo, JM and Losa-Fontangordo, M and Williams, D and Matias-Guiu, J and Corrochano, S}, title = {A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {17}, pages = {}, pmid = {34502460}, issn = {1422-0067}, support = {2018-T1/BMD-10731//Consejería de Educación, Juventud y Deporte, Comunidad de Madrid/ ; }, mesh = {Amyotrophic Lateral Sclerosis/etiology/*metabolism ; Animals ; Disease Models, Animal ; Female ; *Lipid Metabolism ; Mice ; Spinal Cord/*metabolism ; Steroid Hydroxylases/genetics/metabolism ; *Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial and complex fatal degenerative disorder. A number of pathological mechanisms that lead to motor neuron death have been identified, although there are many unknowns in the disease aetiology of ALS. Alterations in lipid metabolism are well documented in the progression of ALS, both at the systemic level and in the spinal cord of mouse models and ALS patients. The origin of these lipid alterations remains unclear. This study aims to identify early lipid metabolic pathways altered before systemic metabolic symptoms in the spinal cord of mouse models of ALS. To do this, we performed a transcriptomic analysis of the spinal cord of SOD1[G93A] mice at an early disease stage, followed by a robust transcriptomic meta-analysis using publicly available RNA-seq data from the spinal cord of SOD1 mice at early and late symptomatic disease stages. The meta-analyses identified few lipid metabolic pathways dysregulated early that were exacerbated at symptomatic stages; mainly cholesterol biosynthesis, ceramide catabolism, and eicosanoid synthesis pathways. We present an insight into the pathological mechanisms in ALS, confirming that lipid metabolic alterations are transcriptionally dysregulated and are central to ALS aetiology, opening new options for the treatment of these devastating conditions.}, } @article {pmid34505708, year = {2021}, author = {Cleary, S and Misiaszek, JE and Wheeler, S and Kalra, S and Genuis, SK and Johnston, WS}, title = {Lung volume recruitment improves volitional airway clearance in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {64}, number = {6}, pages = {676-682}, pmid = {34505708}, issn = {1097-4598}, mesh = {Activities of Daily Living ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Cough ; Cross-Over Studies ; Humans ; Lung Volume Measurements ; Respiratory Function Tests ; }, abstract = {INTRODUCTION/AIMS: In this study we evaluated the effects of lung volume recruitment treatment (LVR), a low-tech, low-cost, manual "breath-stacking" technique used to help people cough with enough force to clear their airways, thereby reducing the risk of aspiration and choking, on five volitional airway clearance and protection behaviors used by people living with amyotrophic lateral sclerosis (PwALS).

METHODS: Using a repeated-measures cross-over design, 29 PwALS performed five volitional airway clearance and protection behaviors in LVR treatment and in no-treatment, control conditions. Peak cough flow (PCF) was used to measure maximum expiratory rate during forced expiration, throat clearing, hawking, post-swallow coughing, and the supraglottic swallowing maneuver. Comparisons were made as a function of condition (treatment or control) and three time-points (pretreatment, and 15 and 30 minutes posttreatment).

RESULTS: LVR treatment had a significant positive effect on maximum expiratory rates during all tested airway clearance and protection behaviors. Increased PCF values lasted for up to 30 minutes post-LVR for all tested behaviors in the treatment condition.

DISCUSSION: We found that LVR treatment could increase control over airway clearance in PwALS, as well as provide improved airway protection for up to 30 minutes, the duration of a typical meal. This study has implications for patient care. These include offering patients control over some of the most feared symptoms of ALS, particularly choking during activities of daily living, and enhanced ALS respiratory care in low-resource settings. Findings may have implications for other neurodegenerative disorders in which dysphagia occurs with retained sensory function.}, } @article {pmid34510973, year = {2022}, author = {Lou, K and Murphy, S and Talbot, C}, title = {Cannabinoids for the treatment of refractory neuropathic pruritus in amyotrophic lateral sclerosis: A case report.}, journal = {Palliative medicine}, volume = {36}, number = {1}, pages = {208-211}, pmid = {34510973}, issn = {1477-030X}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; *Cannabinoids/therapeutic use ; Dronabinol/therapeutic use ; Humans ; Middle Aged ; Pain/drug therapy ; Pruritus/drug therapy/etiology ; }, abstract = {BACKGROUND: Neuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids.

CASE PRESENTATION: A 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies.

POSSIBLE COURSE OF ACTION: Sodium channel and N-methyl-D-aspartate receptor antagonists have evidence for neuropathic symptoms but can cause significant gastrointestinal side effects. Prescription cannabinoids such as nabiximol can be cost prohibitive to use in practice. Synthetic tetrahydrocannabinol products are dose limited by psychoactive side effects.

FORMULATION OF A PLAN: A balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated.

OUTCOME: The patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly.

LESSONS LEARNED FROM CASE: Cannabinoids are possibly safe and effective in management of neuropathic pruritus.

