@article {pmid40774708,
year = {2025},
author = {Brown, KR and Quinton, ML and Tidmarsh, G and Cumming, J},
title = {Athletes' access to, attitudes towards and experiences of help-seeking for mental health: a scoping review.},
journal = {BMJ open},
volume = {15},
number = {8},
pages = {e097492},
pmid = {40774708},
issn = {2044-6055},
mesh = {Humans ; *Athletes/psychology ; *Patient Acceptance of Health Care/psychology ; *Mental Health ; *Mental Disorders/therapy/psychology ; *Help-Seeking Behavior ; *Mental Health Services ; *Health Services Accessibility ; },
abstract = {OBJECTIVES: Athletes have been found to experience a similar prevalence of mental health issues to non-athletes. However, they are subjected to a greater array of barriers to help-seeking for mental health, including sport-specific factors. This scoping review synthesised the literature on athletes' access to, attitudes towards and experiences of help-seeking for mental health from formal (mental health professionals such as psychiatrists) and semiformal sources (those who are not mental health professionals but are a service provider such as a coach).

DESIGN: The Joanna Briggs Institute framework and recommendations were used alongside the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols checklist for scoping reviews. This scoping review was predominantly informed by Arksey and O'Malley's framework for scoping reviews, supplemented by Levac et al's additional recommendations. Rickwood and colleagues' help-seeking frameworks informed the research question, inclusion/exclusion criteria and analysis.

DATA SOURCES: The search terms and synonyms of "athlete" AND "mental health" AND "help-seeking" were searched in PsychINFO, Embase, MEDLINE, APA PsychArticles Full Text, Web of Science Core Collection, Scopus, Sport Discus, CINAHL and Proquest (Education Database, Health & Medical Collection, Nursing & Allied Health database, Psychology Database, Public Health Database, Education Collection, and Medicine & Education). These searches were conducted at three time points between April 2022 and 2024.

ELIGIBILITY CRITERIA: The inclusion and exclusion criteria were initially predetermined and specified in the protocol paper published in BMJ Open. Primary research articles, interventions and systematic reviews that referred to semiformal and formal sources of support were included.

DATA EXTRACTION AND SYNTHESIS: The lead reviewer (KRB) screened all titles and abstracts, and full texts, and extracted data from all included studies. A second reviewer was involved in screening and extracting 20%-30% of studies at each stage. Findings were synthesised descriptively (eg, study population, data collection method and location of studies) and by content (eg, access, attitudes and experiences, sources of support, use of theory and the validity of quantitative measures used).

RESULTS: After screening 4954 titles and abstracts and 275 full texts in Covidence, 104 papers were included in the review. This comprised of 87 primary research articles, 13 interventions and 4 systematic reviews. Most of the primary articles and interventions were published in the USA (50%). 49.4% of the primary articles used quantitative methods, 34.5% used qualitative methods and 16.1% used mixed methods. Attitudes towards mental health help-seeking were investigated in 78.8% of the included studies, experiences of help-seeking in 53.8% and access to sources of support in 31.7% of studies. Of the primary articles and interventions, formal sources were investigated in 55% of studies, semiformal sources in 2% and both in 26% of studies.

CONCLUSIONS: This scoping review of 104 papers showed the benefit of using help-seeking frameworks to shape and analyse a review. Analysing the results using these frameworks provided a novel contribution to the literature, showing where the athlete help-seeking literature base is currently focused and identified gaps for further research. For example, there is a need for further research on athletes in less developed nations, more qualitative and mixed methods studies, and further research on athletes' access to mental health support and their interactions with semiformal sources. The results have applied implications in public health and sport by highlighting the different factors that impact athlete help-seeking, and therefore areas where they require support.},
}

Humans
*Athletes/psychology
*Patient Acceptance of Health Care/psychology
*Mental Health
*Mental Disorders/therapy/psychology
*Help-Seeking Behavior
*Mental Health Services
*Health Services Accessibility

@article {pmid40757018,
year = {2025},
author = {Kato, N and Suzuki, R and Kaneko, H and Horimoto, Y},
title = {Effects of telerehabilitation on physical function and activities of daily living in patients with amyotrophic lateral sclerosis: a scoping review.},
journal = {Journal of physical therapy science},
volume = {37},
number = {8},
pages = {427-434},
pmid = {40757018},
issn = {0915-5287},
abstract = {[Purpose] This study aimed to clarify the effects of telerehabilitation on physical function and activities of daily living in patients with amyotrophic lateral sclerosis through a literature review. [Participants and Methods] We conducted a scoping review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews reporting guidelines. The PubMed, Scopus, Web of Science, and ProQuest databases were searched. Study design, type of interventions, telerehabilitation methods, adherence, effectiveness, adverse events, and patient satisfaction were extracted from the selected literature. [Results] Four case-series and one case-control study were identified. The interventions included respiratory muscle training (two studies), aerobic exercise, stretching, and comprehensive physical therapy (one study each). Various modalities were used, including videoconferencing, on-demand instructional videos, and real-time monitoring of vital signs using wearable devices. No serious adverse events were reported in any study. The dropout rate was 0-21%, and the compliance rate was 90%, indicating high adherence. Improvements in respiratory function and ADL were observed following respiratory rehabilitation. Patient satisfaction with telerehabilitation was high. [Conclusion] Telerehabilitation may improve adherence, respiratory function, and activities of daily living in patients with amyotrophic lateral sclerosis. However, its effects on other aspects of physical function remain unclear. Further high-quality studies are needed to establish evidence-based practices.},
}

@article {pmid39122453,
year = {2024},
author = {Khan, S and Bano, N and Ahamad, S and John, U and Dar, NJ and Bhat, SA},
title = {Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.},
journal = {Aging and disease},
volume = {16},
number = {5},
pages = {2504-2543},
pmid = {39122453},
issn = {2152-5250},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Mitochondria/metabolism/pathology ; Oxidative Stress ; *Ferroptosis/physiology ; Mitophagy ; Animals ; Energy Metabolism ; },
abstract = {Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/physiopathology
*Mitochondria/metabolism/pathology
Oxidative Stress
*Ferroptosis/physiology
Mitophagy
Animals
Energy Metabolism

@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 = {},
number = {},
pages = {1-15},
doi = {10.1080/15368378.2025.2540435},
pmid = {40754996},
issn = {1536-8386},
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 {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.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/therapy/rehabilitation
*Physical and Rehabilitation Medicine/trends/methods
Quality of Life

@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 = {},
number = {},
pages = {178003},
doi = {10.1016/j.ejphar.2025.178003},
pmid = {40744389},
issn = {1879-0712},
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 {pmid40741338,
year = {2025},
author = {Marek, A and Brož, B and Kriegelstein, M and Nováková, G and Hojcsková, J and Blechová, M and Žáková, L and Jiráček, J and Maletínská, L},
title = {Late-stage labeling of diverse peptides and proteins with iodine-125.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {7},
pages = {101198},
pmid = {40741338},
issn = {2214-0883},
abstract = {The preparation of specifically iodine-125 ([125]I)-labeled peptides of high purity and specific activity represents a key tool for the detailed characterization of their binding properties in interaction with their binding partners. Early synthetic methods for the incorporation of iodine faced challenges such as harsh reaction conditions, the use of strong oxidants and low reproducibility. Herein, we review well-established radiolabeling strategies available to incorporate radionuclide into a protein of interest, and our long-term experience with a mild, simple and generally applicable technique of [125]I late-stage-labeling of biomolecules using the Pierce iodination reagent for the direct solid-phase oxidation of radioactive iodide. General recommendations, tips, and details of optimized chromatographic conditions to isolate pure, specifically [125]I-mono-labeled biomolecules are illustrated on a diverse series of (poly)peptides, ranging up to 7.6 kDa and 67 amino acids (aa). These series include peptides that contain at least one tyrosine or histidine residue, along with those featuring disulfide crosslinking or lipophilic derivatization. This mild and straightforward late-stage-labeling technique is easily applicable to longer and more sensitive proteins, as demonstrated in the cases of the insulin-like growth factor binding protein-3 (IGF-BP-3) (29 kDa and 264 aa) and the acid-labile subunit (ALS) (93 kDa and 578 aa).},
}

@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.},
}

Humans
*Proprotein Convertase 9/metabolism/genetics
*PCSK9 Inhibitors/therapeutic use
*Central Nervous System Diseases/drug therapy/metabolism
Animals

@article {pmid40446958,
year = {2025},
author = {Yuan, L and Yang, Y and Guo, Y and Deng, H},
title = {Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jgg.2025.05.008},
pmid = {40446958},
issn = {1673-8527},
abstract = {Amyotrophic lateral sclerosis (ALS), one of the most prevalent neurodegenerative disorders, is pathologically characterized by the progressive degeneration of both upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 2-4 years post-diagnosis. ALS is categorized into familial ALS (FALS) and sporadic ALS, with FALS accounting for approximately 10% of ALS cases. As a genetically heterogeneous disease, ALS exhibits diverse inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked transmission, and genetic factors play pivotal roles in disease pathogenesis. To date, at least 34 disease-causing loci and 32 genes for ALS have been identified. The investigations of mutant protein products and the establishment of animal models have unraveled potential pathogenic pathways, offering insights into the mechanisms of neurodegeneration in ALS. This review focuses on ALS clinical characteristics, neuropathological features, causative loci/genes, genetic susceptibility factors, animal models, and pathogenic mechanisms, with particular attention to recent advances in genetic findings and pathogenic pathways of ALS. Elucidation of the genetic basis of ALS could provide the scientific foundation for personalized treatments to address this recalcitrant disease.},
}

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

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

@article {pmid40738791,
year = {2025},
author = {Roy, A and Dawson, VL and Dawson, TM},
title = {From metabolism to mind: The expanding role of the GLP-1 receptor in neurotherapeutics.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00712},
doi = {10.1016/j.neurot.2025.e00712},
pmid = {40738791},
issn = {1878-7479},
abstract = {GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes and obesity, are now under investigation for neuroprotective effects in a range of neurological disorders. These agents, whose receptors are widely expressed in brain regions involved in cognition and metabolism, modulate neurotransmitter release and promote neurogenesis. While preclinical studies consistently demonstrate benefits in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), clinical trial outcomes have been variable, largely owing to heterogeneity in study populations and trial design. Newer agents, such as NLY01 and tirzepatide, are under development to enhance central nervous system penetration and efficacy. Although GLP-1RAs are generally safe in metabolic conditions, their use in neurological diseases requires careful monitoring and patient selection. Future directions include developing reliable biomarkers, implementing precision medicine strategies, and exploring the use of combination therapies to maximize therapeutic potential.},
}

@article {pmid40732891,
year = {2025},
author = {Hein, ZM and Arbain, MFF and Kumar, S and Mehat, MZ and Hamid, HA and Che Ramli, MD and Che Mohd Nassir, CMN},
title = {Intermittent Fasting as a Neuroprotective Strategy: Gut-Brain Axis Modulation and Metabolic Reprogramming in Neurodegenerative Disorders.},
journal = {Nutrients},
volume = {17},
number = {14},
pages = {},
pmid = {40732891},
issn = {2072-6643},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy ; *Fasting/physiology ; Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; *Neuroprotection ; Energy Metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Metabolic Reprogramming ; Intermittent Fasting ; },
abstract = {Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut-brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF's capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy
*Fasting/physiology
Gastrointestinal Microbiome/physiology
Animals
*Brain/metabolism
*Brain-Gut Axis/physiology
*Neuroprotection
Energy Metabolism
Brain-Derived Neurotrophic Factor/metabolism
Metabolic Reprogramming
Intermittent Fasting

@article {pmid40726565,
year = {2025},
author = {Dukic, S and Govaarts, R and Hillebrand, A and de Visser, M and Seeck, M and McMackin, R},
title = {Novel approaches to EEG and MEG in motor neurone disease: IFCN Handbook Chapter.},
journal = {Clinical neurophysiology practice},
volume = {10},
number = {},
pages = {301-315},
pmid = {40726565},
issn = {2467-981X},
abstract = {Motor neurone diseases (MNDs) are increasingly being acknowledged as network disorders, with cortical dysfunction and degeneration extending beyond the motor cortex. Measures of this broader cortical pathophysiology are providing promising candidates in the search for diagnostic and prognostic biomarkers of the MNDs. Electroencephalography (EEG) and magnetoencephalography (MEG) offer a direct view of neural network activity by detecting changes in electromagnetic fields of the brain. Measurements based on EEG/MEG have often been overlooked in the search for MND biomarkers, largely due to their limited spatial resolution and the perceived challenges associated with noise in these signals. However, with recent developments in sensor technology and source reconstruction algorithms, alongside substantial improvement in pipelines that address noise, EEG/MEG-based measures can now be readily employed for spatiotemporally-precise, economical and non-invasive characterisation of cortical network pathophysiology in MNDs. Here, we provide an overview of how EEG/MEG signals have been employed to quantify neural network function in MND. We outline the advantages and limitations of these measurements, discuss the most clinically promising EEG/MEG studies of MNDs to date, and highlight future directions warranted to harness the full potential of these technologies for understanding and assessing MNDs.},
}

@article {pmid40294208,
year = {2025},
author = {Winek, K and Soreq, H},
title = {Emerging roles of transfer RNA fragments in the CNS.},
journal = {Brain : a journal of neurology},
volume = {148},
number = {8},
pages = {2631-2645},
doi = {10.1093/brain/awaf130},
pmid = {40294208},
issn = {1460-2156},
support = {3213/19//Israel Science Foundation/ ; 1770/20//Israel Science Foundation/ ; 835/23//Israel Science Foundation/ ; 11183//Israel Science Foundation/ ; 5P01AG014449-21/GF/NIH HHS/United States ; },
mesh = {Humans ; *RNA, Transfer/metabolism/genetics ; Animals ; *Central Nervous System/metabolism ; *Central Nervous System Diseases/genetics/metabolism ; *RNA, Small Untranslated/metabolism/genetics ; },
abstract = {Transfer RNA-derived small RNAs (tsRNAs), previously considered inactive tRNA degradation products, have now been shown to be functional small non-coding RNAs. They may play important roles within the CNS and in brain-body interactions, both during normal developmental stages as well as in diverse brain pathologies. Among the cell types found in the CNS, tsRNAs are particularly abundant in neurons. Correspondingly, neurons show cell type specific tRNA expression profiles when compared to other cells of the CNS under homeostatic conditions and defects in tRNA processing may lead to neurological disorders. Disease-specific tsRNA profiles have been identified in a number of CNS disorders, including amyotrophic lateral sclerosis and epilepsy. Elevated levels of specific tsRNAs have been found in the blood before the onset of epileptic seizures; and age-related, sex-specific loss of mitochondrial genome-originated tsRNAs in the nucleus accumbens of female patients is correlated with accelerated cognitive deterioration in Alzheimer's disease. Disease-related tsRNA signatures have also been identified in the CSF of patients with Parkinson's disease, and nucleated blood cells from ischaemic stroke patients show specific elevation of cholinergic-targeted tsRNAs. The mechanisms of action of tsRNAs are still being elucidated but include targeting complementary mRNA to impact RNA levels and translation in a miRNA-like manner, direct interaction with RNA binding proteins, or interference with translation machinery. The function of tsRNAs may be affected by the chemical modifications they inherit from the originating tRNA molecules, which impact tsRNAs production and may modulate their interactions with proteins. Research on the genetics, biochemical properties and regulatory roles of tsRNAs has expanded rapidly in recent years, facilitated by novel sequencing strategies, which include the removal of tRNA modifications and chemically blocked ends that hinder amplification and adapter ligation. Future in-depth profiling of tsRNAs levels, mode(s) of function, and identification of interacting proteins and RNAs may together shed light on the impact of tsRNAs on neuronal function, and enable novel diagnostics/therapeutics avenues for brain diseases in age, sex and disease-specific manner.},
}

