@article {pmid41750236,
year = {2026},
author = {Eisen, A},
title = {Exploring the ALS Multistep Model.},
journal = {Brain sciences},
volume = {16},
number = {2},
pages = {},
pmid = {41750236},
issn = {2076-3425},
abstract = {ALS is a multistep disease, in which (epi)genetic, environmental, and age-related processes, including senescence, converge over decades to reduce resilience resulting in self-sustaining symptomatic disease. The multistep model visualizes five to six impactful events in sporadic ALS, but fewer in those carrying high-penetrance mutations, such as SOD1, FUS, or C9orf72 expansions. The timing, duration, and cumulative effects of specific steps are presumed to have individual variability but, the steps themselves are inferred since they have not been observed and remain agnostic as to biological identity. Nevertheless, the model gives an opportunity to integrate genetics, aging, environmental exposures, and systems-level vulnerability into a single framework. Acting as step modifiers, environmental exposures including trauma lower the threshold for step acquisition, accelerate the accumulation of steps, influence the anatomical site of disease onset, and unmask preclinical disease. Because ALS emerges from the gradual collapse of multiple layers of biological robustness, tackling a single pathway will be insufficient and the multistep model forces a reconsideration of therapeutic timing and strategies. Protection against early-life insults, anti-aging, and anti-senescent therapies may curtail step accumulation preventing ALS from exceeding threshold and disease manifestation.},
}

@article {pmid41746412,
year = {2026},
author = {Tarazona-Santabalbina, FJ and Belenguer-Varea, A and Borrás-Blasco, J and García-Tercero, E and Martin, ML and Prior, NP and Mariscal, G and Valcuende-Rosique, A},
title = {Safety profile of tofersen in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {3},
pages = {},
pmid = {41746412},
issn = {1590-3478},
}

@article {pmid41745965,
year = {2026},
author = {Haroun, M and Tratrat, C and Mathew, RT and Munir, M and Sattar, MN and Shawky, M and Kochkar, H and Aldakhilallah, ON and Ghafoor, A and Turk, KGB and Geronikaki, A and Ghazzawy, HS},
title = {Avian Candidiasis: A Comprehensive Review of Pathogenesis, Diagnosis, and Control.},
journal = {Veterinary sciences},
volume = {13},
number = {2},
pages = {},
pmid = {41745965},
issn = {2306-7381},
support = {Grant number: KFU260519//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia/ ; },
abstract = {This review is a comprehensive investigation of avian candidiasis, mainly caused by Candida albicans, although the prevalence of non-albicans Candida species has increased in domestic and wild birds. Avian candidiasis causes significant economic losses in poultry production through increased mortality, cost of treatments, and reduced growth rates, particularly in young birds and intensive farming operations. The pathogenesis section provides a description of the molecular virulence factors such as adhesin-mediated attachment (ALS, Agglutinin-Like Sequence family; HWP1, Hyphal Wall Protein 1), yeast-to-hypha morphogenesis, tissue damage by Candidalysin, biofilm formation on mucosal and abiotic surfaces, and secreted hydrolytic enzymes including secreted aspartyl proteinases (SAPs) and phospholipases. The identified predisposing factors include immunosuppression, malnutrition, abuse of antibiotics, bad husbandry, and crop stasis. The diagnostic methods discussed encompass cytological analysis and fungal culture on selective media to more sophisticated methods of molecular analysis (PCR, MALDI-TOF MS, and NGS). Antifungal susceptibility investigations indicate that nystatin and amphotericin B are still very effective against most avian isolates and that resistance to the azoles is on the rise, especially with respect to the non-albicans Candida species. Nystatin is still the first-line treatment of localized infections; azoles are still used for resistant or systemic infections despite their hepatotoxicity. Sanitation, proper nutrition, and proper use of antimicrobials are essential to prevent diseases. The knowledge gaps comprise the absence of avian-specific pharmacokinetic information, poor knowledge of species-species virulence phenotypes, and the lack of point-of-care diagnostics. The need to have integrated One Health surveillance systems is emphasized by the zoonotic potential of the avian Candida reservoirs.},
}