VIEW ON RESEARCH PROBLEMS: Additional research is needed to establish efficacy and safety.}, } @article {pmid34512775, year = {2021}, author = {Pan, H and Wang, H and Tao, Y and Yuan, J and Xu, S and Ni, J and Huang, M and Wu, X and Liu, T}, title = {Evidence-Based Research Strategy of Traditional Chinese Medicine for Amyotrophic Lateral Sclerosis.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {3402753}, pmid = {34512775}, issn = {1741-427X}, abstract = {Among adult-onset motor neuron diseases, amyotrophic lateral sclerosis (ALS) is the most common. ALS involves the increasing loss of lower and upper motor neurons. Within a few years of onset, ALS causes patient death via progressive paralysis of respiratory muscles. However, the current drugs used to treat ALS, riluzole, edaravone, and dextromethorphan/quinidine, can only delay the progression of the disease and alleviate a small number of symptoms in some patients, and no completely effective treatment is available. Traditional Chinese medicine (TCM) has shown significant advantages in the treatment of ALS in China and Asia; however, the mechanism of its efficacy is unclear. This review discusses the pathogenetic hypothesis of ALS in detail from the level of neurons and glial cells and uses two current experimental animal models of ALS to design experimental strategies to study TCM treatment. We aim to provide a scientific explanation of the mechanism of the effect of TCM in the treatment of ALS, which will help clinicians and research scientists to accept the theory of TCM to treat ALS and promote the development of TCM modernization.}, } @article {pmid34513831, year = {2021}, author = {Xu, S and Zhang, X and Liu, C and Liu, Q and Chai, H and Luo, Y and Li, S}, title = {Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {688789}, pmid = {34513831}, issn = {2296-634X}, abstract = {Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD[+], in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.}, } @article {pmid34514988, year = {2021}, author = {Beltran-Beltran, V and Benetó, N and Lapeña-Luzón, T and Rodríguez, LR and Pallardó, FV and Gonzalez-Cabo, P}, title = {Role of Adenosine Receptors in Rare Neurodegenerative Diseases with Motor Symptoms.}, journal = {Current protein & peptide science}, volume = {22}, number = {9}, pages = {675-694}, doi = {10.2174/1389203722666210910110126}, pmid = {34514988}, issn = {1875-5550}, support = {PI19/01084//Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación/ ; PROMETEO/2018/135, ACCI-2018-22, ACCI-2019- 22//Generalitat Valenciana/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology ; *Receptors, Purinergic P1/metabolism/genetics ; Adenosine/metabolism ; Animals ; Rare Diseases/metabolism/genetics/drug therapy/pathology ; Purines/metabolism/therapeutic use ; }, abstract = {The approval of istradefylline, an adenosine 2A receptor (A2AR) antagonist, as an addon treatment in adult patients with Parkinson's disease by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), is the latest proof of the importance of the adenosinergic system in the nervous system. Adenosine is an endogenous purine nucleoside with a role as a modulator of both neurotransmission and the inflammatory response. As such, the expression pattern of the 4 adenosine receptors (A1R, A2AR, A2BR and A3R) and the extracellular adenosine levels have attracted great interest in the pathogenesis and possible treatment of rare neurodegenerative diseases with motor symptoms. These include Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Restless Legs Syndrome (RLS) and Machado-Joseph Disease (MJD, also known as spinocerebellar ataxia type 3, SCA3). In this review, we shall focus on the role of the different adenosine receptor subtypes in the development and possible treatment of the aforementioned rare neurodegenerative diseases with motor symptoms using the currently available data. The last section discusses the possibility of a role for the adenosine receptors in the treatment of other rare diseases based on the available molecular pathology knowledge.}, } @article {pmid34536404, year = {2021}, author = {Cudkowicz, M and Genge, A and Maragakis, N and Petri, S and van den Berg, L and Aho, VV and Sarapohja, T and Kuoppamäki, M and Garratt, C and Al-Chalabi, A and , }, title = {Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {20}, number = {10}, pages = {821-831}, doi = {10.1016/S1474-4422(21)00242-8}, pmid = {34536404}, issn = {1474-4465}, mesh = {Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Simendan/therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.

METHODS: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.

FINDINGS: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.

INTERPRETATION: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.

FUNDING: Orion Corporation.}, } @article {pmid34539339, year = {2021}, author = {Valori, CF and Neumann, M}, title = {Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {724891}, pmid = {34539339}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD-TDP-43 or ALS/FTLD-FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.}, } @article {pmid34544176, year = {2021}, author = {Onder, ENA and Ertan, P}, title = {Fibrinogen-to-Albumin Ratio in Familial Mediterranean Fever: Association with Subclinical Inflammation.}, journal = {Klinische Padiatrie}, volume = {233}, number = {6}, pages = {292-298}, doi = {10.1055/a-1610-9745}, pmid = {34544176}, issn = {1439-3824}, mesh = {Albumins ; *Familial Mediterranean Fever/diagnosis/drug therapy/genetics ; *Fibrinogen ; Humans ; Inflammation ; Retrospective Studies ; }, abstract = {BACKGROUND: Familial Mediterranean fever (FMF) is the most seen monogenic periodic fever syndrome characterised by bouts of fever and serositis. It is known that subclinical inflammation (SI) can persist in the symptom-free period and lead to amyloidosis even under colchicine treatment. This study aimed to evaluate the role of the fibrinogen-to-albumin ratio (FAR) in FMF and its correlation with SI.

MATERIAL AND METHODS: A total of 112 patients with FMF and 78 controls were enrolled in this retrospective study. Demographic, laboratory and genetic data were obtained from the hospital records.

RESULTS: The FAR values of the FMF cases were significantly higher than the control group (p<0.001). In the FMF group, the patients with SI had higher FAR values than those without SI (p<0.001). FAR was positively correlated with SI (r=0.413, p<0.001). The receiver operating characteristic curve analysis showed that FAR had a higher area under the curve value than albumin and fibrinogen.

CONCLUSION: Detecting SI in patients with FMF is crucial in preventing amyloidosis, the most devastating complication of FMF. FAR is a simple, inexpensive, easily obtained indicator which can be used for reflecting SI in FMF.