Humans
*RNA, Transfer/metabolism/genetics
Animals
*Central Nervous System/metabolism
*Central Nervous System Diseases/genetics/metabolism
*RNA, Small Untranslated/metabolism/genetics

@article {pmid40181571,
year = {2025},
author = {Yoganathan, K and Dharmadasa, T and Northall, A and Talbot, K and Thompson, AG and Turner, MR},
title = {Asymmetry in amyotrophic lateral sclerosis: Clinical, neuroimaging and histological observations.},
journal = {Brain : a journal of neurology},
volume = {148},
number = {8},
pages = {2605-2615},
doi = {10.1093/brain/awaf121},
pmid = {40181571},
issn = {1460-2156},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/diagnostic imaging ; *Neuroimaging/methods ; *Brain/pathology/diagnostic imaging ; Disease Progression ; Spinal Cord/pathology/diagnostic imaging ; *Functional Laterality/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralized onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post-mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post-mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/physiopathology/diagnostic imaging
*Neuroimaging/methods
*Brain/pathology/diagnostic imaging
Disease Progression
Spinal Cord/pathology/diagnostic imaging
*Functional Laterality/physiology

@article {pmid39163164,
year = {2025},
author = {Raggi, A and Serretti, A and Ferri, R},
title = {The P300 component of the auditory event-related potential in adult psychiatric and neurologic disorders: a narrative review of clinical and experimental evidence.},
journal = {International clinical psychopharmacology},
volume = {40},
number = {5},
pages = {259-274},
doi = {10.1097/YIC.0000000000000566},
pmid = {39163164},
issn = {1473-5857},
mesh = {Humans ; *Event-Related Potentials, P300/physiology ; *Mental Disorders/physiopathology/diagnosis ; *Nervous System Diseases/physiopathology/diagnosis ; *Evoked Potentials, Auditory/physiology ; Adult ; Electroencephalography ; Neuropsychological Tests ; },
abstract = {The auditory P300 wave, also known as P3b, is an event-related potential component thought to reflect central information processes involved in stimulus evaluation or categorization. It is typically elicited using the oddball paradigm, which involves mixing low-probability target items with high-probability standard stimuli. Its latency is associated with the timing of cognitive processes such as stimulus evaluation and response preparation, while its amplitude is related to the amount of attentional resources engaged during the task. Despite decades of use in research settings, its application in clinical practice has been limited. Prolongation of latencies and reduction of amplitudes in the auditory P3b have been observed in both psychiatric and neurological conditions. This includes cases where traditional neuropsychological tests are challenging due to severe motor or speech dysfunctions, or in conditions characterized by subtle cognitive deficits. Additionally, specific laterality patterns in psychoses and a loss of P300 habituation in migraines have been described. The wealth of experimental evidence supports the use of this evoked potential, which can be elicited through a relatively simple paradigm, for objectively evaluating cognition in psychiatric and neurological patients, particularly in follow-up assessments. Therefore, the auditory P300 appears to be a valuable tool for monitoring the clinical course of patients with mental and neurological disorders in certain circumstances.},
}

Humans
*Event-Related Potentials, P300/physiology
*Mental Disorders/physiopathology/diagnosis
*Nervous System Diseases/physiopathology/diagnosis
*Evoked Potentials, Auditory/physiology
Adult
Electroencephalography
Neuropsychological Tests

@article {pmid40725930,
year = {2025},
author = {He, Y and Ming, W and Tan, Y and Wang, Y and Wang, M and Li, H and Jiao, Z and Hou, Y},
title = {The effectiveness of cognitive behavioral therapy in patients with motor neuron disease: A systematic review.},
journal = {Medicine},
volume = {104},
number = {30},
pages = {e43597},
pmid = {40725930},
issn = {1536-5964},
mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Motor Neuron Disease/psychology/therapy ; Quality of Life ; Caregivers/psychology ; Anxiety/therapy/etiology ; Depression/therapy/etiology ; Treatment Outcome ; },
abstract = {BACKGROUND: Motor neuron disease (MND) is a neurodegenerative disorder that causes progressive loss of motor function. With limited disease-modifying drug therapies, cognitive behavioral therapy (CBT) has emerged as a key nonpharmacological intervention. This systematic review evaluated CBT's therapeutic potential across clinical domains to inform psychosocial care of patients with MND.

METHODS: Comprehensive searches were performed in PubMed, Web of Science, Cochrane Library, and Embase, from inception until February 2025. Two researchers independently screened the literature, extracted data, assessed study quality, and resolved disagreements via consensus or third-party consultation.

RESULTS: Five studies involving 561 patients were included. Compared with conventional care, CBT significantly improves patients' quality of life and psychological flexibility. However, the effects on caregiver burden and physical health were not statistically significant. CBT modalities included acceptance and commitment therapy, dialectical behavior therapy, rational-emotive behavior therapy, mindfulness cognitive therapy, and metacognitive training. Traditional CBT demonstrated superior efficacy in reducing anxiety and depression compared to acceptance and commitment therapy.

CONCLUSION: CBT effectively enhances psychological flexibility and quality of life and reduces anxiety and depression in patients with MND. The standardization of outcome measures requires improvement. High-quality randomized controlled trials are needed to further assess CBT's impact of CBT on caregiver burden and patients' physical health.},
}

Humans
*Cognitive Behavioral Therapy/methods
*Motor Neuron Disease/psychology/therapy
Quality of Life
Caregivers/psychology
Anxiety/therapy/etiology
Depression/therapy/etiology
Treatment Outcome

@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.},
}

Humans
*Gastrointestinal Microbiome
*Neuroinflammatory Diseases/metabolism/microbiology/therapy
Animals
*Neurosteroids/metabolism
*Neurodegenerative Diseases/metabolism/microbiology
Brain/metabolism
Inflammation

@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.},
}

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

@article {pmid40722307,
year = {2025},
author = {Ghaderi, S and Mohammadi, S and Fatehi, F},
title = {Magnetic Resonance Neuroimaging in Amyotrophic Lateral Sclerosis: A Comprehensive Umbrella Review of 18 Studies.},
journal = {Brain sciences},
volume = {15},
number = {7},
pages = {},
pmid = {40722307},
issn = {2076-3425},
abstract = {Background/Objectives: Despite extensive research, the underlying causes of amyotrophic lateral sclerosis (ALS) remain unclear. This umbrella review aims to synthesize a vast body of evidence from advanced magnetic resonance imaging (MRI) studies of ALS, encompassing a wide range of neuroimaging techniques and patient cohorts. Methods: Following the PRISMA guidelines, we conducted an extensive search of four databases (PubMed, Scopus, Web of Science, and Embase) for articles published until 3 December 2024. Data extraction and quality assessment were independently performed using the AMSTAR2 tool. Results: This review included 18 studies that incorporated data from over 29,000 ALS patients. Structural MRI consistently showed gray matter atrophy in the motor and extra-motor regions, with significant white matter (WM) atrophy in the corticospinal tract and corpus callosum. Magnetic resonance spectroscopy revealed metabolic disruptions, including reduced N-acetylaspartate and elevated choline levels. Functional MRI studies have demonstrated altered brain activation patterns and functional connectivity, reflecting compensatory mechanisms and neurodegeneration. fMRI also demonstrated disrupted motor network connectivity and alterations in the default mode network. Diffusion MRI highlighted microstructural changes, particularly reduced fractional anisotropy in the WM tracts. Susceptibility-weighted imaging and quantitative susceptibility mapping revealed iron accumulation in the motor cortex and non-motor regions. Perfusion MRI indicated hypoperfusion in regions associated with cognitive impairment. Conclusions: Multiparametric MRI consistently highlights widespread structural, functional, and metabolic changes in ALS, reflecting neurodegeneration and compensatory mechanisms.},
}

@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 {pmid40717876,
year = {2025},
author = {Castillo-Bustamante, M and Anderson, C and Gutierrez, VA},
title = {The Use of Posturography in Vestibular Evaluation of Neurodegenerative Disorders: Diagnostic and Rehabilitative Impacts.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e88752},
pmid = {40717876},
issn = {2168-8184},
abstract = {Neurodegenerative disorders, such as Parkinson's disease, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, frequently present with vestibular dysfunction and balance disturbances, significantly impacting patients' quality of life and increasing the risk of falls. Vestibular impairments in these conditions can manifest as dizziness, unsteadiness, and difficulty maintaining postural control, further complicating the motor and cognitive deficits typical of these diseases. As a result, the assessment and management of balance dysfunction in neurodegenerative disorders have become crucial components of care. Posturography, an objective method for evaluating postural stability and balance control, has emerged as a valuable tool in the vestibular evaluation of patients with neurodegenerative conditions. By providing precise, quantitative measurements of balance deficits, posturography allows for a detailed analysis of postural control mechanisms that may be compromised due to vestibular involvement. This technique not only aids in diagnosing vestibular dysfunction but also plays a key role in developing targeted rehabilitation strategies. When integrated into vestibular rehabilitation (VR) programs, posturography can guide individualized therapy aimed at mitigating fall risk, improving functional mobility, and enhancing patients' overall quality of life. VR exercises, tailored to address specific balance deficits identified through posturographic analysis, can be particularly beneficial in promoting compensatory mechanisms and optimizing patients' functional abilities. This review highlights the significance of posturography as both a diagnostic and therapeutic tool in managing vestibular impairments associated with neurodegenerative diseases, offering the potential for improved outcomes through more personalized and effective rehabilitation interventions.},
}

@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 {pmid40713843,
year = {2025},
author = {Burg, T and Van Den Bosch, L},
title = {Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {85},
pmid = {40713843},
issn = {1750-1326},
support = {#00099187//Fondation Thierry Latran/ ; ABMM//ABMM/ ; ALS Liga België (A cure for ALS)//ALS Liga België (A cure for ALS)/ ; 12AIK24N//FWO/ ; G0C1620N//FWO/ ; G088523N//FWO/ ; G026924N//FWO/ ; C14/22/132//Onderzoeksraad, KU Leuven/ ; IDN/22/ 012//Onderzoeksraad, KU Leuven/ ; Muscular Dystrophy Association//Muscular Dystrophy Association/ ; Target ALS//Target ALS/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Glycerophospholipids/metabolism ; Animals ; Lipid Metabolism/physiology ; Motor Neurons/metabolism/pathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
Humans
*Glycerophospholipids/metabolism
Animals
Lipid Metabolism/physiology
Motor Neurons/metabolism/pathology

@article {pmid40712472,
year = {2025},
author = {Yousef, AM and Cantor-Cutiva, LC and Hunter, EJ},
title = {Mapping 74 years in acoustic analysis of voice disorders: A bibliometric review and future research directions.},
journal = {Journal of communication disorders},
volume = {117},
number = {},
pages = {106555},
doi = {10.1016/j.jcomdis.2025.106555},
pmid = {40712472},
issn = {1873-7994},
abstract = {PURPOSE: This paper conducts a bibliometric analysis to identify and examine the strengths, gaps, and trends in research on acoustic voice assessment for voice disorders.

METHODS: A bibliometric analysis was performed on journal articles about voice disorders and acoustic voice assessment in English, Spanish, and Portuguese using seven indexed databases. The analyzed bibliometric parameters included publication year, authors, institutions, countries, journals, subject areas, and keywords. VOSviewer software was used for keyword co-occurrence analysis and authorships network analysis. The initial search yielded 6532 publications, with 1253 relevant papers after screening (1951-2024).

RESULTS: Publications in acoustic voice assessment had 74 years of exponential growth (25 % published after 2021). The publishing journals covered 80 categories and subjects. Artificial Intelligence, though recent, was among the top journal subjects. Health conditions like dementia, Alzheimer's, Amyotrophic lateral sclerosis, and depression were underassessed compared to Parkinson's. The literature focused on four separate themes: physiology of voice-affecting conditions; speech acoustics for evaluating dysphonia; speech production measurements for treating voice disorders; machine learning integration for voice disorder assessment.