@article {pmid41744765,
year = {2026},
author = {Dellazizzo Toth, T and Bond, S and Saxena, S},
title = {The Calcium Connection: Explaining Motor Neuron Vulnerability in ALS.},
journal = {Cells},
volume = {15},
number = {4},
pages = {},
pmid = {41744765},
issn = {2073-4409},
abstract = {ALS is a severe neuromuscular disease classically characterized by the progressive loss of motor neurons, leading to incremental muscle weakness and eventually death. Current treatment options for ALS have proven to have limited effect, merely delaying the progression of symptoms and prolonging patient survival. This motor neuron subtype-related differential vulnerability has been linked to neuron excitability, metabolism, and protein aggregation. Calcium dysregulation, which serves as an important second messenger in neural signaling pathways, has been implicated in each of these mechanisms and represents a potential target for therapeutic intervention. Armed with cutting-edge tools for visualizing and recording calcium transients in vivo, ALS researchers have delved deeper into the role of calcium dysregulation in disease in recent years. Vulnerable motor neuron populations display an excess of calcium-permeable ion channels together with reduced expression of calcium-binding proteins, generating a cellular environment primed for excitotoxic stress. Loss of inhibitory synaptic input further heightens susceptibility to calcium overload. Paradoxically, some evidence suggests that elevated neuronal activity can exert neuroprotective effects, highlighting the complexity of activity-dependent calcium signaling in ALS. Additionally, ALS-related toxic protein accumulation disrupts calcium homeostasis, contributing to endoplasmic reticulum stress and mitochondrial dysfunction. Emerging data indicate that calcium dysregulation impairs neuron-glia communication, amplifying neuroinflammation and accelerating disease progression. This review aims to synthesize current evidence on how calcium imbalance contributes to motor neuron vulnerability and degeneration in ALS. By exploring the cellular, synaptic, and network-level mechanisms of calcium dysregulation in ALS, the review examines its interplay with mitochondrial and ER stress and explores its impact on neuron-glia interactions with the aim of synthesizing key mechanistic insights into the disease pathogenesis and therapeutic targets.},
}

@article {pmid41743427,
year = {2026},
author = {Luo, Y and Liu, X and Yang, M},
title = {Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.},
journal = {Frontiers in rehabilitation sciences},
volume = {7},
number = {},
pages = {1666530},
pmid = {41743427},
issn = {2673-6861},
abstract = {Neurological disorders represent a significant category of diseases that profoundly affect human health, accounting for the second leading cause of global mortality. This group of conditions includes stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, Parkinson's disease, and cerebral palsy, among others. These disorders are highly susceptible to sequelae and profoundly impact individuals' daily lives. In this context, Brain-Computer Interface (BCI) technology has demonstrated considerable potential in the domain of neurorehabilitation, although numerous challenges remain. The manuscript provides a comprehensive review of recent advancements in research and clinical applications, highlighting current limitations and outlining future directions. It elucidates the applicability and constraints of Brain-Computer Interface (BCI) technology across various diseases and patient populations. To facilitate insights across different conditions, comparative tables are presented, aligning BCI strategies with therapeutic targets, outcomes, advantages, limitations, and existing evidence gaps. The scope extends beyond motor restoration to include under-explored domains, such as neuropathic pain, with a focus on real-world translation, including home and community feasibility and the distinction between assistive and rehabilitative applications. The review distills overarching limitations within the field, such as small sample sizes, protocol heterogeneity, and limited longitudinal evidence, while synthesizing the most recent studies. An actionable research and development roadmap is proposed to guide next-generation BCI rehabilitation, incorporating individualized cortical-network simulators, self-architecting decoders, adaptive therapy approaches akin to game seasons, and proprioceptive "write-back" mechanisms via peripheral interfaces. Moreover, the review reveals significant research focal points and critical issues that warrant further investigation in the context of neurological rehabilitation utilizing BCI technology.},
}

@article {pmid41741312,
year = {2026},
author = {Herrero Babiloni, A and Dal Fabbro, C and Samin, F and Schmittbuhl, M and Blanchet, PJ and Lavigne, GJ and Rouleau, G},
title = {The role of dentists in the recognition of neurodegenerative and systemic conditions with neurological involvement.},
journal = {Oral surgery, oral medicine, oral pathology and oral radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.oooo.2026.01.010},
pmid = {41741312},
issn = {2212-4411},
abstract = {Dentists are often the first healthcare providers to observe subtle orofacial and behavioral changes that may reflect underlying neurological diseases, including altered salivary flow, dysphagia, oral burning sensations, unusual orofacial movements, or tremors and pain, among others. These are symptoms of conditions such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other systemic disorders with neurological involvement, which are frequently misattributed to local or functional causes, thereby delaying diagnosis and care. As the frequency of neurodegenerative and neuromuscular conditions rises with aging, the dental setting offers a critical opportunity for early recognition and referral. This clinical review summarizes orofacial manifestations, dental care challenges, and referral strategies across different neurological and systemic diseases. Organized by disease stage and functional impairment, the review provides practical tools for decision-making. Guidance on screening, behavioral adaptation, and care coordination is also provided, including multiple practical tables, figures, and chairside screening tools to support early recognition and referral. Finally, the review advocates for improved training, interdisciplinary collaboration, and progressive integration of artificial intelligence, machine learning, and other emerging technologies (e.g., biosensors, salivary biomarker platforms, or high-density electrophysiologic tools) to support clinicians in recognizing neurological diseases.},
}