HINTERGRUND: Familiäres Mittelmeerfieber (FMF) ist das am häufigsten auftretende monogene periodische Fiebersyndrom, das durch Fieberschübe und Serositis gekennzeichnet wird. Die subklinische Entzündung (SI) kann bekanntlich auch in der symptomfreien Phase fortbestehen und zu Amyloidose führen, selbst unter Behandlung mit Colchicin. Ziel dieser Studie ist es, die Beziehung zwischen Fibrinogen und Albumin (AFR) bei FMF und deren Korrelation mit SI zu untersuchen.

MATERIAL UND METHODEN: Insgesamt wurden für diese retrospektive Studie 112 Patienten mit FMF und 78 Kontrollpatienten eingeschlossen. Die demographischen, labortechnischen und genetischen Daten wurden aus den Krankenhausunterlagen entnommen.

ERGEBNISSE: Die Werte von AFR bei Patienten mit FMF waren signifikant höher als die der Kontrollgruppe (<0,001). Patienten mit FMF mit SI zeigten höhere AFR-Werte als FMF-Patienten ohne SI (<0,001). AFR korrelierte positiv mit SI (r=0,413, p<0,001). Die Analyse der ROC-Kurve (Receiver Operating Characteristic) zeigte, dass AFR einen höheren Wert der Fläche unter der Kurve (AUC) hatte als Albumin und Fibrinogen.

DISKUSSION: Die Erkennung von SI bei FMF-Patienten ist entscheidend für die Vermeidung von Amyloidose, der schlimmsten Komplikation von FMF. AFR ist ein einfacher, kostengünstiger, leicht durchzuführender Indikator, der in FMF zur Spiegelung von SI verwendet werden kann.}, } @article {pmid34554894, year = {2021}, author = {Chiò, A and Canosa, A and Calvo, A and Moglia, C and Cicolin, A and Mora, G}, title = {Developments in the assessment of non-motor disease progression in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {21}, number = {12}, pages = {1419-1440}, doi = {10.1080/14737175.2021.1984883}, pmid = {34554894}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; *Cognitive Dysfunction ; Disease Progression ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: The burden of non-motor symptoms is a major determinant of quality of life and outcome in amyotrophic lateral sclerosis (ALS) and has profound negative effect also on caregivers.

AREAS COVERED: Non-motor symptoms in ALS include cognitive impairment, neurobehavioral symptoms, depression and anxiety, suicidal ideation, pain, disordered sleep, fatigue, weight loss and reduced appetite, and autonomic dysfunctions. This review summarizes the measures used for the assessment of non-motor symptoms and their properties and recaps the frequency and progression of these symptoms along the course of ALS.

EXPERT OPINION: Non-motor symptoms in ALS represent a major component of the disease and span over several domains. These symptoms require a high level of medical attention and should be checked at each visit using ad hoc questionnaires and proactively treated. Several instruments assessing non-motor symptoms have been used in ALS. Specific screening questionnaires for non-motor symptoms can be used for monitoring patients during telehealth visits and for remote surveillance through sensors and apps installed on smartphones. Novel trials for non-motor symptoms treatment specifically designed for ALS are necessary to increase and refine the therapeutic armamentarium. Finally, scales assessing the most frequent and burdensome non-motor symptoms should be included in clinical trials.}, } @article {pmid34558138, year = {2022}, author = {Erekat, NS}, title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {35}, number = {1}, pages = {65-78}, doi = {10.1002/ca.23792}, pmid = {34558138}, issn = {1098-2353}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.}, } @article {pmid34560374, year = {2021}, author = {Sahu, R and Upadhayay, S and Mehan, S}, title = {Inhibition of extracellular regulated kinase (ERK)-1/2 signaling pathway in the prevention of ALS: Target inhibitors and influences on neurological dysfunctions.}, journal = {European journal of cell biology}, volume = {100}, number = {7-8}, pages = {151179}, doi = {10.1016/j.ejcb.2021.151179}, pmid = {34560374}, issn = {1618-1298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Cell Proliferation ; Humans ; MAP Kinase Signaling System ; Neurons ; Signal Transduction ; }, abstract = {Cell signal transduction pathways are essential modulators of several physiological and pathological processes in the brain. During overactivation, these signaling processes may lead to disease progression. Abnormal protein kinase activation is associated with several biological dysfunctions that facilitate neurodegeneration under different biological conditions. As a result, these signaling pathways are essential in understanding brain disorders' development or progression. Recent research findings indicate the crucial role of extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling during the neuronal development process. ERK-1/2 is a key component of its mitogen-activated protein kinase (MAPK) group, controlling certain neurological activities by regulating metabolic pathways, cell proliferation, differentiation, and apoptosis. ERK-1/2 also influences neuronal elastic properties, nerve growth, and neurological and cognitive processing during brain injuries. The primary goal of this review is to elucidate the activation of ERK1/2 signaling, which is involved in the development of several ALS-related neuropathological dysfunctions. ALS is a rare neurological disorder category that mainly affects the nerve cells responsible for regulating voluntary muscle activity. ALS is progressive, which means that the symptoms are getting worse over time, and there is no cure for ALS and no effective treatment to avoid or reverse. Genetic abnormalities, oligodendrocyte degradation, glial overactivation, and immune deregulation are associated with ALS progression. Furthermore, the current review also identifies ERK-1/2 signaling inhibitors that can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of ALS. As a result, in the future, the potential ERK-1/2 signaling inhibitors could be used in the treatment of ALS and related neurocomplications.}, } @article {pmid34560799, year = {2023}, author = {Raspe, H and Lill, C}, title = {[Inflammatory Bowel Diseases: Regional Deprivation, Disease Characteristics and Relevant Health Care].}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {85}, number = {3}, pages = {149-157}, doi = {10.1055/a-1530-5529}, pmid = {34560799}, issn = {1439-4421}, mesh = {Humans ; *Quality of Life ; Germany ; *Medicine ; Delivery of Health Care ; Histamine/analogs & derivatives ; }, abstract = {HINTERGRUND: Regionale Deprivation ist als ökologischer Parameter eine Komponente der sozialen Determinanten von Gesundheit. Zu ihrer Messung stehen in Deutschland der "German Index of Multiple Deprivation" (GIMD) und der "German Index of Socioeconomic Deprivation" (GISD) zur Verfügung. Chronisch entzündliche Darmerkrankungen (CED) sind keine häufigen, aber ernste körperliche Erkrankungen unklarer Ätiologie, mit vergleichsweise frühem Auftreten im Erwachsenenalter, oft chronisch-behandlungsbedürftigem Verlauf und unsicherer Prognose. Daten einer kontrollierten Versorgungsstudie erlauben es, Assoziationen zwischen regio-naler Deprivation und Merkmalen der Krankheit und ihrer Versorgung zu untersuchen. Wir erwarteten ungünstigere Krankheitsverhältnisse bei höherer Deprivation.