CONCLUSIONS: Taking a wide view of acoustic voice assessment demonstrated research strengths and gaps-highlighting where it is used and not used-and the co-occurrence of various voice assessment topics. These insights reveal future opportunities to implement acoustic voice assessment.},
}

@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.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology
*Dysarthria/therapy/diagnosis/etiology/physiopathology/complications
Quality of Life

@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 {pmid40702789,
year = {2025},
author = {Zota, I and Calogeropoulou, T and Chanoumidou, K and Charalampopoulos, I and Gravanis, A},
title = {Synthetic microneurotrophins: Neurotrophin receptors for therapeutics of neurodegenerative diseases.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70143},
pmid = {40702789},
issn = {1476-5381},
support = {Dinnesmin//FP7 Health/ ; //European Regional Development Fund of the European Union and Greek/ ; },
abstract = {Neurodegenerative disorders are characterised by the chronic progressive degeneration of specific neuronal subtypes, neuroinflammation, myelin damage and synaptic loss. Despite their growing incidence, advancements in effective treatments remain limited, because of lack of knowledge for the aetiology of the diverse pathophysiology to design systematic therapies. Several studies highlight the role of neurotrophic factors (NTFs) as potential neuroprotective, regenerative therapies for these disorders. Although NTFs hold protective and regenerative potential for chronic neuroinflammatory and neurodegenerative conditions, major hurdles impair their clinical use, such as optimising the dosage of NTFs, minimising the invasiveness of delivery methods, overcoming blood-brain-barrier (BBB) impermeability and managing side effects. In the last two decades our group have synthesised and screened a large chemical library of steroidal analogues of dehydroepiandrosterone (DHEA), an endogenous steroid hormone, for their ability to mimic neurotrophin neuroprotective and neurogenic actions. Interestingly, DHEA was shown to interact with all neurotrophin receptors, acting most probably as an ancestral neurotrophin early in evolution. However, its chronic pharmacological use is questioned by its action as a major precursor of steroidogenesis. This review highlights the findings of numerous preclinical studies on these synthetic, non-toxic, BBB permeable DHEA derivatives, named microneurotrophins (MNTs), deprived of endocrine actions, activators of specific neurotrophin receptors. The multimodal actions of MNTs against neuronal death and activation of microglia, in addition to their beneficial effects in synaptogenesis and neurogenesis, place them as interesting lead molecules in the armamentarium of therapeutics for neurodegeneration.},
}

@article {pmid40702249,
year = {2025},
author = {Sulthana, N and Mittal, P and Goyal, A and Ballal, S and Maharana, L and Rana, AJ and Khan, Y and Goyal, K and Mishra, R and Ali, H and Gupta, G and Hussain, MS},
title = {Targeting ASK1 signaling in neurodegeneration: molecular insights and therapeutic promise.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {},
number = {},
pages = {},
pmid = {40702249},
issn = {1573-675X},
abstract = {Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensitive member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is a master regulator of neuronal apoptosis as well as neuroinflammation in neurodegenerative disorders (NDs). Under oxidative and endoplasmic reticulum stress conditions, ASK1 sets off a series of pathways, ultimately leading to impairment of cellular functions and the cell's demise. The comprehensive review focuses on the diverse contributions of ASK1 to neurodegeneration driven by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Human and animal evidence links dysregulated ASK1 signaling is related to amyloid deposition, tau hyperphosphorylation, neuroinflammation, abnormal protein folding, and subsequent neurodegeneration. ASK1 plays a role in tau hyperphosphorylation and amyloid-beta-induced neurotoxicity in AD. ASK1-mediated apoptosis of dopaminergic neurons caused by oxidative stress and aggregation of α-synuclein contributes to PD. Furthermore, ASK1 activation is associated with motor neuron degeneration in ALS related to endoplasmic reticulum stress caused by mutant SOD1. Moreover, the pathogenesis of HD involves the activation of ASK1 by the cellular stress caused by mutant huntingtin protein. ASK1 signaling potentiates inflammatory signals in MS because it is involved in demyelination and neuronal injury. Nonetheless, obstacles persist such as developing brain-targeted therapies, reducing adverse systemic effects, and defining disease-stage-specific functions of ASK1. This review aims to comprehensively examine the role of ASK1 signaling in major NDs, discuss its upstream and downstream regulatory mechanisms, and evaluate the current and emerging therapeutic strategies targeting ASK1.},
}

@article {pmid40699743,
year = {2025},
author = {Wang, S and Pan, L and Sun, C and Ma, C and Pan, H},
title = {Balancing Microglial Density and Activation in Central Nervous System Development and Disease.},
journal = {Current issues in molecular biology},
volume = {47},
number = {5},
pages = {},
doi = {10.3390/cimb47050344},
pmid = {40699743},
issn = {1467-3045},
support = {32260194 to S.Wang, and 82071245 and 82360238 to H.Pan//National Natural Science Foundation of China/ ; 20224BAB206038 to S.Wang, 20224BAB206042 to C.Sun, and 20202ACB215003 and 20232ACB205008 to H.Pan//Natural Science Foundation of Jiangxi Province/ ; },
abstract = {Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity.},
}

@article {pmid40699658,
year = {2025},
author = {Brezic, N and Gligorevic, S and Sic, A and Knezevic, NN},
title = {Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases.},
journal = {Current issues in molecular biology},
volume = {47},
number = {4},
pages = {},
doi = {10.3390/cimb47040259},
pmid = {40699658},
issn = {1467-3045},
abstract = {Chronic pain, defined by persistent pain beyond normal healing time, is a pervasive and debilitating condition affecting up to 30-50% of adults globally. In parallel, neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and cognitive or motor decline, often underpinned by pathological protein misfolding and aggregation. Emerging evidence suggests a potential mechanistic link between chronic pain and NDs, with persistent pain contributing to neuroinflammatory states and protein homeostasis disturbances that mirror processes in neurodegeneration. This review explores the hypothesis that protein misfolding and aggregation serve as a mechanistic bridge between chronic pain and neurodegeneration. We systematically examine molecular pathways of protein misfolding, proteostasis dysfunction in chronic pain, and shared neuroimmune mechanisms, highlighting prion-like propagation of misfolded proteins, chronic neuroinflammation, and oxidative stress as common denominators. We further discuss evidence from experimental models and clinical studies linking chronic pain to accelerated neurodegenerative pathology-including tau accumulation, amyloid dysregulation, and microglial activation-and consider how these insights open avenues for novel therapeutics. Targeting protein aggregation, enhancing chaperone function, modulating the unfolded protein response (UPR), and attenuating glial activation are explored as potential strategies to mitigate chronic pain and possibly slow neurodegeneration. Understanding this intersection not only elucidates chronic pain's role in cognitive decline but also suggests that interventions addressing proteostasis and inflammation could yield dual benefits in pain management and neurodegenerative disease modification.},
}

@article {pmid40694206,
year = {2025},
author = {Mahto, K and Kuwar, OK and Maloo, A and Kalia, N},
title = {Therapeutic potential of luteolin in neurodegenerative disorders: targeting Nrf2, NFĸB, MAPK, and JAK-STAT pathways to combat neuroinflammation and apoptosis.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40694206},
issn = {1568-5608},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's disease, Multiple sclerosis and Amyotrophic Lateral Sclerosis, are characterized by progressive neuronal loss, oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and apoptosis. The Nrf2/ARE, IĸB/NFĸB, MAPK/AP-1, and JAK-STAT signaling pathways play a pivotal role in these pathological processes, making them promising therapeutic targets. Luteolin, a naturally occurring flavonoid, has demonstrated potent antioxidant, anti-inflammatory, and neuroprotective properties by modulating these interconnected pathways. Activation of Nrf2/ARE signaling by luteolin enhances cellular antioxidant defences, while its inhibition of NFĸB, MAPK/AP-1, and JAK-STAT pathways suppresses neuroinflammation and apoptotic signalling, thereby mitigating neuronal damage. Emerging evidences suggest that luteolin effectively reduces neurotoxic effects by regulating inflammatory cytokine production, stabilizing mitochondrial function, and maintaining redox homeostasis. Its ability to interfere with crosstalk between these signaling pathways highlights its potential as a multi-targeted neuroprotective agent. Preclinical studies have provided strong evidence supporting luteolin's role in mitigating neurodegeneration, suggesting its applicability in neurodegenerative disease management. These findings underscore the therapeutic potential of luteolin in neurodegenerative diseases by targeting multiple pathological mechanisms. However, further investigations are needed to fully elucidate its molecular mechanisms and optimize its therapeutic benefits.},
}

@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 {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 = {},
number = {},
pages = {e70099},
doi = {10.1111/cpr.70099},
pmid = {40685330},
issn = {1365-2184},
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 {pmid40683546,
year = {2025},
author = {Mehboodi, M and Mohammad Ali Namdari, MP and Abdollahi, Z and Mobarezi, Z and Kiani, M and Chamani, F and Khanbabaie, H and Rabiei, S and Maleki, MH and Sanati, H and Shahedin, GJ and Isaei, E},
title = {The relationship between increased levels of microbiota-derived lipopolysaccharide in obesity and the pathophysiology of neurodegenerative diseases.},
journal = {Microbial pathogenesis},
volume = {},
number = {},
pages = {107905},
doi = {10.1016/j.micpath.2025.107905},
pmid = {40683546},
issn = {1096-1208},
abstract = {Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin derived from the outer membrane of Gram-negative bacteria, has been identified as a crucial link between obesity-related systemic inflammation and the onset of neurodegenerative diseases. Modifications in gut microbiota associated with obesity disrupt the integrity of the intestinal barrier, resulting in increased permeability and heightened levels of circulating LPS a phenomenon known as metabolic endotoxemia. The elevated presence of LPS promotes persistent low-grade inflammation and oxidative stress, both of which are critical contributors to neurodegeneration. This review aims to explore the biological pathways through which LPS influences the development and advancement of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). The role of LPS in exacerbating neuroinflammation through the activation of microglia and the impairment of the blood-brain barrier (BBB) is thoroughly examined. Moreover, the review delves into the interrelated effects of obesity-related systemic inflammation, insulin resistance, and mitochondrial dysfunction in enhancing LPS-driven neurodegenerative mechanisms. Special emphasis is placed on the common pathological characteristics present in these disorders, such as protein misfolding, neuronal apoptosis, and disrupted synaptic function, which may be exacerbated by LPS-related processes. By clarifying the relationships between obesity, LPS, and neurodegenerative diseases, this review underscores potential therapeutic approaches aimed at modulating gut microbiota, improving intestinal barrier function, and mitigating systemic inflammation to prevent or decelerate the progression of these debilitating disorders.},
}

@article {pmid40682794,
year = {2025},
author = {Sheikh Saleh, D and Mraer, L and Fatima, H and Gubari, H and Alsayed, MA and Hassan, FE},
title = {Decoding the Dialogue: Immunity and central nervous system interactions in neurodegenerative diseases.},
journal = {The Egyptian journal of immunology},
volume = {32},
number = {3},
pages = {20-31},
doi = {10.55133/eji.320303},
pmid = {40682794},
issn = {1110-4902},
mesh = {Humans ; *Neurodegenerative Diseases/immunology ; *Central Nervous System/immunology ; Animals ; Immunity, Innate ; *Neuroimmunomodulation ; Microglia/immunology ; Astrocytes/immunology ; Blood-Brain Barrier/immunology ; },
abstract = {This review article aims to discuss neuroimmune interactions by emphasizing the role of central and peripheral immunities in central nervous system (CNS) protection and function, as well as how abnormalities in this relationship may be implicated in the genesis of neurodegenerative diseases (NDDs). Immune elements that play roles within the CNS both during stable and infectious states are described. Innate CNS immunity is explored as a distinct entity comprised of the brain blood barrier, CNS parenchyma, and resident immune cells-microglia and astrocytes, whose roles in antigen recognition and clearance and neuromodulation are further enumerated. Due to the inability of the CNS to independently initiate an adaptive immune response, the necessary recruitment and regulation of elements from the peripheral immune system (PIS) are described in a process that, in chief, utilizes resident antigen-presenting cells to prime naïve T-cells, which later enter the CNS through areas of access to the cerebrospinal fluid. The previous modes of interaction especially enable microglia, astrocytes, and T-cells to play part in neurodevelopment and plasticity, and the proposed mechanisms by which they participate in synaptic pruning, neurogenesis, and memory are examined. In addition to its protective role, the PIS has also been shown to play a regulatory role in the CNS, where it drives responses that optimize immune function, such as fever and sickness behavior. Due to the high level of involvement of the immune system within the CNS, dysregulations of the immune system are thought to be implicated in numerous NDD pathogeneses, where neuroinflammation both causes and is caused by immune reactions. Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are particularly discussed.},
}

Humans
*Neurodegenerative Diseases/immunology
*Central Nervous System/immunology
Animals
Immunity, Innate
*Neuroimmunomodulation
Microglia/immunology
Astrocytes/immunology
Blood-Brain Barrier/immunology

@article {pmid40681220,
year = {2025},
author = {Abd El-Aziz, MK and Wadan, AS and Albahttiti, ATI and Moradikor, N},
title = {Emotional stress and cardiovascular health: Impacts on neurodegenerative disease progression.},
journal = {Progress in brain research},
volume = {294},
number = {},
pages = {101-133},
doi = {10.1016/bs.pbr.2025.04.004},
pmid = {40681220},
issn = {1875-7855},
mesh = {Humans ; *Stress, Psychological/physiopathology/complications/metabolism ; *Neurodegenerative Diseases/physiopathology/metabolism ; *Cardiovascular Diseases/physiopathology/metabolism ; Disease Progression ; Hypothalamo-Hypophyseal System/physiopathology/metabolism ; Pituitary-Adrenal System/physiopathology/metabolism ; },
abstract = {Stress is an inevitable part of people's lives and is considered to have a severe impact on health, especially in the case of cardiovascular diseases and neurodegenerative diseases. This chapter aims to reveal the links between emotional stress, cardiovascular health, and neurodegenerative disease progression. Chronic stress is therefore recognized as a significant cause of cardiovascular diseases mainly because of the effects it has on the hypothalamic-pituitary-adrenal (HPA) axis and the (SNS) sympathetic which neurodegenerative nervous are diseases system such (as ALS) through inflammation of Alzheimer's mechanisms and disease, vascular such as Parkinson's functions. The mechanisms of work also establish the crosstalk between CVD and NDD, demonstrating that they share genetic, molecular, and systemic associations. It is essential to know these pathways to design interventions that will help prevent or lessen the effects of stress on health and thus enhance patient care.},
}

Humans
*Stress, Psychological/physiopathology/complications/metabolism
*Neurodegenerative Diseases/physiopathology/metabolism
*Cardiovascular Diseases/physiopathology/metabolism
Disease Progression
Hypothalamo-Hypophyseal System/physiopathology/metabolism
Pituitary-Adrenal System/physiopathology/metabolism

@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 (CoQ10), creatine, and N-acetylcysteine (NAC) 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 such conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's 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 {pmid40084393,
year = {2025},
author = {Helmold, B and Nathaniel, G and Barkhaus, P and Bertorini, T and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Denson, K and Glass, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Maragakis, N and Cadavid, JM and Mcdermott, C and Pattee, G and Pierce, K and Wang, O and Wicks, P and Bedlack, R},
title = {ALSUntangled #78: Zinc.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {5-6},
pages = {599-603},
doi = {10.1080/21678421.2025.2476688},
pmid = {40084393},
issn = {2167-9223},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/diet therapy ; Humans ; *Zinc/therapeutic use/administration & dosage ; *Dietary Supplements ; Animals ; Disease Progression ; },
abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we assess the utilization of dietary zinc supplements for modulating ALS pathology and progression. Studies in mouse models of ALS have demonstrated that high-dose zinc supplementation may be harmful, but moderate doses could potentially be beneficial. Clinical data is limited, and only one trial has explored zinc supplementation within PALS. This study reported potential benefits in slowing ALS progression but lacked statistical analyses and failed to report quantitative evidence. Numerous case reports from individual patients at varying doses have demonstrated no benefit. Zinc supplements at moderate doses are generally low cost and not associated with severe complications, but further research is required to determine the safety and efficacy of zinc supplementation within PALS. Therefore, we cannot at this time, endorse zinc supplementation to slow ALS progression.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/diet therapy
Humans
*Zinc/therapeutic use/administration & dosage
*Dietary Supplements
Animals
Disease Progression