@article {pmid41737317,
year = {2026},
author = {Luo, R},
title = {Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.},
journal = {Innovation (Cambridge (Mass.))},
volume = {7},
number = {1},
pages = {100989},
pmid = {41737317},
issn = {2666-6758},
abstract = {Autophagy, a key cellular degradation pathway, is central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Despite progress in understanding its role, critical questions remain. This perspective highlights pressing issues, including cell-type-specific autophagy regulation, interactions with other cellular pathways, and challenges in translating autophagy-modulating therapies to clinical practice. Addressing these questions will advance our understanding of neurodegenerative diseases and pave the way for novel therapeutics.},
}

@article {pmid41734662,
year = {2026},
author = {Alam, P and Hasan, GM and Mohammad, T and Hassan, MI},
title = {Next-generation computational strategies for neurodegenerative biomarkers: Multi-omics integration, AI, and molecular modeling.},
journal = {Computational biology and chemistry},
volume = {123},
number = {},
pages = {108973},
doi = {10.1016/j.compbiolchem.2026.108973},
pmid = {41734662},
issn = {1476-928X},
abstract = {Neurodegenerative diseases (NDs) are progressively debilitating conditions driven by complex molecular perturbations and selective neuronal loss. Conventional approaches to discovering biomarkers, using single-omics or empirical screening, often fail to capture the multi-factorial nature of these disorders. It is now possible to integrate large-scale omics data with structural and molecular modeling methods to reveal mechanistically relevant biomarkers using integrative computational biology. Here, we review recent advances in integrative computational strategies that combine multi-omics, encompassing genomics, transcriptomics, proteomics, and metabolomics, with structural bioinformatics and molecular modeling to identify mechanistically informative biomarkers. We cover systems-level and network-based integration methods, machine learning (ML) and artificial intelligence (AI) frameworks, and structure-guided validation approaches, including homology/AI-based modeling, molecular docking, and molecular dynamics. We also discuss case studies illustrating how omics-based predictions are validated through protein structure modeling to identify key biomarkers and therapeutic targets. Finally, we discuss major challenges, such as data heterogeneity, reproducibility, and limitations of structural modeling, and emerging trends, such as AI-powered multi-omics, single-cell spatial profiling, and digital twin simulations. Together, the integrative computational strategies are likely to accelerate the discovery of reliable, mechanistically informative, and clinically translatable biomarkers for precision medicine in NDs.},
}

@article {pmid41731547,
year = {2026},
author = {Jammal, JK and Gomez, EA and Al-Chalabi, A and Iacoangeli, A},
title = {Classification of ALS molecular subtypes: a literature review on machine learning applications and their clinical value.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04725-y},
pmid = {41731547},
issn = {1741-7015},
support = {772376-EScORIAL/ERC_/European Research Council/International ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by considerable heterogeneity in both its underlying biological mechanisms and clinical presentation. High-dimensional transcriptomic datasets offer an opportunity to characterise this variation at the molecular level; however, traditional statistical methods struggle with their scale and complexity.

MAIN BODY: Machine learning approaches can reduce dimensionality and uncover latent patterns, enabling the identification of molecular subtypes that may refine prognosis and support patient stratification. Recent transcriptomic studies employing unsupervised machine learning have identified ALS subtypes with distinct molecular and clinical characteristics. Redefining ALS into more homogeneous molecular and clinical subtypes could transform all areas of ALS research by supporting novel experimental designs and precision medicine approaches.

CONCLUSIONS: In this review, we summarise and critically assess these studies, discussing their findings, strengths, and limitations, and highlighting research gaps and challenges that must be addressed to enable their translation into biomedical and clinical practice.},
}

@article {pmid41729684,
year = {2026},
author = {Paulo-Ramos, A and Rhymes, ER and Villarroel-Campos, D and Sleigh, JN},
title = {Disruption of BDNF signalling in neuropathologies.},
journal = {Biochemical Society transactions},
volume = {54},
number = {2},
pages = {},
doi = {10.1042/BST20253079},
pmid = {41729684},
issn = {1470-8752},
support = {MR/Y010949/1/MRC_/Medical Research Council/United Kingdom ; 23GRO-PG36-0675-1//Muscular Dystrophy UK/ ; },
mesh = {*Brain-Derived Neurotrophic Factor/metabolism/genetics ; Humans ; *Signal Transduction ; Animals ; Receptor, trkB/metabolism ; Neuronal Plasticity ; Neurons/metabolism ; },
abstract = {The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential.},
}