METHODIK: Vorgestellt werden deskriptive Zusatzauswertungen (n=530) der 2016 bis 2019 durchgeführten MERCED-Studie zu Wirksamkeit und Nutzen einer stationären medizinischen Rehabilitation bei Sozialversicherten mit einer CED. Analysiert wurden Daten aus der Basisbefragung zu selbstberichteten Krankheitsmerkmalen, Krankheitsfolgen und Versorgungsleistungen in ihrem Zusammenhang mit dem Ausmaß regionaler Deprivation der Wohnregion (Kreisebene).

ERGEBNISSE: Die Zuordnung der Wohnregion der Kranken zu den Quintilen von GIMD und GISD korrelieren unter rho=0,76 miteinander (gewichtetes kappa=0,74). Regionale Deprivation zeigt, gemessen mit dem GIMD, überzufällige Unterschiede allein in den sozialen Teilhabeeinschränkungen (IMET) und der Zahl der "Einschränkungstage". Dabei schildern sich Personen aus dem niedrigsten Deprivationsquintil als am stärksten eingeschränkt. Für die Einschränkungstage findet sich ein irre-guläres Muster. Beim GISD wird eine unsystematische Variation der gesundheitsbezogenen Lebensqualität (EQ-VAS) statistisch auffällig. Auch hier berichten Personen mit der geringsten regionalen Deprivation von einer besonders schlechten Lebensqualität. In einem Extremgruppenvergleich weisen Personen, die in nach GIMD und GISD stark deprivierten Regionen leben, günstigere Werte im Krankheitsverlauf beim IMET und EQ-VAS auf. Auch für Parameter der medizinischen Versorgung lassen sich keine systematischen Zusammenhänge mit den Deprivationsindizes darstellen.

SCHLUSSFOLGERUNG: Krankheitsmerkmale, Krankheitsfolgen und die medizinische Versorgung von CED-Kranken zeigen sich weitgehend unabhängig vom Ausmaß der mit zwei Indizes bestimmten regionalen Deprivation. Die wenigen auffälligen Unterschiede weisen in eine überraschende Richtung: Personen aus deprivierten Regionen berichten günstigere Krankheitsverhältnisse.

BACKGROUND: As an ecological parameter, area deprivation is one component of the social determinants of health. For Germany two indices to measure area deprivation are currently available: The German Index of Multiple Deprivation (GIMD) and the German Index of Socioeconomic Deprivation (GISD). Inflammatory bowel diseases (IBD) are not frequent but severe diseases of so far unknown etiology, comparatively early manifestation in adulthood, often chronic course requiring long-lasting medical attention, and uncertain prognosis. Data of a controlled health care trial enable us to study associations between area deprivation and disease and treatment variables. We expected more unfavourable conditions with increasing level of deprivation.

METHODS: We present secondary descriptive analyses of an RCT on effectiveness and benefit of medical inpatient rehab of 530 socially insured IBD patients. We used data from the initial assessment of numerous self-reported disease characteristics, consequences of disease, and health care items in relation to the extent of area deprivation at patients' county ("Kreis") level.

RESULTS: Grouped into quintiles, patients' results from GIMD and GISD are closely correlated (rho=0.76; weighted kappa=0.74). Regional deprivation, as assessed by GIMD, shows noticeable associations only with participation restriction (IMET scale) and number of disability days. However, subjects from least deprived areas report highest restrictions whereas the distribution of disability days exhibits an irregular pattern. GISD data are weakly and unsystematically related to quality of life measurements. Again, patients from least deprived areas show a considerably low quality of life. A comparison of two extreme groups (very low vs. very high deprivation in GIMD and GISD combined) corroborates the finding: Subjects from highly deprived areas report in general more favourable disease characteristics. We found no association between deprivation and any health care item.