@article {pmid40673975,
year = {2025},
author = {Perreault, MC and Heckman, CJ and Giorgi, A},
title = {Spinally Projecting Serotonergic Neurons in Motor Network Modulation.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00139.2025},
pmid = {40673975},
issn = {1522-1598},
support = {20153//National Science Foundation (NSF)/ ; },
abstract = {Spinally projecting serotonergic (5-HTsp) neurons represent a heterogeneous population of neurons in the brainstem whose relevance in the control of movement has largely been inferred. Numerous studies across a variety of species have suggested that 5-HTsp neurons exert a widespread influence on spinal sensorimotor networks, operating at multiple levels (primary afferents, interneurons, and motoneurons) through various serotonin receptor subtypes. However, despite the anatomical and neurochemical complexity of the 5-HTsp system, most supporting evidence has largely been derived from indirect approaches (e.g., exogenous application of 5-HT and agonists/antagonists of 5-HT receptors). Direct demonstrations of specific anatomical and functional connectivity have been limited, occasionally yielding apparent discrepant results. Consequently, as the primary provider of serotonin to the spinal cord, the exact contributions of the 5-HTsp neurons remain to be fully elucidated. For this mini-review, we sifted through the literature of the last six decades, starting after the characterization of the brainstem raphe nuclei and monoaminergic systems [1-3], to provide a clearer picture of what is currently known of the anatomy and influences of the different populations of 5-HTsp neurons on sensorimotor circuits and motor behaviors. We focused on studies reporting direct manipulation of brainstem 5-HTsp neurons, excluding those targeting 5-HT neurotransmission by exogenous application of 5-HT. This emphasis aims to highlight the urgency of resolving how 5-HTsp neuron subpopulations differentiate anatomically and functionally, so that they can be integrated as dedicated components in current models of supraspinal control of movement and motor diseases such as Parkinson's and amyotrophic lateral sclerosis. Along the way, we point out gaps in knowledge that may be filled using newly available research tools.},
}

@article {pmid40664112,
year = {2025},
author = {Sahoo, BR and Bardwell, JC},
title = {Protein and RNA chaperones.},
journal = {Molecular aspects of medicine},
volume = {104},
number = {},
pages = {101384},
doi = {10.1016/j.mam.2025.101384},
pmid = {40664112},
issn = {1872-9452},
abstract = {Cells preserve macromolecular homeostasis by utilizing molecular chaperones that prevent aggregation or promote correct folding of protein and RNA. Here we discuss non-traditional proteinaceous chaperones like RNA-binding chaperones that work by modulating RNA structure, preventing aberrant interactions, and regulating intracellular granule dynamics. We also discuss the chaperone functions of other macromolecules such as nucleic acids, and in particular G-quadruplexes, which are very effective at preventing protein aggregation and accelerating protein folding. These chaperones are particularly important in G-quadruplex linked amyloid aggregation and repeat-expansion diseases such as Parkinson's disease and amyotrophic lateral sclerosis, where RNA aggregation and misfolded protein accumulation co-occur. By comparing protein and non-protein chaperone systems, we highlight the principles that underlie chaperone action across molecular classes.},
}

@article {pmid40661315,
year = {2025},
author = {Anjum, F and Bakhuraysah, M and Alsharif, A and Mohammad, T and Shamsi, A and Hassan, MI},
title = {Emerging biomarkers in amyotrophic lateral sclerosis: from pathogenesis to clinical applications.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1608853},
pmid = {40661315},
issn = {2296-889X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition marked by the gradual loss of motor neurons in the brain and spinal cord. As the most common adult-onset motor neuron disease, ALS manifests through gradually worsening muscle weakness that ultimately progresses to complete paralysis. The disease presents in both sporadic and familial forms. Diagnosis is often delayed until substantial and irreversible motor neuron damage has already occurred. Clinical outcomes in ALS have only been defined through large-scale clinical trials with lengthy follow-up periods due to the disease's inherent heterogeneity and the absence of disease-specific biomarkers. Current biomarker detection methods, such as invasive cerebrospinal fluid (CSF) analysis or advanced imaging, are impractical for routine use, particularly in late-stage ALS. Several blood-based biomarkers have shown promise, including neurofilament levels, cryptic RNA-derived peptides, and immune-mediated changes, which may enable non-invasive monitoring. Nevertheless, the development of these methods is hindered by technical challenges, such as blood matrix interference and low analyte abundance. Among the emerging biomarkers, neurofilament light chain (NfL) appears to be the most promising, as its concentrations change in line with disease progression and distinguish clinically relevant groups. NfL facilitates patient stratification based on clinical progression rates (e.g., rapid vs slow progressors), while cryptic exon-derived peptides, such as UNC13A-derived peptides, enable genetic stratification by identifying molecular subtypes linked to TDP-43 pathology (e.g., C9orf72 vs sporadic ALS). These biomarkers hold promise to optimize clinical trial design through enriched cohort selection and accelerating therapeutic translation by monitoring target engagement. In this review, we have summarized recent developments in ALS biomarker studies, focusing on neurofilaments in each biofluid, transcriptomic signatures, and neuroinflammatory biomarkers, emphasizing technical challenges surrounding reproducibility in measurement. Finally, we discussed the potential integration of these biomarkers into clinical practice to advance drug development through precision medicine, thereby enabling shorter and more targeted clinical trials.},
}

@article {pmid40658257,
year = {2025},
author = {Fasano, A and Vacchiano, V and Bonan, L and McMackin, R and Nasseroleslami, B and Hardiman, O and Liguori, R},
title = {Neurophysiological biomarkers of networks impairment in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {507},
pmid = {40658257},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Biomarkers ; Transcranial Magnetic Stimulation ; *Nerve Net/physiopathology ; Electroencephalography ; Electromyography ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease involving motor system as well as cognitive domains. There is an urgent need for objective biomarkers that can subcategorize subjects into homogeneous groups based on disease pathobiology.In this review, we discuss novel neurophysiological techniques that provide detailed, multiscale and multidimensional insights into ALS networks impairment, spanning from the micro-columnar architecture of the motor cortex to motor and cognitive networks. Specifically, Transcranial Magnetic Stimulation (TMS) paradigms can be used to evaluate the status of excitatory and inhibitory networks within the layers of the motor cortex. Abnormalities in functional connectivity between the two motor areas, as well as within the frontal-temporal and frontal parietal networks, can be characterized using novel source-localization analysis of high-density electroencephalography (EEG). TMS and EEG techniques provide data that correlate with both motor and cognitive impairment. Furthermore, cortico-muscular coherence analysis can be used to assess functional dysregulation within the entire motor system, and novel surface electromyography (EMG) techniques, such as motor unit number estimation, motor unit number index, and nerve excitability testing studies provide useful insights into axonal loss and membrane ion channel dysfunctions in lower motor neurons.The integrated analysis of these biomarkers provides valuable insights into the clinical and biologic heterogeneity of the disease, aiding the intelligent design of next generation precision-based therapeutics.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis
Biomarkers
Transcranial Magnetic Stimulation
*Nerve Net/physiopathology
Electroencephalography
Electromyography

@article {pmid40655970,
year = {2023},
author = {Vardheim, EG and Toft, A and Nielsen, JE and Hasselbalch, SG and Simonsen, AH},
title = {Cerebrospinal fluid ubiquitin as a biomarker for neurodegenerative diseases: A systematic review.},
journal = {Neuroscience applied},
volume = {2},
number = {},
pages = {102438},
pmid = {40655970},
issn = {2772-4085},
abstract = {Ubiquitin plays a vital role in neuronal proteostasis, as a major but often overlooked component of neurotoxic protein aggregates across neurodegenerative diseases. Although neuropathological changes can be present for years before clinical onset, early and accurate diagnosis remains an immense challenge in this disease category. The level of ubiquitin in cerebrospinal fluid (CSF) has been assessed as a biomarker for several disease entities. This systematic review compares current findings and evaluates the potential of CSF ubiquitin as a fluid biomarker. A systematic literature search identified studies comparing CSF ubiquitin levels between a control group and patients with one of the following diseases: Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Lewy body dementia (DLB), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). All included studies were reviewed systematically by two independent authors. 171 studies were identified. A total of 17 studies met the eligibility criteria and were included. Nine out of 13 studies found a significant increase of CSF ubiquitin in AD patients compared with control groups. Correlations between CSF ubiquitin and other established biomarkers were demonstrated in seven studies. A single study was included for both HD and DLB respectively, each showing significantly higher CSF ubiquitin in patients compared to controls. In patients with PD, FTD or ALS, CSF ubiquitin levels were generally equal to those of the control groups, with two studies showing significantly decreased concentrations in a PD and an FTD cohort. Presently, the available body of research is insufficient to assess whether CSF ubiquitin could contribute to the clinical setting, alongside established markers of neurodegeneration. The correlation of elevated CSF ubiquitin with AD is well-founded, whilst validation of reduced or unchanged levels in the other neurodegenerative diseases will determine the usefulness of the biomarker in clinical practice.},
}

@article {pmid40130694,
year = {2025},
author = {Burke, KM and Arulanandam, V and Scirocco, E and Royse, T and Hall, S and Weber, H and Arnold, J and Pathak, P and Walsh, C and Paganoni, S},
title = {Assistive Technology in ALS: A Scoping Review of Devices for Limb, Trunk, and Neck Weakness.},
journal = {American journal of physical medicine & rehabilitation},
volume = {104},
number = {8},
pages = {e115-e124},
pmid = {40130694},
issn = {1537-7385},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; *Self-Help Devices ; *Muscle Weakness/rehabilitation/etiology/physiopathology ; Activities of Daily Living ; Torso/physiopathology ; },
abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease affecting upper and lower motor neurons that control voluntary muscles. With no known cure, clinical care is focused on symptom management to maximize function and quality of life. Assistive technology plays a crucial role and enables some restoration of movement and function despite disease progression. This scoping review assesses the effectiveness of assistive technologies tested in people living with amyotrophic lateral sclerosis, specifically those designed to compensate for upper and lower extremity, trunk, and cervical muscle weakness. A comprehensive search was conducted across PubMed, CINAHL, ERIC, and Google Scholar and through citation chasing. We included 26 articles that tested an assistive device on at least one person living with amyotrophic lateral sclerosis and evaluated the device's effectiveness in restoring movement or providing stabilization to support functional mobility or activities of daily living. Most studies were pilot feasibility or usability trials, with small numbers of amyotrophic lateral sclerosis participants. The devices showed various benefits, including improved range of motion, function, and participation in daily activities. This review highlights the potential for assistive devices to enhance function in people living with amyotrophic lateral sclerosis and underscores the need for comprehensive studies involving larger cohorts of individuals at different stages of amyotrophic lateral sclerosis.},
}

Humans
*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology
*Self-Help Devices
*Muscle Weakness/rehabilitation/etiology/physiopathology
Activities of Daily Living
Torso/physiopathology

@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},
doi = {10.1016/j.pharmr.2025.100071},
pmid = {40652712},
issn = {1521-0081},
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 {pmid40651187,
year = {2025},
author = {Chang, J and Teo, AH and Shaw, TB and Dupuis, L and Ngo, ST and Steyn, FJ},
title = {Deciphering hypothalamic pathology in ALS: insights into non-motor symptoms and disease progression.},
journal = {EBioMedicine},
volume = {118},
number = {},
pages = {105845},
doi = {10.1016/j.ebiom.2025.105845},
pmid = {40651187},
issn = {2352-3964},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with highly heterogeneous clinical presentations. Among the non-motor features increasingly recognised as clinically relevant is the dysregulation of energy balance, with weight loss-particularly due to fat mass loss-emerging as a significant modifier of disease risk, progression, and survival. In this context, the hypothalamus-a key regulator of homeostatic and metabolic processes-has gained attention for its potential role in ALS pathophysiology. This Review synthesises emerging evidence of hypothalamic involvement in ALS, including neuronal loss, proteinopathy, and volume loss observed through histological and neuroimaging studies. We critically examine current imaging approaches and their technical limitations and explore neuroendocrine dysfunction across the hypothalamic-pituitary axes. Collectively, these findings suggest that hypothalamic dysfunction may contribute to clinically relevant metabolic, sleep, behavioural, and cognitive changes in ALS, adding to our understanding of ALS as a multisystem disease. Continued investigation of the hypothalamus may reveal novel biomarkers, inform risk stratification, and identify therapeutic opportunities to address disease heterogeneity and improve clinical outcomes.},
}

@article {pmid40650046,
year = {2025},
author = {Cattaneo, M and Giagnorio, E and Lauria, G and Marcuzzo, S},
title = {Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
pmid = {40650046},
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"/ ; prog. 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 = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; Animals ; DNA Repeat Expansion ; Gene Editing ; Genetic Therapy/methods ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. One of its major genetic causes is C9ORF72, where mutations lead to hexanucleotide repeat expansions in the C9ORF72 gene. These expansions drive disease progression through mechanisms, including the formation of toxic RNAs and the accumulation of damaged proteins such as dipeptide repeats (DPRs). This review highlights these pathogenic mechanisms, focusing on RNA foci formation and the accumulation of toxic DPRs, which contribute to neuronal damage. It also discusses promising targeted therapies, including small molecules and biological drugs, designed to counteract these specific molecular events. Small molecules such as G-quadruplex stabilizers, proteasome and autophagy modulators, and RNase-targeting chimeras show potential in reducing RNA foci and DPR accumulation. Furthermore, targeting enzymes involved in repeat-associated non-AUG (RAN) translation and nucleocytoplasmic transport, which are crucial for disease pathogenesis, opens new therapeutic avenues. Even some anti-viral drugs show encouraging results in preclinical studies. Biological drugs, such as antisense oligonucleotides and gene-editing technologies like CRISPR-Cas, were explored for their potential to specifically target C9ORF72 mutations and modify the disease's molecular foundations. While preclinical and early clinical data show promise, challenges remain in optimizing delivery methods, ensuring long-term safety, and improving efficacy. This review concludes by emphasizing the importance of continued research and the potential for these therapies to alter the disease trajectory and improve patient outcomes.},
}

Humans
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology
Animals
DNA Repeat Expansion
Gene Editing
Genetic Therapy/methods
Mutation
Oligonucleotides, Antisense/therapeutic use

@article {pmid40649976,
year = {2025},
author = {Jiménez-García, AM and Tortorella, ME and Nishimura, AL and Arias, N},
title = {The Differential Effects of Genetic Mutations in ALS and FTD Genes on Behavioural and Cognitive Changes: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
pmid = {40649976},
issn = {1422-0067},
support = {PID2023-151715OB-IOO//Ministry of Science and Innovation/ ; PLEC2022-009464//European Union NextGeneration EU/PRTR/ ; CPP2022-009646//European Union NextGeneration EU/PRTR/ ; },
mesh = {Humans ; *Frontotemporal Dementia/genetics/psychology ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Mutation ; *Cognition ; tau Proteins/genetics ; C9orf72 Protein/genetics ; Progranulins/genetics ; Superoxide Dismutase-1/genetics ; Endosomal Sorting Complexes Required for Transport/genetics ; RNA-Binding Protein FUS/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support.},
}