*Brain-Derived Neurotrophic Factor/metabolism/genetics
Humans
*Signal Transduction
Animals
Receptor, trkB/metabolism
Neuronal Plasticity
Neurons/metabolism

@article {pmid41724277,
year = {2026},
author = {Zhao, X and Pu, L and Zeng, X and Nie, J},
title = {Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.},
journal = {Biochemical pharmacology},
volume = {248},
number = {},
pages = {117831},
doi = {10.1016/j.bcp.2026.117831},
pmid = {41724277},
issn = {1873-2968},
abstract = {Nuclear import receptors (NIRs), particularly the importin α/β heterodimer system, function as essential gatekeepers of nucleocytoplasmic trafficking by decoding diverse nuclear localization signals (NLSs) to orchestrate cellular proteostasis. This review delineates the structural basis of NLS recognition and the coordinated mechanisms that facilitate the nuclear import of critical cargoes, including transcription factors, RNA-binding proteins, and DNA repair factors. Beyond their canonical transport role, we emphasize the emerging functions of NIRs as molecular chaperones that suppress aberrant phase separation and their co-translational regulatory roles in ensuring proper protein biogenesis and folding. The collapse of these regulatory functions underpins the pathogenesis of major human diseases. We examine in detail the pathological consequences of nuclear import dysfunction, highlighting its central role in specific neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), oncogenic transformation, and viral pathogenesis. The discussion provides a critical appraisal of emerging therapeutic strategies that target the nuclear import machinery, including small-molecule inhibitors (e.g., importazole, ivermectin), peptide competitors, and advanced delivery platforms. We conclude by providing the associated challenges such as achieving tissue specificity, avoiding off-target effects and the significant opportunities that lie in pharmacologically modulating this fundamental pathway to restore proteostasis and develop disease modifying therapies.},
}

@article {pmid41720758,
year = {2026},
author = {Falahati, M and Orangi, K and Shaabanpoor Haghighi, A and Pouroushaninia, N and Niknam, N and Soltani, S and Radnia, P and Arab Bafrani, M and Shirdel, S and Aarabi, MH},
title = {Microstructural alterations of the amygdala in neurodegenerative and neuroinflammatory disorders: insights from diffusion tensor imaging.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {41720758},
issn = {2191-0200},
abstract = {Diffusion tensor imaging (DTI) is a valuable method for evaluating microstructural changes in the amygdala associated with neurodegenerative and neuroinflammatory disorders. This systematic review examines amygdala microstructural alterations in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), and multiple sclerosis (MS) using DTI metrics. Following PRISMA 2020 guidelines, we searched PubMed, Scopus, and Web of Science databases through August 2025, identifying 4,442 records. After screening and eligibility assessment, 13 studies were included, comprising 1,412 patients and 1,146 healthy controls. Due to sample heterogeneity and lack of standardized effect size measures, meta-analysis was not performed. Across disorders, elevated mean diffusivity (MD) emerged as the most consistent finding, present in 100 % of AD patients and observed in all examined conditions. Reduced fractional anisotropy (FA) was the second most frequent alteration, with 36.6 % of AD patients showing decreased FA. In MS, increased radial diffusivity (RD) was prominent, while longitudinal DLB studies revealed progressive free water (FW) increases. These DTI-based microstructural changes often preceded volumetric atrophy and correlated with clinical severity. Our findings demonstrate that DTI metrics, particularly MD and FA, serve as sensitive markers of amygdala pathology across neurodegenerative diseases and may facilitate early diagnosis, disease monitoring, and differential diagnosis of these conditions.},
}

@article {pmid41718986,
year = {2026},
author = {Shadfar, S and Assar Kashani, S and Gautam, S and Takalloo, Z and Farzana, F and Parakh, S and Atkin, JD},
title = {The Role of the Golgi Apparatus in Neurodegeneration.},
journal = {Sub-cellular biochemistry},
volume = {111},
number = {},
pages = {413-440},
pmid = {41718986},
issn = {0306-0225},
mesh = {*Golgi Apparatus/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Neurons/metabolism/pathology ; },
abstract = {The Golgi apparatus has important, well characterised functions in the trafficking, processing, and post-translational modification of proteins and lipids. However, roles in other cellular processes are increasingly reported, including autophagy, apoptosis, DNA repair, and cytoskeletal (microtubules and actin) function. The Golgi therefore serves as a regulatory hub for multiple signalling pathways that maintain essential cellular activities. The Golgi normally consists of flattened stacks of membrane (cisternae), but during normal physiology and pathological conditions it 'fragments', resulting in altered morphology and distribution. This is well described as an early pathological feature of many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and prion diseases, and amyotrophic lateral sclerosis (ALS). These age-related conditions are characterised by the death of neurons: highly specialised, unique cells that form the foundation of the nervous system. Interestingly, many Golgi-related functions are also dysregulated in these diseases. However, this has received relatively little attention compared to other pathogenic mechanisms. The Golgi apparatus in neurons shares features common to other eukaryotic cells but it also has unique properties, such as the presence of distinctive assemblies: Golgi outposts and satellites, which remain poorly characterised. Here we discuss the increasing evidence describing dysfunction and fragmentation of the Golgi apparatus and its possible role in the pathogenesis of neurodegenerative diseases.},
}