CONCLUSION: Disease characteristics, psychosocial consequences, and health care of IBD seem to be mainly independent of the extent of area deprivation. The few statistically noticeable associations are unexpected: Patients from more deprived counties give more favourable reports.}, } @article {pmid34569363, year = {2022}, author = {Salmon, K and Anoja, N and Breiner, A and Chum, M and Dionne, A and Dupré, N and Fiander, A and Fok, D and Ghavanini, A and Gosselin, S and Izenberg, A and Johnston, W and Kalra, S and Matte, G and Melanson, M and O'Connell, C and Ritsma, B and Schellenberg, K and Shoesmith, C and Tremblay, S and Williams, H and Genge, A}, title = {Genetic testing for amyotrophic lateral sclerosis in Canada - an assessment of current practices.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {3-4}, pages = {305-312}, doi = {10.1080/21678421.2021.1980890}, pmid = {34569363}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Canada/epidemiology ; Genetic Counseling ; Genetic Testing ; Humans ; Surveys and Questionnaires ; }, abstract = {Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.}, } @article {pmid34573264, year = {2021}, author = {Brakemeier, S and Stolte, B and Thimm, A and Kizina, K and Totzeck, A and Munoz-Rosales, J and Kleinschnitz, C and Hagenacker, T}, title = {Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen.}, journal = {Brain sciences}, volume = {11}, number = {9}, pages = {}, pmid = {34573264}, issn = {2076-3425}, abstract = {The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.}, } @article {pmid34573864, year = {2021}, author = {Krause, K and Wulf, M and Sommer, P and Barkovits, K and Vorgerd, M and Marcus, K and Eggers, B}, title = {CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {34573864}, issn = {2075-4418}, abstract = {Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications.}, } @article {pmid34575481, year = {2021}, author = {Kang, DW and Kim, JH and Kim, KM and Cho, SJ and Jang, HW and Chang, JW and Dong, SM and Lim, JW and Kim, JS and Cho, HY}, title = {Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704.}, journal = {Pharmaceutics}, volume = {13}, number = {9}, pages = {}, pmid = {34575481}, issn = {1999-4923}, support = {202000380001//Theragen Etex Co. Ltd/ ; }, abstract = {Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.}, } @article {pmid34575906, year = {2021}, author = {Bolcato, G and Cescon, E and Pavan, M and Bissaro, M and Bassani, D and Federico, S and Spalluto, G and Sturlese, M and Moro, S}, title = {A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34575906}, issn = {1422-0067}, support = {2017MT3993//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Binding Sites ; Casein Kinase Idelta/*antagonists & inhibitors/*chemistry ; Drug Discovery/*methods ; Humans ; *Models, Molecular ; Molecular Conformation ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Protein Kinase Inhibitors/*chemistry/*pharmacology ; Structure-Activity Relationship ; Workflow ; }, abstract = {Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib. In the Kinase family, protein kinase CK1 isoform δ (CK1δ) has become a promising target in the treatment of different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition.}, } @article {pmid34576165, year = {2021}, author = {Polgár, TF and Meszlényi, V and Nógrádi, B and Körmöczy, L and Spisák, K and Tripolszki, K and Széll, M and Obál, I and Engelhardt, JI and Siklós, L and Patai, R}, title = {Passive Transfer of Blood Sera from ALS Patients with Identified Mutations Results in Elevated Motoneuronal Calcium Level and Loss of Motor Neurons in the Spinal Cord of Mice.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34576165}, issn = {1422-0067}, support = {GINOP-2.3.2-15-2016-00034//Nemzetgazdasági Minisztérium/ ; FEIF/433-4/2020-ITM_SZERZ//Innovációs és Technológiai Minisztérium/ ; NTP-NFTÖ-21-B-0203//Emberi Eroforrások Minisztériuma/ ; EFOP 3.6.3-VEKOP-16-2017-00009//Pénzügyminisztérium/ ; }, mesh = {Amyotrophic Lateral Sclerosis/blood/*metabolism ; Animals ; Calcium/*metabolism ; Disease Models, Animal ; Immunoglobulins/genetics/metabolism ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Motor Neurons/*metabolism ; Mutation/genetics ; }, abstract = {Introduction: Previously, we demonstrated the degeneration of axon terminals in mice after repeated injections of blood sera from amyotrophic lateral sclerosis (ALS) patients with identified mutations. However, whether a similar treatment affects the cell body of motor neurons (MNs) remained unresolved. Methods: Sera from healthy individuals or ALS patients with a mutation in different ALS-related genes were intraperitoneally injected into ten-week-old male Balb/c mice (n = 3/serum) for two days. Afterward, the perikaryal calcium level was measured using electron microscopy. Furthermore, the optical disector method was used to evaluate the number of lumbar MNs. Results: The cytoplasmic calcium level of the lumbar MNs of the ALS-serum-treated mice, compared to untreated and healthy-serum-treated controls, was significantly elevated. While injections of the healthy serum did not reduce the number of MNs compared to the untreated control group, ALS sera induced a remarkable loss of MNs. Discussion: Similarly to the distant motor axon terminals, the injection of blood sera of ALS patients has a rapid degenerative effect on MNs. Analogously, the magnitude of the evoked changes was specific to the type of mutation; furthermore, the degeneration was most pronounced in the group treated with sera from ALS patients with a mutation in the chromosome 9 open reading frame 72 gene.