Humans
*Frontotemporal Dementia/genetics/psychology
*Amyotrophic Lateral Sclerosis/genetics/psychology
*Mutation
*Cognition
tau Proteins/genetics
C9orf72 Protein/genetics
Progranulins/genetics
Superoxide Dismutase-1/genetics
Endosomal Sorting Complexes Required for Transport/genetics
RNA-Binding Protein FUS/genetics

@article {pmid40649921,
year = {2025},
author = {Neumann, S and Heumann, R},
title = {Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
pmid = {40649921},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Voltage-Dependent Anion Channels/metabolism/genetics ; Animals ; Mitochondria/metabolism ; },
abstract = {The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Voltage-Dependent Anion Channels/metabolism/genetics
Animals
Mitochondria/metabolism

@article {pmid40649859,
year = {2025},
author = {Tomczak, J and Kapsa, A and Boczek, T},
title = {Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136081},
pmid = {40649859},
issn = {1422-0067},
support = {2020/39/D/NZ4/01250//National Science Center/ ; },
mesh = {Humans ; *Adenylyl Cyclases/metabolism ; Animals ; *Nerve Regeneration/drug effects ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuronal Plasticity ; },
abstract = {Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling-a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses-including gene transcription, cytoskeletal remodeling, and neurotransmitter release-to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting.},
}

Humans
*Adenylyl Cyclases/metabolism
Animals
*Nerve Regeneration/drug effects
Signal Transduction/drug effects
Cyclic AMP/metabolism
*Neurodegenerative Diseases/drug therapy/metabolism
Neuronal Plasticity

@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 = {},
doi = {10.3390/foods14132193},
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 {pmid40641139,
year = {2025},
author = {Sun, Y and Wei, K and Liao, X and Wang, J and Gao, L and Pang, B},
title = {Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).},
journal = {International journal of molecular medicine},
volume = {56},
number = {3},
pages = {},
doi = {10.3892/ijmm.2025.5580},
pmid = {40641139},
issn = {1791-244X},
mesh = {*Microglia/metabolism/pathology ; Humans ; *Lipid Metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.},
}

*Microglia/metabolism/pathology
Humans
*Lipid Metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology/therapy

@article {pmid40640916,
year = {2025},
author = {Lemarchant, S and Engelhardt, B and Cicchetti, F and Bix, GJ and Janus, A and Godfrin, Y and Blasco, H and Campbell, M and de Rus Jacquet, A},
title = {Restoring brain barriers: an innovative approach for treating neurological disorders.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {72},
pmid = {40640916},
issn = {2045-8118},
mesh = {Humans ; *Blood-Brain Barrier/drug effects/physiopathology/pathology/metabolism ; *Nervous System Diseases/drug therapy/therapy/pathology ; Animals ; },
abstract = {The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.},
}

Humans
*Blood-Brain Barrier/drug effects/physiopathology/pathology/metabolism
*Nervous System Diseases/drug therapy/therapy/pathology
Animals

@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.},
}

Humans
*Microglia/metabolism
*Neurodegenerative Diseases/metabolism/therapy
*Biomarkers/metabolism
Animals

@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 = {},
number = {},
pages = {},
pmid = {40640528},
issn = {1179-1934},
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 {pmid40639550,
year = {2025},
author = {Mondal, M and Chouksey, A and Gurjar, V and Tiwari, R and Srivasatava, RK and Mishra, PK},
title = {Micro(nano)plastics in the brain: Epigenetic perturbations in progression to neurodegenerative diseases.},
journal = {Neurotoxicology and teratology},
volume = {110},
number = {},
pages = {107521},
doi = {10.1016/j.ntt.2025.107521},
pmid = {40639550},
issn = {1872-9738},
abstract = {As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.},
}

@article {pmid40629407,
year = {2025},
author = {Choi, Y and Chung, WS},
title = {Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {81},
pmid = {40629407},
issn = {1750-1326},
support = {2020M3E5D9079912//Ministry of Science and ICT, South Korea/ ; 2021R1A2C3005704//Ministry of Science and ICT, South Korea/ ; 2022M3E5E8081188//Ministry of Science and ICT, South Korea/ ; IBS-R025-A1//Institute for Basic Science/ ; },
mesh = {Humans ; *Neuroglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Phagocytosis/physiology ; *Synapses/metabolism/pathology ; Animals ; },
abstract = {Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.},
}

Humans
*Neuroglia/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Phagocytosis/physiology
*Synapses/metabolism/pathology
Animals

@article {pmid40626296,
year = {2025},
author = {Li, D and Wang, P and Zhang, M and Zhang, X and Yao, H and Liu, X},
title = {Advances in examination methods for adolescent idiopathic scoliosis.},
journal = {Pediatric discovery..},
volume = {3},
number = {1},
pages = {e2518},
pmid = {40626296},
issn = {2835-5598},
abstract = {The purpose of this article is to provide an overview of techniques for evaluating patients with adolescent idiopathic scoliosis (AIS). It encompasses the history, clinical examinations, and diagnostic imaging methods for AIS. These methods include digital radiological examination, EOS® imaging, nuclear medicine, ultrasound, body surface topography techniques such as the Moiré pattern technique, raster stereophotography, and DIERS formetric 4D as well as computed tomography and magnetic resonance imaging (MRI). Traditionally, full-spine standing X-rays have been the standard for diagnosing AIS. High-quality clinical assessments may continue as a reference for assessing other spinal deformities. However, the new diagnostic imaging methods aim to reduce radiation exposure while maintaining image quality and practicality. Emerging technologies demonstrate strong reliability and effectiveness in diagnostic imaging of AlS. These techniques may be beneficial for diagnosing and monitoring AIS and its progression without requiring high levels of radiation exposure. The article is a search and summary of the PubMed electronic database to understand the current and future status of AIS imaging technology, which can not only help to introduce other researchers to the field but also serve as a valuable source for healthcare professionals to study existing methods, develop new ones, or select evaluation strategies.},
}

@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 = {},
number = {},
pages = {},
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/ ; },
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 {pmid40621104,
year = {2025},
author = {Rosene, MJ and Benitez, BA},
title = {Cysteine string protein α and a link between rare and common neurodegenerative dementias.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {15},
pmid = {40621104},
issn = {3005-1940},
abstract = {The maintenance of protein homeostasis and overall protein quality control dysfunction are associated with dementia. Cysteine string protein α (CSPα) is an endolysosomal cochaperone that facilitates the fusion of secretory and synaptic vesicles to the cell membrane. CSPα interacts with multiple proteins related to the proteostasis network and exocytic pathways and is often dysfunctional in synaptopathies. Since the initial discovery of CSPα 30 years ago, subsequent research has demonstrated a protective role of CSPα, especially in synaptic maintenance. However, the discovery of heterozygous CSPα mutations in 2011 causing adult-onset neuronal ceroid lipofuscinosis (ANCL) shifted the back-then prevalent dogma of unique synaptic function to include an endolysosomal role for CSPα. Recently, CSPα has been involved in the exocytosis of aggregate-prone proteins through either the misfolding-associated protein secretion (MAPS) or unconventional secretory pathways linking the molecular mechanism of rare and common neurodegenerative diseases. Here, we propose a novel molecular and pathophysiological model of CSPα-associated dementia, outline the increasing evidence of a broader role of CSPα in neurodegeneration, propose the role of CSPα in the synaptic secretion of neurodegenerative-associated proteins, and discuss the modulation of CSPα as a molecular target for common dementias.},
}

@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 ; *Extracellular Vesicles/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; *Mesenchymal Stem Cells/cytology/metabolism ; Animals ; Mesenchymal Stem Cell Transplantation ; },
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.},
}

Humans
*Extracellular Vesicles/transplantation/metabolism
*Neurodegenerative Diseases/therapy
*Mesenchymal Stem Cells/cytology/metabolism
Animals
Mesenchymal Stem Cell Transplantation

@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.},
}

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

@article {pmid40618376,
year = {2025},
author = {Scirocco, E and Allen, MD and Giacomelli, E and Ajroud-Driss, S and Andrews, J and Banack, S and Bede, P and Benatar, M and Cheung, K and Corcia, P and de Carvalho, M and Elman, L and Fink, JK and Genge, A and Hardiman, O and Harms, M and Heitzman, D and Jang, G and Kano, O and Kiernan, MC and Lee, I and Ludolph, A and Mehta, P and Ozdinler, H and Rezania, K and Schito, P and Sherman, AV and Silani, V and Sorenson, E and Turner, MR and Van Den Berg, L and Mitsumoto, H and Paganoni, S},
title = {Toward therapeutic trials in primary lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2527123},
pmid = {40618376},
issn = {2167-9223},
abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder primarily affecting the upper motor neurons. People living with PLS experience progressive physical and communication disability, which typically evolves slowly over several years. In contrast to amyotrophic lateral sclerosis (ALS), life expectancy is anticipated to be normal. Disease-modifying medications are not available and PLS drug development has been challenging. This review considers recent advances and ongoing initiatives aimed at promoting clinical trial readiness for PLS. Ongoing clinical research efforts include patient registries and biorepositories, natural history studies, outcome measure validation, and biomarker development. These international collaborative efforts are essential for developing the first therapeutic trials for people living with PLS.},
}

@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 = {},
number = {},
pages = {106276},
doi = {10.1016/j.neubiorev.2025.106276},
pmid = {40614949},
issn = {1873-7528},
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 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 studies on humans and rodents regarding the involvement of NLRP3 inflammasomes 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 scrutinised the relationship of NLRP3 inflammasomes to intestinal microbiota alterations in these diseases. Both NLRP3 inflammasomes and P2X7R have been shown to play important roles in the progression of these neurodegenerative diseases. However, most studies have focused on central nervous system pathology, particularly within the brain, with comparatively less attention given to their contribution to gut pathology. Additionally, changes in the microbial environment of the intestine have also been correlated to these disorders. However, the association between gut microbiota alteration and inflammasome activity in the pathology of these neurodegenerative disorders has been poorly understood. Therefore, further investigation is needed to explore the microbiota-inflammasome-brain axis in these conditions, with the aim of better understanding their contribution to disease progression and identifying novel therapeutic targets.},
}

@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 {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.},
}

Humans
*Proteostasis
*Neurodegenerative Diseases/metabolism/therapy/pathology
Animals
Autophagy
*Protein Aggregation, Pathological/metabolism/therapy/pathology
*Protein Aggregates

@article {pmid40609398,
year = {2025},
author = {Yazdanian, T and Azimi, P and Babu, S},
title = {Cervical spinal cord MRI in ALS individuals: a systematic review and meta-analysis.},
journal = {NeuroImage. Clinical},
volume = {47},
number = {},
pages = {103832},
doi = {10.1016/j.nicl.2025.103832},
pmid = {40609398},
issn = {2213-1582},
abstract = {BACKGROUND: Disease tracking and prognostication of amyotrophic lateral sclerosis (ALS) can be quite challenging in people living with ALS, due to the complexity of central nervous system disease biology. This systematic review and meta-analysis aim to summarize cervical spinal cord quantitative MRI (qMRI) biomarker changes in individuals with ALS.

METHODS: PubMed, Scopus, Cochrane Library, and Web of Science databases were searched up to August 2023. The terms used were "ALS", "cervical spinal cord", "MRI"," diffusion tensor imaging (DTI)", " fractional anisotropy (FA)", " mean diffusivity (MD) "," magnetization transfer ratio (MTR)", " cross-sectional area (CSA)", " radial diffusivity (RD) ", and " atrophy ". The Newcastle-Ottawa scale (NOS) was used to assess study quality. We calculated the pooled: 1) Standardized mean difference (SMD) and 95% CIs for comparative assessment of qMRI parameters in ALS individuals and the healthy population. 2) Estimate the mean of qMRI parameters for normative values in two groups by CMA software. Heterogeneity and publication bias were determined by the I-squared statistic and funnel plots.

RESULTS: Thirty studies, with 1817 participants (35.9 % female) were included in this review, and 29 had a NOS ≥ 5 which indicates high-quality of data overall. The SMD analysis showed (a) significant decrease in CSA along the whole length of cervical cord (C1-C7) (p value < 0.0001), with a preferential thinning of the cervical enlargement region (C4-C6 region) (p value < 0.0001) (b) significant decrease in FA (p value < 0.0001), particularly FA left lateral corticospinal tract (p value < 0.0001) and (c) a significant increase in MD (p value < 0.0001) in ALS individuals compared to controls. The pooled analysis reveals that the mean (SD) values for ALS individuals versus controls for (a) CSA (in mm[2]) were C1 [73.4 (0.75), 78.5 (0.67), 6.9 % difference]; C2 [70.6 (3.1), 71.5 (3.5), 1.2 % difference]; C3 [69.8(1.5), 74.9 (1.9), 7.3 % difference]; C4 [71.9 (1.8), 77.6 (2.8), 7.9 % difference]; C5 [71.8 (2.5), 79.5 (3.3), 10.7 % difference]; C6 [66.8 (2.7), 73.7 (3.7), 10.3 % difference]; C7 [56.7 (F2.2), 62.1 (2.5), 9.5 % difference]; (b) FA [0.54 (0.03), 0.56 (0.03)]; (c) MD[1.11 (0.18), 0.88(0)]; and (d) FA LLCST [ 0.65 (0.04), 0.77 (0.04)], respectively. The mean (SD) value of the MTR and RD for ALS individuals was 40.3 (2.3), and 0.70 (0.0).

CONCLUSIONS: qMRI metrics of spinal cord show discriminatory potential between ALS and healthy controls. The selective atrophy of the cervical enlargement (C4-C6) is replicable across multiple studies as seen in this metanalysis and hence is a potential imaging marker for quantifying and tracking lower motor neuron degeneration in ALS.},
}

@article {pmid40608189,
year = {2025},
author = {Sharma, VK},
title = {Dysbiosis and Neurodegeneration in ALS: Unraveling the Gut-Brain Axis.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {50},
pmid = {40608189},
issn = {1559-1174},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/microbiology/therapy ; *Dysbiosis/complications/physiopathology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain-Gut Axis/physiology ; *Brain/physiopathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder marked by the progressive degeneration of motor neurons in the brain and spinal cord. Despite decades of research, ALS remains incurable, diagnostically elusive, and is accompanied by rapid clinical decline, morbidity, and mortality. Its pathophysiology involves a complex interplay of genetic mutations (SOD1, C9/f72), environmental triggers, oxidative stress, neuroinflammation, and the accumulation of misfolded proteins, such as TDP-43 and SOD1. These factors disrupt cellular homeostasis aggravates excitotoxicity and neuronal death. Existing treatments, such as riluzole (a glutamate release modulator) and edaravone (a free radical scavenger), offer limited benefits, modestly prolonging survival or slowing functional decline without halting progression. Investigational approaches include antisense oligonucleotides targeting mutant SOD1 or C9orf72 genes, stem cell-based motor neuron replacement, and biomarker discovery to enable earlier diagnosis and progression monitoring. ALS patients frequently exhibit gastrointestinal (GI) symptoms, including dysphagia, sialorrhea, constipation, delayed gastric emptying, and pancreatic/parotid deficiencies. These observations underscore a close association between GI dysfunction and ALS pathogenesis. Also, recent studies implicate the gut-brain-microbiota axis in disease evolution, with microbial metabolites influencing neuroimmune interactions, synaptic plasticity, myelination, and skeletal muscle function. These studies indicate that dysbiosis-an imbalance in gut microbiota-may have a crucial role in ALS progression by impairing intestinal barrier integrity, promoting endotoxemia, and driving systemic inflammation. Conversely, ALS progression itself worsens dysbiosis, creating a vicious cycle of neuroinflammation and neurodegeneration. Preclinical and clinical evidence suggests that interventions targeting gut microbiota-such as prebiotics, probiotics, antibiotics, or phage therapy-could alleviate symptoms and slow disease progression and specific probiotic strains have also shown promise in reducing oxidative stress and inflammation in animal models. These findings highlight the urgent need to elucidate the functional role of gut microbiota in ALS to unlock novel diagnostic and therapeutic avenues. This review synthesizes current knowledge on the pathophysiology of ALS, with a focus on the emerging role of the gut-brain-microbiota axis. It highlights how dysbiosis influences diverse disease markers and neurodegenerative mechanisms, offering insights into potential therapeutic strategies and identifying key research gaps and future directions.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology/microbiology/therapy
*Dysbiosis/complications/physiopathology/therapy
*Gastrointestinal Microbiome/physiology
Animals
*Brain-Gut Axis/physiology
*Brain/physiopathology

@article {pmid40188806,
year = {2025},
author = {Saller, R and Schwabl, H and Rostock, M and Dal Cero, M},
title = {[Vom Spezifischen zum Systemischen - am Beispiel Tormentill/Blutwurz, der Heilpflanze des Jahres 2024].},
journal = {Complementary medicine research},
volume = {32},
number = {3},
pages = {260-263},
doi = {10.1159/000545128},
pmid = {40188806},
issn = {2504-2106},
mesh = {Humans ; *Plants, Medicinal/chemistry ; *Phytotherapy ; *Plant Extracts/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; },
abstract = {Am Beispiel des in verschiedenen lokalen Traditionen genutzten Blutwurz, auch Tormentill (Potentilla erecta L.), wird exemplarisch eine offensichtliche Kluft zwischen üblichen indikationsgetriebenen Zulassungsverfahren und der empirischen Realität sowie dem Potential vieler Heilpflanzen aufgezeigt. Für Tormentillae rhizoma ist ein breites Spektrum an Inhaltsstoffen und das mit dem Vielstoffgemisch einhergehende Wirkprofil einer u.a. vielfältig antiinflammatorisch wirkenden systemischen Droge experimentell belegt. Die traditionelle Empirie der dämpfenden Effekte im Entzündungsgeschehen wird dadurch plausibilisiert. Die moderne Forschung liefert also Daten für einen sinnvollen Einsatz einer gut verträglichen Heilpflanze mit vielfältigen Anwendungsmöglichkeiten für Haut und Schleimhaut (innerlich und äusserlich). Auf dem Markt gibt es aber, abgesehen von vereinzelten topischen Spezialitäten und Arzneitees, kaum Zubereitungen als zugelassene Arzneispezialität. Denn die derzeitige Praxis der Arzneimittelzulassung bevorzugt die spezifischen und organbezogenen Wirkungen und übersieht dabei das systemische Potential, die Modulationsfähigkeit dieser natürlichen Stoffgemische, wie sie durch traditionelle und empirische Belege angezeigt wird. Systemische Wirkungen zeigen ihre Stärke gerade im Zusammenspiel mit anderen Therapien insbesondere beim additiven Einsatz mit Spezifika, indem sie bestimmte Wirkungen verstärken bzw. abschwächen oder die Verträglichkeit der Spezifika erhöhen bzw. deren Nebenwirkungen abmildern. Die Kombination von spezifisch wirkenden Arzneimitteln mit solchen Systemmitteln (wie z.B. Blutwurz/Tormentill) stellt damit eine weitere Therapieoption dar, die als sinnvolle Ergänzung, wenn nicht sogar als Grundlage bei Prävention, Therapie und Lebensgestaltung zu werten ist. The example of tormentil (Potentilla erecta L.), which is used in various local traditions, is taken to illustrate an obvious gap between the common indication-driven authorization procedures and the empirical reality and potential of many medicinal plants. For Tormentillae rhizoma, a broad spectrum of active compounds and the active profile of a systemic drug with multiple anti-inflammatory effects have been experimentally proven. The traditional empiricism of the dampening effects in the inflammatory process is thus made plausible. Modern research, therefore, provides data for the effective use of a well-tolerated medicinal plant with a wide range of possible applications for the skin and mucous membranes (internally and externally). However, apart from a few topical specialties and medicinal teas, there are hardly any preparations on the market as authorized medicinal specialties. This is because the current practice of marketing authorization favors the specific and organ-related effects and overlooks the systemic potential, the modulation capacity of these natural substance mixtures, as indicated by traditional and empirical evidence. Systemic effects show their strength particularly in combination with other therapies, especially when used additively with specific agents, in that they strengthen or weaken certain effects or increase the tolerability of the specific agents or minimize their side effects. The combination of specific drugs with such systemic drugs (e.g., bloodroot/tormentil) therefore represents a further therapeutic option that can be seen as a valuable addition, if not a basis for prevention, therapy and lifestyle.},
}

Humans
*Plants, Medicinal/chemistry
*Phytotherapy
*Plant Extracts/therapeutic use
Anti-Inflammatory Agents/therapeutic use

@article {pmid40608121,
year = {2025},
author = {Ruzi, Z and Zha, W and Yuan, HY and Liu, J},
title = {RNA G-quadruplexes: emerging regulators of gene expression and therapeutic targets.},
journal = {Functional & integrative genomics},
volume = {25},
number = {1},
pages = {143},
pmid = {40608121},
issn = {1438-7948},
support = {22262002//National Natural Science Foundation of China/ ; },
mesh = {*G-Quadruplexes ; Humans ; *Gene Expression Regulation ; *RNA/chemistry/genetics/metabolism ; Animals ; Neoplasms/genetics ; SARS-CoV-2 ; Neurodegenerative Diseases/genetics ; Alternative Splicing ; },
abstract = {RNA G-quadruplexes (rG4s) are non-canonical, four-stranded secondary structures formed by guanine-rich RNA sequences. These dynamic elements have garnered significant attention for their critical roles in regulating gene expression, including translation, alternative splicing, mRNA localization, and stability. This review synthesizes recent progress in understanding the structural determinants and formation dynamics of rG4s, highlighting the contributions of sequence motifs, ionic conditions, and RNA-binding proteins to their stability and function. Functional studies reveal that rG4s modulate key oncogenic transcripts (e.g., MYC, BCL2), contribute to splicing regulation, and influence intracellular RNA trafficking. In pathological contexts, rG4s have been implicated in the molecular etiology of cancers, neurodegenerative diseases such as amyotrophic lateral sclerosis and Fragile X syndrome, and viral replication mechanisms in pathogens including HIV and SARS-CoV-2. Advances in high-throughput techniques, such as G4-seq, rG4-seq, and live-cell imaging, have facilitated the global identification and characterization of rG4s in physiological and disease settings. Moreover, the therapeutic targeting of rG4s using small molecules holds promise for selective gene regulation and biomarker development. Comparative analyses across in vitro, in vivo, and clinical studies underscore the cell-type-specific and context-dependent roles of rG4s, especially in mediating stress responses and apoptosis. Despite methodological limitations and challenges in achieving targeted delivery, rG4s represent a compelling frontier for precision medicine. This review outlines current insights and future directions toward harnessing rG4 biology for therapeutic innovation.},
}

*G-Quadruplexes
Humans
*Gene Expression Regulation
*RNA/chemistry/genetics/metabolism
Animals
Neoplasms/genetics
SARS-CoV-2
Neurodegenerative Diseases/genetics
Alternative Splicing

@article {pmid40603051,
year = {2025},
author = {Ito, L and Galipon, J},
title = {[Development of RNA Hydrogels as a Potential System for Intracellular Biomimicry: A Method for the In Vitro Synthesis of ALS/FTD-related (G4C2)n RNA with over 100 Repeats].},
journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan},
volume = {145},
number = {7},
pages = {601-607},
doi = {10.1248/yakushi.24-00209-3},
pmid = {40603051},
issn = {1347-5231},
mesh = {*Amyotrophic Lateral Sclerosis/genetics ; *RNA/chemical synthesis/genetics/chemistry ; Humans ; *Hydrogels ; G-Quadruplexes ; C9orf72 Protein/genetics ; DNA-Directed RNA Polymerases ; *Repetitive Sequences, Nucleic Acid/genetics ; Viral Proteins ; *Biomimetics/methods ; RNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics ; },
abstract = {In the motor neurons of amyotrophic lateral sclerosis (ALS) patients, excessive (G4C2)n repeats in the intronic region of the C9orf72 gene are transcribed to RNA, forming G-quadruplexes that sequester RNA-binding proteins, leading to gelation within the cytoplasm as one of the many mechanisms leading to pathogenesis. While ALS patients frequently harbor over 700 repeats, this kind of 100% GC-rich region is very difficult to clone, and past studies report the necessity to add additional sequences in the middle to clone more than a few dozen repeats. The goal of this study was the in vitro production of the longest repetitive RNA to date consisting solely of (G4C2)n repeats. T4 DNA ligase was used to connect (G4C2)10 stretches of DNA with 3nt overhangs. Then, using a heat-resistant T7 RNA polymerase, the RNA obtained contained transcripts over 100 repeats. Artificial biomimetic RNA gels generated by scaling up this synthesis method are expected to contribute to elucidating the molecular mechanisms of repetitive sequence-related pathogenesis, as well as screening for drugs that can disrupt the gel structure.},
}

*Amyotrophic Lateral Sclerosis/genetics
*RNA/chemical synthesis/genetics/chemistry
Humans
*Hydrogels
G-Quadruplexes
C9orf72 Protein/genetics
DNA-Directed RNA Polymerases
*Repetitive Sequences, Nucleic Acid/genetics
Viral Proteins
*Biomimetics/methods
RNA-Binding Proteins/metabolism
*Frontotemporal Dementia/genetics

@article {pmid40603049,
year = {2025},
author = {Tsuiji, H},
title = {[Elucidation of the Molecular Mechanism Underlying Aberrant Formation of RNA Granules in Neurons of ALS Patients and Its Regulation].},
journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan},
volume = {145},
number = {7},
pages = {583-588},
doi = {10.1248/yakushi.24-00209-1},
pmid = {40603049},
issn = {1347-5231},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy/etiology ; Humans ; RNA-Binding Protein FUS/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; C9orf72 Protein/genetics ; *RNA/metabolism/genetics ; *Motor Neurons/metabolism ; Animals ; RNA Splicing/genetics ; RNA-Binding Proteins/metabolism ; *Cytoplasmic Granules/metabolism ; Dipeptides/metabolism ; Protein Biosynthesis/genetics ; Spliceosomes/metabolism ; DNA Repeat Expansion/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by progressive muscle atrophy throughout the body. In nearly all ALS patients, abnormal accumulation of the RNA-binding protein TDP-43 is observed in degenerating motor neurons. We have found that RNA-binding proteins such as TDP-43 and FUS are concentrated in GEM bodies, where they contribute to the integrity of the spliceosome machinery involved in pre-RNA splicing. Additionally, the most common cause of ALS, repeat expansion in the C9orf72 gene, triggers abnormal repeat-associated non-AUG (RAN) translation, leading to the accumulation of neurotoxic dipeptide repeat (DPR) proteins. We have identified that these DPR proteins may inhibit GEM body formation and contribute to ALS pathology. Furthermore, therapeutic approaches to suppress RAN translation using dCas13 technology are under development, offering promising new strategies to address abnormalities in RNA metabolism in ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy/etiology
Humans
RNA-Binding Protein FUS/metabolism
*DNA-Binding Proteins/metabolism/genetics
C9orf72 Protein/genetics
*RNA/metabolism/genetics
*Motor Neurons/metabolism
Animals
RNA Splicing/genetics
RNA-Binding Proteins/metabolism
*Cytoplasmic Granules/metabolism
Dipeptides/metabolism
Protein Biosynthesis/genetics
Spliceosomes/metabolism
DNA Repeat Expansion/genetics

@article {pmid40589786,
year = {2025},
author = {Arreola-Aldape, CA and Moran-Guerrero, JA and Pons-Monnier, GK and Flores-Salcido, RE and Martinez-Ledesma, E and Ruiz-Manriquez, LM and Razo-Alvarez, KR and Mares-Custodio, D and Avalos-Montes, PJ and Figueroa-Sanchez, JA and Ortiz-Lopez, R and Martínez, HR and Cuevas-Diaz Duran, R},
title = {A systematic review and functional in-silico analysis of genes and variants associated with amyotrophic lateral sclerosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1598336},
pmid = {40589786},
issn = {1662-4548},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the deterioration of upper and lower motor neurons. Affected patients experience progressive muscle weakness, including difficulty in swallowing and breathing; being respiratory failure the main cause of death. However, there is considerable phenotypic heterogeneity, and its diagnosis is based on clinical criteria. Moreover, most ALS cases remain unexplained, suggesting a complex genetic background.

METHODS: To better understand the molecular mechanisms underlying ALS, we comprehensively analyzed, filtered and classified genes from 4,293 abstracts retrieved from PubMed, 7,343 variants from ClinVar, and 33 study accessions from GWAS catalog. To address the importance of ALS-associated genes and variants, we performed diverse bioinformatic analyses, including gene set enrichment, drug-gene interactions, and differential gene expression analysis using public databases.

RESULTS: Our analysis yielded a catalog of 300 genes with 479 ALS-associated variants. Most of these genes and variants are found in coding regions and their proteins are allocated to the cytoplasm and the nucleus, underscoring the relevance of toxic protein aggregates. Moreover, protein-coding genes enriched ALS-specific pathways, for example spasticity, dysarthria and dyspnea. ALS-associated genes are targeted by commonly used drugs, including Riluzole and Edaravone, and by the recently approved antisense oligonucleotide therapy (Tofersen). Moreover, we observed transcriptional dysregulation of ALS-associated genes in peripheral blood mononuclear cell and postmortem cortex samples.