}, } @article {pmid34585475, year = {2022}, author = {Gento-Caro, Á and Vilches-Herrando, E and Portillo, F and González-Forero, D and Moreno-López, B}, title = {Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {32}, number = {3}, pages = {e13022}, pmid = {34585475}, issn = {1750-3639}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Neurons/metabolism ; Nerve Degeneration/pathology ; RNA, Messenger/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {A preclinical strategy to broaden the search of potentially effective treatments in amyotrophic lateral sclerosis (ALS) relies on identifying factors controlling motor neuron (MN) excitability. These partners might be part of still unknown pathogenic pathways and/or useful for the design of new interventions to affect disease progression. In this framework, the bioactive membrane-derived phospholipid lysophosphatidic acid (LPA) affects MN excitability through LPA receptor 1 (LPA1). Furthermore, LPA1 knockdown is neuroprotective in transgenic ALS SOD1-G93A mice. On this basis, we raised the hypothesis that the major LPA-synthesizing ectoenzyme, autotaxin (ATX), regulates MN excitability and is a potential target to modulate disease development in ALS mice. We show here that PF-8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, supporting that baseline ATX activity regulates MN IME. PF-8380-induced alterations were prevented by a small-interfering RNA directed against mRNA for lpa1 . These outcomes support that impact of ATX-originated lysophospholipids on MN IME engages, at least, the G-protein-coupled receptor LPA1 . Interestingly, mRNAatx levels increased in the spinal cord of pre-symptomatic (1-2 months old) SOD1-G93A mice, thus preceding MN loss. The rise in transcripts levels also occurred in cultured spinal cord MNs from SOD1-G93A embryos, suggesting that mRNAatx upregulation in MNs is an etiopathogenic event in the ALS cell model. Remarkably, chronic administration in the drinking water of the orally bioavailable ATX inhibitor PF-8380 delayed MN loss, motor deterioration and prolonged life span in ALS mice. Treatment also led to a reduction in LPA1 -immunoreactive patches in transgenic animals mostly in MNs. These outcomes support that neuroprotective effects of interfering with ATX in SOD1-G93A mice rely, at least in part, on LPA1 knockdown in MNs. Therefore, we propose ATX as a potential target and/or a biomarker in ALS and highlight ATX inhibitors as reasonable tools with therapeutic usefulness for this lethal pathology.}, } @article {pmid34588483, year = {2021}, author = {Lum, JS and Brown, ML and Farrawell, NE and McAlary, L and Ly, D and Chisholm, CG and Snow, J and Vine, KL and Karl, T and Kreilaus, F and McInnes, LE and Nikseresht, S and Donnelly, PS and Crouch, PJ and Yerbury, JJ}, title = {CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1[G93A] mice with a C57BL/6 background.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {19392}, pmid = {34588483}, issn = {2045-2322}, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; Disease Progression ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents/*administration & dosage ; *Organocopper Compounds/administration & dosage/adverse effects/pharmacology ; Superoxide Dismutase-1/*metabolism ; }, abstract = {The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1[G93A] mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3-51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1[G93A] mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.}, } @article {pmid34590512, year = {2022}, author = {Vucic, S and Wray, N and Henders, A and Henderson, RD and Talman, P and Mathers, S and Bellgard, M and Aoun, S and Birks, C and Thomas, G and Hansen, C and Thomas, G and Hogden, A and Needham, M and Schultz, D and Soulis, T and Sheean, B and Milne, J and Rowe, D and Zoing, M and Kiernan, MC}, title = {MiNDAUS partnership: a roadmap for the cure and management of motor Neurone disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {23}, number = {5-6}, pages = {321-328}, doi = {10.1080/21678421.2021.1980889}, pmid = {34590512}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis ; Australia ; Caregivers ; Data Collection ; Humans ; *Motor Neuron Disease/therapy ; }, abstract = {An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.}, } @article {pmid34606852, year = {2021}, author = {Gupta, R and Jha, A and Ambasta, RK and Kumar, P}, title = {Regulatory mechanism of cyclins and cyclin-dependent kinases in post-mitotic neuronal cell division.}, journal = {Life sciences}, volume = {285}, number = {}, pages = {120006}, doi = {10.1016/j.lfs.2021.120006}, pmid = {34606852}, issn = {1879-0631}, mesh = {Acetylation ; Animals ; Cyclin-Dependent Kinases/*metabolism ; Cyclins/*metabolism ; Histone Deacetylases/metabolism ; Humans ; *Mitosis ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurons/*metabolism/*pathology ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) are the most common life-threatening disease of the central nervous system and it cause the progressive loss of neuronal cells. The exact mechanism of the disease's progression is not clear and thus line of treatment for NDDs is a baffling issue. During the progression of NDDs, oxidative stress and DNA damage play an important regulatory function, and ultimately induces neurodegeneration. Recently, aberrant cell cycle events have been demonstrated in the progression of different NDDs. However, the pertinent role of signaling mechanism, for instance, post-translational modifications, oxidative stress, DNA damage response pathway, JNK/p38 MAPK, MEK/ERK cascade, actively participated in the aberrant cell cycle reentry induced neuronal cell death. Mounting evidence has demonstrated that aberrant cell cycle re-entry is a major contributing factor in the pathogenesis of NDDs rather than a secondary phenomenon. In the brain of AD patients with mild cognitive impairment, post miotic cell division can be seen in the early stage of the disease. However, in the brain of PD patients, response to various neurotoxic signals, the cell cycle re-entry has been observed that causes neuronal apoptosis. On contrary, the contributing factors that leads to the induction of cell cycle events in mature neurons in HD and ALS brain pathology is remain unclear. Various pharmacological drugs have been developed to reduce the pathogenesis of NDDs, but they are still not helpful in eliminating the cause of these NDDs.}, } @article {pmid34616479, year = {2021}, author = {Yang, EJ}, title = {A Novel Supplement Attenuates Oxidative Stress-Induced TDP-43-Related Pathogenesis in TDP-43-Expressed Cells.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {6773260}, pmid = {34616479}, issn = {1741-427X}, abstract = {Amyotrophic lateral sclerosis (ALS) is caused by selective the loss of spinal motor neurons by multifactorial pathological mechanisms and results in muscle atrophy. Incidence rates of ALS are increasing over time, but there are no effective treatments at present due to limitations on approved therapies (riluzole and edaravone). Therefore, this study investigated whether combined treatment with Bojungikgi-tang and riluzole could act synergistically in transactive response DNA-binding protein 43 (TDP-43) stress granule cells. To examine the effect of combined treatment on oxidative stress-induced cell death, the CCK8 assay was performed for the detection of cell viability. The expression of oxidative stress-induced proteins was determined by Western blot. Quantification of sodium arsenite-induced reactive oxygen species (ROS) was measured in TDP-43 stress granular cells using 2,7-diacetyl dichlorofluorescein diacetate. To investigate the effect of combined treatment on TDP-43 aggregation, immunofluorescence and immunoblotting were performed in TDP-43 stress granular cells. This combined treatment alleviated oxidative stress-induced cell death by increasing the expression levels of antioxidation proteins, such as heme oxygenase-1 and B cell lymphoma-2-associated X protein. Furthermore, it reduced oxidative stress-induced TDP-43 aggregates and lowered the levels of autophagy-related proteins, including p62, light chain 3b, and ATG8, in TDP-43-expressing cells. Our results suggest that this combined treatment could be helpful for autophagy regulation in other neurodegenerative diseases.}, } @article {pmid34624328, year = {2022}, author = {Sajjadi, E and Seven, YB and Ehrbar, JG and Wymer, JP and Mitchell, GS and Smith, BK}, title = {Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: A preliminary study.}, journal = {Experimental neurology}, volume = {347}, number = {}, pages = {113890}, pmid = {34624328}, issn = {1090-2430}, support = {UL1 TR001427/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*therapy ; Female ; Humans ; *Hypoxia ; Male ; Middle Aged ; Respiratory Mechanics/physiology ; Respiratory Muscles/*physiology ; }, abstract = {Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O2, 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted.}, } @article {pmid34635103, year = {2021}, author = {Chang, CP and Wu, KC and Lin, CY and Chern, Y}, title = {Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.}, journal = {Journal of biomedical science}, volume = {28}, number = {1}, pages = {70}, pmid = {34635103}, issn = {1423-0127}, support = {AS-BRPT-110-11//academia sinica/ ; MOST 110-2321-B-001-011//ministry of science and technology, taiwan/ ; }, mesh = {Adenosine/*physiology ; Brain/*physiopathology ; *Homeostasis ; Humans ; Neurodegenerative Diseases/*physiopathology ; Proteins/*metabolism ; }, abstract = {In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.}, } @article {pmid34635126, year = {2021}, author = {Wang, J and Tierney, L and Mann, R and Lonsway, T and Walker, CL}, title = {Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis.}, journal = {Molecular brain}, volume = {14}, number = {1}, pages = {155}, pmid = {34635126}, issn = {1756-6606}, support = {IK2 RX002688/RX/RRD VA/United States ; }, mesh = {Amyotrophic Lateral Sclerosis/*drug therapy/pathology ; Animals ; Anterior Horn Cells/drug effects ; Cells, Cultured ; Chromones/pharmacology ; Culture Media, Serum-Free/pharmacology ; Humans ; Mice, Transgenic ; Microglia/drug effects ; Models, Animal ; Morpholines/pharmacology ; Motor Neurons/*drug effects ; Muscular Atrophy/etiology/pathology ; Mutation, Missense ; Neuromuscular Junction/drug effects ; Neuroprotective Agents/pharmacology/*therapeutic use ; PTEN Phosphohydrolase/antagonists & inhibitors ; Point Mutation ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Superoxide Dismutase-1/deficiency/genetics ; Vanadium Compounds/pharmacology/*therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1[G93A]) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1[G93A] motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1[G93A] mice intraperitoneally daily with 400 μg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1[G93A] mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1[G93A] and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.}, } @article {pmid34636234, year = {2021}, author = {Collibee, SE and Bergnes, G and Chuang, C and Ashcraft, L and Gardina, J and Garard, M and Jamison, CR and Lu, K and Lu, PP and Muci, A and Romero, A and Valkevich, E and Wang, W and Warrington, J and Yao, B and Durham, N and Hartman, J and Marquez, A and Hinken, A and Schaletzky, J and Xu, D and Hwee, DT and Morgans, D and Malik, FI and Morgan, BP}, title = {Discovery of Reldesemtiv, a Fast Skeletal Muscle Troponin Activator for the Treatment of Impaired Muscle Function.}, journal = {Journal of medicinal chemistry}, volume = {64}, number = {20}, pages = {14930-14941}, doi = {10.1021/acs.jmedchem.1c01067}, pmid = {34636234}, issn = {1520-4804}, mesh = {Dose-Response Relationship, Drug ; *Drug Discovery ; Humans ; Molecular Structure ; Muscle, Skeletal/*drug effects/metabolism/pathology ; Structure-Activity Relationship ; Troponin/*metabolism ; }, abstract = {The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.}, } @article {pmid34637802, year = {2022}, author = {Vose, AK and Welch, JF and Nair, J and Dale, EA and Fox, EJ and Muir, GD and Trumbower, RD and Mitchell, GS}, title = {Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.}, journal = {Experimental neurology}, volume = {347}, number = {}, pages = {113891}, pmid = {34637802}, issn = {1090-2430}, support = {R01 HD081274/HD/NICHD NIH HHS/United States ; R01 HL147554/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Hypoxia ; Neuromuscular Diseases/*therapy ; Spinal Cord Injuries/*therapy ; *Translational Research, Biomedical ; }, abstract = {We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.}, } @article {pmid34640573, year = {2021}, author = {Vogt, S and Schlichte, I and Schreiber, S and Wigand, B and Debska-Vielhaber, G and Heitmann, J and Meyer, T and Dengler, R and Petri, S and Haghikia, A and Vielhaber, S}, title = {A Multi-Center Cohort Study on Characteristics of Pain, Its Impact and Pharmacotherapeutic Management in Patients with ALS.}, journal = {Journal of clinical medicine}, volume = {10}, number = {19}, pages = {}, pmid = {34640573}, issn = {2077-0383}, support = {none//Deutsche Gesellschaft für Muskelkranke/ ; none//Stiftung für Medizinische Wissenschaft Frankfurt am Main/ ; }, abstract = {BACKGROUND: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified.