CONCLUSION: Overall, this ALS catalog can serve as a foundational tool for advancing early diagnosis, identifying biomarkers, and developing personalized therapeutic strategies.},
}

@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.},
}

*Fecal Microbiota Transplantation/methods
Humans
*Gastrointestinal Microbiome
Feces/microbiology
*Nervous System Diseases/therapy

@article {pmid40587877,
year = {2025},
author = {Moalefshahri, R and Hashemy, SI and Hosseini, H and Sahebkar, A},
title = {Neuroprotective effect of Kaempferol through modulation of autophagy.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/1028415X.2025.2524702},
pmid = {40587877},
issn = {1476-8305},
abstract = {Objective: Autophagy is a critical cellular mechanism that ensures the breakdown of damaged or unnecessary components. This process helps ensure cellular health by maintaining cellular balance, protecting cells from stress, and providing an alternative energy source during metabolic stress. Disruptions in autophagy have been linked to neurological disorders.Method: In this review, the neuroprotective effects of Kaempferol through autophagy modulation are elaborated. Methods: An electronic search in scientific databases was performed to find relevant studies exploring the neuroprotective effects of kaempferol mediated via modulation of autophagy.Results: Kaempferol, a natural flavonoid found in fruits, vegetables, and plant-based products like tea, has been shown to demonstrate a variety of health-promoting properties, including antimicrobial, antioxidant, and antiinflammatory effects. This review summarizes the current understanding of how Kaempferol modulates autophagy and discusses its potential impact on various neurological disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemic stroke, and depression. Studies increasingly indicate that Kaempferol could be a vital factor in maintaining neural health by influencing autophagy mechanisms.Conclusion: Numerous studies have established Kaempferol's neuroprotective potential through autophagy regulation, which suggests opprotunities for potential therapeutic applications.},
}

@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 {pmid40584177,
year = {2025},
author = {Wu, Q and Yang, J and Duan, Y and Ma, Y and Zhang, Y and Tan, S and Wang, J and Wang, Y and Liu, B and Zhang, J and Liu, X},
title = {Environmental risk factors, protective factors, and biomarkers for amyotrophic lateral sclerosis: an umbrella review.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1541779},
pmid = {40584177},
issn = {1663-4365},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the rapid loss of motor neurons. Given the significant global economic impact of ALS, effective preventive measures are urgently needed to reduce the incidence of this devastating disease. Recent meta-analyses have explored potential links between environmental factors, biomarkers, and ALS occurrence. However, the findings of these studies have been inconsistent and controversial. Therefore, we present a comprehensive umbrella review of recent meta-analyses to systematically summarize the available epidemiological evidence and evaluate its credibility.

METHODS: A systematic search was conducted in PubMed and Embase from inception until 01 October 2024, to identify meta-analyses of observational studies examining associations between environmental risk factors, protective factors, biomarkers, and ALS susceptibility. For each meta-analysis, summary effect estimates, 95% confidence intervals (CIs), 95% prediction intervals, study heterogeneity, small study effects, and excess significance biases were calculated independently by two investigators. The methodological quality was evaluated using the AMSTAR 2 criteria. The strength of the epidemiological evidence was categorized into five levels based on predefined criteria.

RESULTS: Out of 1,902 articles identified, 43 met the inclusion criteria, resulting in 103 included meta-analyses. These analyses covered 46 environmental risk and protective factors (344,597 cases, 71,415,574 population) and 57 cerebrospinal fluid (CSF) and serum biomarkers (30,941 cases, 2,180,797 population). The evidence was classified as convincing (Class I) for the regular use of antihypertensive drugs (OR: 0.85, 95% CI: 0.81-0.88) and highly suggestive (Class II) for premorbid body mass index (OR: 0.97, 95% CI: 0.95 to 0.98), trauma (OR: 1.51, 95% CI: 1.32 to 1.73), CSF NFL levels (SMD: 2.06, 95% CI: 1.61 to 2.51), serum NFL levels (SMD: 1.57, 95% CI: 1.29 to 1.85), ferritin levels (SMD: 0.66, 95% CI: 0.50 to 0.83), and uric acid levels (SMD: -0.72; 95% CI: -0.98 to -0.46).

DISCUSSION: This umbrella review offers new insights into the epidemiological evidence regarding the associations between environmental factors, biomarkers, and ALS susceptibility. We aim for our study to enhance the understanding of the roles of environmental factors and biomarkers in ALS occurrence and assist clinicians in developing evidence-based prevention and control strategies.},
}

@article {pmid40583472,
year = {2025},
author = {Salehirozveh, M and Dehghani, P and Mijakovic, I},
title = {Nanopore-Based Neurotransmitter Detection: Advances, Challenges, and Future Perspectives.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c04662},
pmid = {40583472},
issn = {1936-086X},
abstract = {Neurotransmitters play a pivotal role in neural communication, synaptic plasticity, and overall brain function. Disruptions in neurotransmitter homeostasis are closely linked to various neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia, depression, and amyotrophic lateral sclerosis. This review explores the critical role of neurotransmitters in neurological disorders and highlights recent advances in nanopore-based neurotransmitter detection. Solid-state nanopores (SSNs), with their superior mechanical and chemical durability, have emerged as highly sensitive molecular sensors capable of real-time monitoring of neurotransmitter dynamics. We discuss the integration of SSNs into diagnostic frameworks, emphasizing their potential for early disease detection and personalized therapeutic interventions. Additionally, we examine the complementary role of nanopipettes in neurotransmitter detection, focusing on their high spatial resolution and real-time monitoring capabilities. The review also addresses the challenges and future perspectives of nanopore-based sensing technology, including the need for improved sensitivity, stability, and reproducibility. By integrating insights from neuroscience, bioengineering, and nanotechnology, this review aims to provide a comprehensive overview of how nanopore sensing can revolutionize neurotransmitter analysis and contribute to the development of next-generation diagnostic and therapeutic approaches for neurological diseases.},
}

@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},
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 {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},
doi = {10.4062/biomolther.2025.022},
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 {pmid40580315,
year = {2025},
author = {Jellinger, KA},
title = {Co-occurrence of amyotrophic lateral sclerosis and multiple sclerosis: a rare but interesting association.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40580315},
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/ ; },
abstract = {Multiple sclerosis (MS) is an inflammatory demyelinating disease with highly variable clinical course and usual onset in younger age, caused by genetic and environmental factors. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord, resulting in gradual loss of voluntary muscle and respiratory control. Both ALS and MS exhibit distinct underlying causes and disease mechanisms, despite some shared clinical effects. About 10% of ALS are linked to genetic factors, such as C9orf72, the remaining sporadic ones being potentially influenced by environmental, toxic and oxidative stress, while MS is an autoimmune disorder where the immune system leads to inflammation and attacks the myelin sheath, genetic predisposition and viral infections playing a role in its susceptibility. The co-occurrence of ALS and MS is extremely rare, with 46 cases being reported in the available literature from 1986 to 2024, while in the earlier literature, cases with coincidental muscular atrophy simulating ALS were described. In the overwhelming majority, ALS manifested between one and 41 years after the onset of MS; only in four cases was ALS present before detection of MS. The concurrence of MS and ALS can be explained by similarities in their pathogenesis related to neurodegeneration, inflammation, and/or genetic susceptibility. The role of rare genetic ALS forms in this comorbidity deserves further studies. The shared inflammatory component with a cascade of oxidative stress and other noxious mechanisms leads to progressive motor and bulbar or other symptoms that underscore the potential for cross-disease research to yield insights applicable to both conditions and their relations to immune-mediated disorders.},
}

@article {pmid40580199,
year = {2025},
author = {Allen, MD and Van Eijk, RPA and Knox, L and Carlton, J and Hobson, E and Mcdermott, CJ and Murray, D and Berry, J and Meyer, T and Genge, A},
title = {Variability across versions of the self-administered ALSFRS-R: a review and call for harmonization.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/21678421.2025.2522400},
pmid = {40580199},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease predominantly affecting motor neurons resulting in substantial, progressive disability. The amyotrophic lateral sclerosis functional rating scale - revised (ALSFRS-R) is commonly used to assess and monitor functional status in patients with ALS. Additionally, it is the current regulatory accepted primary outcome measure documenting functional status in ALS clinical trials. The ALSFRS-R was originally designed to be administered to a patient by a trained professional. But over time it has been adapted to be performed independently by patients or their caregivers without assistance. Several different versions of the self-administered ALSFRS-R have been created over the past two decades, each with subtle but important differences. Some of these differences are related to language used in item wording or the platform for which the scale was intended to be administered (e.g. digitally). These differences across versions of the self-administered scale may be problematic as they could increase the heterogeneity of data collected across clinical trials or complicate interpretation of results across trials. Therefore, we highlight the need for a harmonized version of the self-administered ALSFRS-R to be used across all clinics and clinical trial sites internationally.},
}

@article {pmid40578028,
year = {2025},
author = {Yang, JL and Qian, SY and Cheng, ML and Wang, LX and Wang, Y and Liu, JJ and Xi, CS and Yang, YX and Li, Y and Gao, C and Zheng, GQ},
title = {Skeletal muscle, neuromuscular organoids and assembloids: a scoping review.},
journal = {EBioMedicine},
volume = {118},
number = {},
pages = {105825},
doi = {10.1016/j.ebiom.2025.105825},
pmid = {40578028},
issn = {2352-3964},
abstract = {Skeletal muscle organoids (SKMOs), neuromuscular organoids (NMOs), and assembloids have emerged as powerful in vitro models that simulate the intricate cellular interactions between muscle and nerve, offering a promising approach to study function, development, and disease at the neuromuscular junction (NMJ). Given the relevance of NMJ dysfunction in diseases such as amyotrophic lateral sclerosis (ALS), these models provide insights into disease modelling. Scoping reviews are particularly valuable when exploring broad or emerging areas, as they help identify key concepts and evolving methodologies. Here, we conducted a scoping review by searching five databases, ultimately including 17 studies focussing on the development and application of SKMOs, NMOs, and assembloids in muscle function modelling. We highlight recent advancements and summarise various differentiation protocols, primarily utilising the Wnt signalling pathway agonist CHIR99021 and basic fibroblast growth factor (bFGF) to induce pluripotent stem cells into 2D neuromesodermal progenitors, further differentiated into SKMOs, NMOs, and assembloids. We also reviewed their cellular compositions, including motor neurons, neural stem cells, terminal Schwann cells, and astrocytes, alongside related research outcomes. Additionally, we discuss key challenges such as iPSC donor selection, standardisation, vascularisation, and 3D organoid imaging. This scoping review provides a foundation for future research on muscle function modelling.},
}

@article {pmid40576748,
year = {2025},
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 = {},
number = {},
pages = {},
pmid = {40576748},
issn = {1867-1314},
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 {pmid40566997,
year = {2025},
author = {Wu, J and Yan, S and Bian, Y and Liu, R and Lyu, X and Zhang, Z and Huang, S and Chen, T and Cheng, L},
title = {The Impact of Splicing Dysregulation on Neuromuscular Disorders and Current Neuromuscular Genetic Therapies.},
journal = {Journal of neurochemistry},
volume = {169},
number = {6},
pages = {e70133},
doi = {10.1111/jnc.70133},
pmid = {40566997},
issn = {1471-4159},
support = {ZR2022QC052//Natural Science Foundation of Shandong Province/ ; 32200464//National Natural Science Foundation of China/ ; ZD2021036//Science and Technology Project of Hebei Education Department/ ; },
mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neuromuscular Diseases/genetics/therapy ; Animals ; *RNA Splicing/genetics ; Alternative Splicing ; },
abstract = {Eukaryotic genes contain non-coding segments known as introns, which interrupt coding sequences. Consequently, eukaryotic transcription produces precursor messenger RNA (pre-mRNA) that relies on precise splicing to remove highly diverse introns from the genome and to generate the mature mRNA essential for maintaining normal cellular activities. The extensive heterogeneity of neurons necessitates complex splicing regulation, particularly alternative splicing, to ensure the accuracy of gene expression in neurogenesis, signal transduction, and synaptic function and to maintain stability and adaptability in the nervous system. With the improvement of genetic testing technology, aberrant splicing has been identified as a contributing factor to the pathogenesis of neuromuscular disorders (NMDs) such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM), Charcot-Marie-Tooth disease (CMT), myasthenia gravis (MG), and multiple sclerosis (MS). Studying the correlation between splicing defects and neuromuscular disorders is crucial for gaining a more comprehensive understanding of the pathogenesis of these diseases and for developing effective therapies. In this review, we introduce the intricate process and key factors of pre-mRNA splicing, with a focus on aberrant splicing and pathogenesis in several major neuromuscular disorders, providing an overview of the latest therapeutic strategies.},
}

Humans
*Genetic Therapy/methods/trends
*Neuromuscular Diseases/genetics/therapy
Animals
*RNA Splicing/genetics
Alternative Splicing

@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 = {},
number = {},
pages = {},
doi = {10.1002/ame2.70054},
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/ ; },
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 {pmid40565515,
year = {2025},
author = {Falduti, A and Giovinazzo, A and Lo Feudo, E and Rocca, V and Brighina, F and Messina, A and Conforti, FL and Iuliano, R},
title = {The Role of Non-Coding RNAs in ALS.},
journal = {Genes},
volume = {16},
number = {6},
pages = {},
pmid = {40565515},
issn = {2073-4425},
support = {Project P20225J5NB//Project P20225J5NB "Identifying pathogenic pathways in sporadic Amyotrophic Lateral Sclerosis: a genetic, omics and functional study" PRIN PNRR/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *RNA, Long Noncoding/genetics ; *MicroRNAs/genetics ; *RNA, Circular/genetics ; Motor Neurons/metabolism/pathology ; Animals ; *RNA, Untranslated/genetics ; Biomarkers/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventually death. The pathogenesis of ALS is influenced by genetic factors, environmental factors, and age-related dysfunctions. These factors, taken together, are responsible for sporadic cases of ALS, which account for approximately 85-90% of ALS cases, while familial ALS accounts for the remaining 10-15% of cases, usually with dominant traits. Despite advances in understanding and studying the disease, the cause of the onset of ALS remains unknown. Emerging evidence suggests that non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in the pathogenesis of the disease. An abnormal expression of these molecules is implicated in various ALS-related processes, including motor neuron survival, protein aggregation, and inflammation. Here, we describe the dysregulation of non-coding RNAs in the pathogenic mechanism of ALS, highlighting the potential roles of miRNAs, lncRNAs, and circRNAs as biomarkers or therapeutic targets to examine the progression of the disease.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology
Humans
*RNA, Long Noncoding/genetics
*MicroRNAs/genetics
*RNA, Circular/genetics
Motor Neurons/metabolism/pathology
Animals
*RNA, Untranslated/genetics
Biomarkers/metabolism