METHODS: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale-Extension and to participate in semi-structured telephone interviews.

RESULTS: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity ≥4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value ≥4. Eleven of them-mainly in the context of high pain interference with daily functions-were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy.

CONCLUSION: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients' barriers to pain therapy.}, } @article {pmid34644838, year = {1990}, author = {Paradis, M and Lemay, S and Scott, DW and Miller, WH and Wellington, J and Panich, R}, title = {Efficacy of Enrofloxacin in the Treatment of Canine Bacterial Pyoderma.}, journal = {Veterinary dermatology}, volume = {1}, number = {3}, pages = {123-127}, doi = {10.1111/j.1365-3164.1990.tb00090.x}, pmid = {34644838}, issn = {1365-3164}, abstract = {Abstract- Bacterial pyoderma was diagnosed in 30 dogs which were subsequently treated with enrofloxacin administered orally at 2.5 mg.kg[-1] of body weight every 12 h, for 2 to 14 weeks. Dogs were re-examined at the conclusion of antibiotic treatment and 28 (93.3 per cent) were found to have an excellent response. Relapses were seen in 25 per cent of these dogs after follow up periods of 1 to 4 months. Minor side effects were seen in only 1 dog. On the basis of this study, enrofloxacin is an excellent antibiotic for the treatment of canine bacterial pyoderma but must be administered well beyond the manufacturer's maximum recommendation for duration of therapy. Résumé- Une pyodermite bactérienne a été diagnostiquée chez 30 chiens qui furent traités avec de l'enrofloxacine administrée par voie orale à la dose de 2.5 mg/Kg toutes les 12 heures, pour une durée allant de 2.5 à 14 semaines. Les chiens furent réexaminés à la fin de l'antibiothérapie et 28 d'entre eux (93.3%) présentaient une excellente réponse au traitement. Des rechutes furent observées chez 25% des chiens lors de suivis portant sur des périodes de 1 à 4 mois. Des effets secondaires mineurs furent observés chez l'un des chiens. Cette étude montre que l'enrofloxacine est un excellent antibiotique pour le traitement des pyodermites canines mais, qu'il doit être administré pendant des délais beaucoup plus longs que ceux qui sont indiqués par le fabricant. Zusammenfassung- 30 Hunde mit bakteríellen Pyodermien wurden zweieinhalb bis vierzehn Wochen lang oral mit Enrofloxacin behandelt (2 täglich 2.5 mg/kg KGW). Nach Abschluß der Behandlung wurden die Tiere erneut untersucht. Bei 28 Patienten (93.3%) wurden hervorragende Ergebnisse erzielt. Bei 25% kam as nach 1 bis 4 Monaten zu Rezidiven. Geringe Nebenwirkungen wurden nur in einem Fall beobachtet. Die vorliegende Untersuchung zeigt, daß Enrofloxacin ein hervorragendes Antibiotikum für die Behandlung von Pyodermien ist, aber wesentlich länger als vom Hersteller angegeben verabreicht werden muß. Resumen Treinta perros, a los cuales se había diagnosticado una epiderma bacteriana, fueron tratado con Enrofloxacina via oral a una dosis de 2,5 mg/kg de peso corporal cada 12 horas durante un período de tiempo que oscíló entre las 2,5 semanas y las 14 semanas. Los perros se examinaron clínicamente de nuevo cuando acabó el tratamiento antibiótico y se observó en 28 (93,3%) una respuesta excelente. En un 25% de estos perros se observaron recidivas en un período comprendido entre uno y cuatro meses. Efectos colaterales de poca importancia se observaron úicamente en un animal. Según estos resultados puede concluirse que la Enrofloxacina es un antibiótico excelente para el tratamiento de las piodermas bacterianas del perro, aunque debe administrarse durante un período de tiempo superior al que recomiendan los productores.}, } @article {pmid34644878, year = {1996}, author = {Medleau, L and Ristic, Z and McElveen, DR}, title = {Daily ivermectin for treatment of generalized demodicosis in dogs.}, journal = {Veterinary dermatology}, volume = {7}, number = {4}, pages = {209-212}, doi = {10.1111/j.1365-3164.1996.tb00248.x}, pmid = {34644878}, issn = {1365-3164}, abstract = {Abstract Twelve dogs with generalized demodicosis were treated with oral administration of ivermectin, 0.4 mg kg[-1] of body weight given once every 24 h. Results of skin scrapings were used to determine whether administration of ivermectin should be continued or stopped. Dogs that were free of clinical signs of demodicosis 12 months after administration of ivermectin was discontinued were considered cured. Five dogs were cured. The medían duration of treatment was 15 weeks (range 5-21 weeks). Seven dogs were failures, with five relapsing 3-11. 5 months after treatment was stopped, and two having persistent demodicosis in spite of treatment. Mild ivermectin toxicosis developed in one dog after 5 weeks of treatment; side-effects resolved shortly after the treatment was stopped. Resumen Se trataron doce perros con demodicosis generalizada con ivermectina oral, 0.4 mg/Kg de peso corporal una vez cada 24 h. Se realizaron raspados cutáneos para déterminar si debia retirarse o continuar con la administración de ivermectina. Se consideraron curados aquellos perros sin sintomatologia de demodicosis 12 meses después de retirar la terapia con ivermectina. La duración medía del tratamiento con ivermectina fue de 15 semanas (rango de 5-21). Se fracasó en siete perros, con cinco recidivas a los 3-11, 5 meses después de parar la terapia y dos con demodicosis persistente a pesar del tratamiento. Un perro desarrolló una toxicosis leve a la ivermectina a las 5 semanas del tratamiento; los efectos secundarios desaparecieron al poco de retirar el tratamient