@article {pmid40565514,
year = {2025},
author = {Roque-Ramírez, B and Ríos-López, KE and López-Hernández, LB},
title = {Decoding Neuromuscular Disorders: The Complex Role of Genetic and Epigenetic Regulators.},
journal = {Genes},
volume = {16},
number = {6},
pages = {},
pmid = {40565514},
issn = {2073-4425},
mesh = {Humans ; *Epigenesis, Genetic ; *Neuromuscular Diseases/genetics ; DNA Methylation/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Animals ; },
abstract = {Neuromuscular disorders (NMDs), such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies (e.g., Duchenne muscular dystrophy, DMD), are primarily driven by genetic mutations but are critically modulated by epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNA activity. These epigenetic processes contribute to phenotypic variability and disease progression, and emerging evidence suggests that environmental factors, particularly nutrition and exercise, may further influence the molecular pathways that modulate these diseases. Dietary bioactive compounds (e.g., polyphenols and omega-3 fatty acids) exhibit epigenetic modulatory properties, which could mitigate oxidative stress, inflammation, and muscle degeneration in NMDs. For example, the inhibition of DNMTs and HDACs by curcumin in ALS models and the promyogenic effects of green tea catechins in DMD suggest plausible, though still requiring investigation, therapeutic avenues. However, the clinical application of nutriepigenetic interventions is preliminary and requires further validation. This review examines the interaction of genetic and epigenetic factors in ALS, SMA, and muscular dystrophies, highlighting their combined role in the heterogeneity of these diseases. Integrative therapeutic strategies combining gene therapies, epigenetic modulators, and lifestyle interventions may offer a multidimensional approach to the management of NMD. A deeper understanding of these interactions will be essential for advancing precision medicine and improving patient outcomes.},
}

Humans
*Epigenesis, Genetic
*Neuromuscular Diseases/genetics
DNA Methylation/genetics
Amyotrophic Lateral Sclerosis/genetics
Animals

@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.},
}

*Amyotrophic Lateral Sclerosis/therapy/genetics/diagnosis/metabolism
Humans
*Genetic Therapy/methods
*Biomarkers/metabolism
C9orf72 Protein/genetics
Animals
Gene Editing
Superoxide Dismutase-1/genetics

@article {pmid40564128,
year = {2025},
author = {Drewes, N and Fang, X and Gupta, N and Nie, D},
title = {Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061409},
pmid = {40564128},
issn = {2227-9059},
abstract = {Originally identified as a potential receptor for opioids, the sigma-1 receptor is now recognized as an intracellular chaperone protein associated with mitochondria-associated membranes at the endoplasmic reticulum (ER). Over the past two decades, extensive research has revealed that the sigma-1 receptor regulates many cellular processes, such as calcium homeostasis, oxidative stress responses, protein folding, and mitochondrial function. The various functions of the sigma-1 receptor highlight its role as a central modulator of neuronal health and may be a promising pharmacological target across multiple neurodegenerative conditions. Herein, we provide an overview of the current pharmacological understanding of the sigma-1 receptor with an emphasis on the signaling mechanisms involved. We examine its pathological implications in common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. We then highlight how sigma-1 receptor modulation may influence disease progression as well as potential pharmacological mechanisms to alter disease outcomes. The translational potential of sigma-1 receptor therapies is discussed, as well as the most up-to-date results of ongoing clinical trials. This review aims to clarify the therapeutic potential of the sigma-1 receptor in neurodegeneration and guide future research in these diseases.},
}

@article {pmid40563824,
year = {2025},
author = {Hasan, A and Scuderi, SA and Capra, AP and Giosa, D and Bonomo, A and Ardizzone, A and Esposito, E},
title = {An Updated and Comprehensive Review Exploring the Gut-Brain Axis in Neurodegenerative Disorders and Neurotraumas: Implications for Therapeutic Strategies.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060654},
pmid = {40563824},
issn = {2076-3425},
abstract = {The gut-brain axis (GBA) refers to the biochemical bidirectional communication between the central nervous system (CNS) and the gastrointestinal tract, linking brain and gut functions. It comprises a complex network of interactions involving the endocrine, immune, autonomic, and enteric nervous systems. The balance of this bidirectional pathway depends on the composition of the gut microbiome and its metabolites. While the causes of neurodegenerative diseases (NDDs) vary, the gut microbiome plays a crucial role in their development and prognosis. NDDs are often associated with an inflammation-related gut microbiome. However, restoring balance to the gut microbiome and reducing inflammation may have therapeutic benefits. In particular, introducing short-chain fatty acid-producing bacteria, key metabolites that support gut homeostasis, can help counteract the inflammatory microbiome. This strong pathological link between the gut and NDDs underscores the gut-brain axis (GBA) as a promising target for therapeutic intervention. This review, by scrutinizing the more recent original research articles published in PubMed (MEDLINE) database, emphasizes the emerging notion that GBA is an equally important pathological marker for neurological movement disorders, particularly in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease and neurotraumatic disorders such as traumatic brain injury and spinal cord injury. Additionally, the GBA presents a promising therapeutic target for managing these diseases.},
}

@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 = {},
doi = {10.3390/brainsci15060601},
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 {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 = {},
doi = {10.3390/brainsci15060600},
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 {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 = {},
doi = {10.3390/antiox14060696},
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 {pmid40562281,
year = {2025},
author = {Sharma, J and Thakur, A and Rain, M and Khosla, R and Maity, K and Mathur, GR and Anand, A},
title = {Interplay between Exercise and Neuregulin in providing neuroprotection.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115710},
doi = {10.1016/j.bbr.2025.115710},
pmid = {40562281},
issn = {1872-7549},
abstract = {Exercise has been shown to have a positive impact on brain health including neuroprotective function. It has been demonstrated to increase the synthesis of neurotrophic factors, support neuronal survival, and improve neuroplasticity. Concurrently, neuregulin plays a vital role in the development, maintenance, and repair of both the central and peripheral nervous system. The link between exercise and neuregulin in mediating neuroprotection has been the subject of increased research to better understand the possible applications for the deterrence of neurodegenerative disorders. Understanding this link is of great interest because it has the potential to lead to new strategies for preventing or slowing the progression of neurodegenerative diseases. With an emphasis on exercise-induced neuregulin-mediated neuroprotection, this article reviews the literature on the neuroprotective effects of exercise and neuregulin. The synergistic effects of exercise and neuregulin on neuroprotection will be clarified and valuable insights will be gained from this review, with potential implications for the development of novel therapeutic strategies for neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD).},
}

@article {pmid40560475,
year = {2025},
author = {Bamber, R and Stavroulakis, T and McDermott, C and Carlton, J},
title = {Health-related quality of life of informal carers in ALS: a systematic review of person reported outcome measures.},
journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation},
volume = {},
number = {},
pages = {},
pmid = {40560475},
issn = {1573-2649},
support = {NIHR301648//National Institute for Health and Care Research/ ; },
abstract = {PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition with swift progression. The devastating impact of ALS affects the health-related quality of life (HRQoL) of informal carers. Various person reported outcome measures (PROMs) have been used to assess HRQoL in informal carers in ALS, yet their validity remains unclear. This review aimed to identify and evaluate the content validity of HRQoL PROMs for informal carers in ALS.

METHODS: This review was conducted according to best practice COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology. Two literature searches were conducted in November 2023 and April 2024 across MEDLINE, PsycINFO, Embase, CINAHL, the Cochrane Database of Systematic Reviews, CENTRAL and Google Scholar, to identify HRQoL PROMs used with informal carers in ALS, PROM development articles, and psychometric literature. Evidence synthesis followed COSMIN guidance.

RESULTS: 12,276 articles were screened, and 109 PROMs were identified, with 43 undergoing full COSMIN assessment. Content validity ratings were 'Inconsistent' or 'Insufficient' for all PROMs. All PROMs, except the CarerQoL, were rated 'Insufficient' for comprehensiveness. Only 18.6% of PROMs included informal carers in development. Quality of evidence supporting content validity ratings was 'Very Low' for 93% of PROMs.

CONCLUSION: HRQoL PROMs used with informal carers in ALS lack evidence to support their content validity, restricting their utility for this purpose. Existing literature on the impact of caring in ALS on informal carers' HRQoL should be interpreted cautiously. Further research is required to establish the content validity of HRQoL PROMs used for this cohort.},
}

@article {pmid40559965,
year = {2025},
author = {Kim, WW and Zarus, G and Alman, B and Ruiz, P and Han, M and Mehta, P and Ji, C and Qureshi, H and Antonini, J and Shoeb, M},
title = {Metal-Induced Genotoxic Events: Possible Distinction Between Sporadic and Familial ALS.},
journal = {Toxics},
volume = {13},
number = {6},
pages = {},
pmid = {40559965},
issn = {2305-6304},
abstract = {Metal exposure is a potential risk factor for amyotrophic lateral sclerosis (ALS). Increasing evidence suggests that elevated levels of DNA damage are present in both familial (fALS) and sporadic (sALS) forms of ALS, characterized by the selective loss of motor neurons in the brain, brainstem, and spinal cord. However, identifying and differentiating initial biomarkers of DNA damage response (DDR) in both forms of ALS remains unclear. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and our previous studies have demonstrated the influence of metal exposure-induced genotoxicity and neurodegeneration. A comprehensive overview of the ATSDR's toxicological profiles and the available literature identified 15 metals (aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), selenium (Se), uranium (U), vanadium (V), and zinc (Zn)) showing exposure-induced genotoxicity indicators associated with ALS pathogenesis. Genetic factors including mutations seen in ALS types and with concomitant metal exposure were distinguished, showing that heavy metal exposure can exacerbate the downstream effect of existing genetic mutations in fALS and may contribute to motor neuron degeneration in sALS. Substantial evidence associates heavy metal exposure to genotoxic endpoints in both forms of ALS; however, a data gap has been observed for several of these endpoints. This review aims to (1) provide a comprehensive overview of metal exposure-induced genotoxicity in ALS patients and experimental models, and its potential role in disease risk, (2) summarize the evidence for DNA damage and associated biomarkers in ALS pathogenesis, (3) discuss possible mechanisms for metal exposure-induced genotoxic contributions to ALS pathogenesis, and (4) explore the potential distinction of genotoxic biomarkers in both forms of ALS. Our findings support the association between metal exposure and ALS, highlighting under or unexplored genotoxic endpoints, signaling key data gaps. Given the high prevalence of sALS and studies showing associations with environmental exposures, understanding the mechanisms and identifying early biomarkers is vital for developing preventative therapies and early interventions. Limitations include variability in exposure assessment and the complexity of gene-environment interactions. Studies focusing on longitudinal exposure assessments, mechanistic studies, and biomarker identification to inform preventative and therapeutic strategies for ALS is warranted.},
}

@article {pmid40559225,
year = {2025},
author = {Elgenidy, A and Hassan, IA and Hamed, Y and Hashem, HA and Abuel-Naga, O and Abdel-Rahman, HI and Mohamed, KR and Hamed, BM and Shehab, MA and Zeyada, M and Kassab, S and Abdelgawad, SSA and Ibrahim, AI and Hasanin, EH and Elhoufey, AA and Mahmoud, KH and Saad, K},
title = {Sonographic Evaluation of Peripheral Nerves and Cervical Nerve Roots in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {13},
number = {2},
pages = {},
pmid = {40559225},
issn = {2076-3271},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Ultrasonography/methods ; *Peripheral Nerves/diagnostic imaging/pathology ; *Spinal Nerve Roots/diagnostic imaging/pathology ; Middle Aged ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to nerve atrophy. Ultrasonography has a significant role in the diagnosis of ALS.

AIM: We aimed to sonographically assess the size of all peripheral nerves and cervical nerve roots in ALS compared to controls.

METHODS: We searched MEDLINE (PubMed), Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Scopus using comprehensive MeSH terms for the keywords nerve, ultrasound, and ALS. We extracted data regarding cross-sectional area (CSA) or diameter for the following nerves: vagus, phrenic, tibial, fibular, sural, radial, ulnar, and median nerves, and the roots of C5, C6, C7, and C8 in both ALS patients and controls.

RESULTS: Our study included 2683 participants, of which 1631 were ALS patients (mean age = 60.36), 792 were healthy controls (mean age = 57.79), and 260 were patients with other neurological disorders. ALS patients had significantly smaller nerve size compared to controls. Nerve size differences were observed in the vagus nerve [MD = -0.23], phrenic nerve [MD = -0.25], C5 nerve root [SMD = -0.94], C6 nerve root [SMD = -1.56], C7 nerve root [SMD = -1.18], C8 nerve root [MD = -1.9], accessory nerve [MD = -0.32], sciatic nerve [MD = -11], tibial nerve [MD = -0.68], sural nerve [MD = -0.32,], ulnar nerve [MD = -0.80], and median nerve [MD = -1.21].

CONCLUSIONS: Our findings showed that ALS patients have a sonographically smaller nerve size than healthy controls. Therefore, this is a potential marker for neuronal diseases.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology
Ultrasonography/methods
*Peripheral Nerves/diagnostic imaging/pathology
*Spinal Nerve Roots/diagnostic imaging/pathology
Middle Aged

@article {pmid40558500,
year = {2025},
author = {Mai, HA and Thomas, CM and Nge, GG and Elefant, F},
title = {Modulating Cognition-Linked Histone Acetyltransferases (HATs) as a Therapeutic Strategy for Neurodegenerative Diseases: Recent Advances and Future Trends.},
journal = {Cells},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/cells14120873},
pmid = {40558500},
issn = {2073-4409},
support = {2RF1NS095799//National Institutes of Health NINDS/ ; 2RF1NS095799/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Neurodegenerative Diseases/therapy/enzymology/drug therapy ; *Histone Acetyltransferases/metabolism ; *Cognition/physiology ; Animals ; Protein Processing, Post-Translational ; Histones/metabolism ; Epigenesis, Genetic ; Acetylation ; Aging ; },
abstract = {Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized PTMs shown to be required for neuronal function and cognition. Histone acetylation initiates neural circuitry plasticity via chromatin control, enabling neurons to respond to external environmental stimuli and adapt their transcriptional responses accordingly. While interplay between histone acetylation and deacetylation is critical for these functions, dysregulation during the aging process can lead to significant alterations in the neuroepigenetic landscape. These alterations contribute to impaired cognitive functions, neuronal cell death, and brain atrophy, all hallmarks of age-related neurodegenerative disease. Significantly, while age-related generation of DNA mutations remains irreversible, most neuroepigenetic PTMs are reversible. Thus, manipulation of the neural epigenome is proving to be an effective therapeutic strategy for neuroprotection in multiple types of age-related neurodegenerative disorders (NDs) that include Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Here, we highlight recent progress in research focusing on specific HAT-based neuroepigenetic mechanisms that underlie cognition and pathogenesis that is hallmarked in age-related NDs. We further discuss how these findings have potential to be translated into HAT-mediated cognitive-enhancing therapeutics to treat these debilitating disorders.},
}

Humans
*Neurodegenerative Diseases/therapy/enzymology/drug therapy
*Histone Acetyltransferases/metabolism
*Cognition/physiology
Animals
Protein Processing, Post-Translational
Histones/metabolism
Epigenesis, Genetic
Acetylation
Aging