*Golgi Apparatus/metabolism/pathology
Humans
*Neurodegenerative Diseases/metabolism/pathology
Animals
*Neurons/metabolism/pathology

@article {pmid41718496,
year = {2026},
author = {Judge, S and Ballesteros, K and McDermott, CJ and Bloch, S},
title = {Timing of communication and technology control support in ALS - a systematic review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2627899},
pmid = {41718496},
issn = {2167-9223},
abstract = {Objective: To review evidence on the optimal timing of interventions that support communication and technology control for people living with Amyotrophic Lateral sclerosis (ALS). Methods: A systematic review was conducted following a pre-registered protocol. Databases were searched for studies involving people living with ALS that addressed timing of assistive technology interventions for communication or technology control. Screening and data extraction were completed in duplicate, findings were synthesized using a thematic analysis, and relevant findings presented as a descriptive summary. Results: Twenty-eight studies met the inclusion criteria. Evidence focused overwhelmingly on communication support rather than wider assistive technology interventions. Need for a communication aid typically occurs between one and five years from diagnosis and the timing of this varies significantly according to the site of onset of ALS. There are significant variations in the timing of changes for individuals within these groupings and there are likely a larger number of groupings that would be clinically useful. A significant correlation between changes in speaking rate and intelligibility has been shown. Once changes to speech do start to occur then the time to the loss of functional speech appears relatively consistent across the types of ALS. Conclusion: Current best practice guidelines are not reflective of the findings of this review and do not support professionals in identifying how to provide timely support. Monitoring speech changes systematically may support timely intervention. There is potential for individual level predictive modeling to help support people living with ALS to be proactive and prepared for changes.},
}

@article {pmid41714394,
year = {2026},
author = {Warmann, S},
title = {[Motor neuron diseases from a radiological perspective : Focus on amyotrophic lateral sclerosis].},
journal = {Radiologie (Heidelberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {41714394},
issn = {2731-7056},
abstract = {BACKGROUND: Motor neuron diseases (MND) affect the upper and/or lower motor neurons. Radiological diagnostics primarily serve to systematically exclude treatable mimics and support the clinical and electrophysiological diagnosis. The focus is on amyotrophic lateral sclerosis (ALS); supplementary progressive muscular atrophy (PMA, purely lower motor neuron, LMN disease) and spinal muscular atrophy (SMA).

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

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

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

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

DISCUSSION: The diagnosis remains primarily clinical; EMG and MRI are supportive. The radiological priority is the exclusion of mimics. The UMN markers increase diagnostic certainty in the context of clinical/EMG findings but do not replace them. Clear findings facilitate classification according to Gold Coast. The PMA and SMA require careful differential diagnostics; characteristic MRI patterns support progression and treatment planning.},
}

@article {pmid41673645,
year = {2026},
author = {Sterr, K and Bachner, J and Scheller, DA and Mess, F and Blaschke, S and Mühlberg, T and Butscher, F and Schmid-Ellinger, J},
title = {No healthy schools without healthy teachers: a scoping review on implementation determinants, strategies and outcomes of mental health-promoting interventions for school teachers.},
journal = {BMC public health},
volume = {26},
number = {},
pages = {},
pmid = {41673645},
issn = {1471-2458},
abstract = {BACKGROUND: The mental health and well-being of school teachers is critical not only for their individual health but also for the quality and stability of educational systems. Numerous interventions have been developed to address teachers’ mental health challenges, yet their implementation in everyday school settings remains limited. Understanding implementation determinants, strategies, and outcomes is essential for improving sustainable implementation, intervention effectiveness and broader public health impact. This scoping review explored how implementation is addressed in studies evaluating mental health-promoting interventions for teachers.

METHODS: Following Arksey and O’Malley’s (2005) and Levac et al.’s (2010) frameworks and PRISMA-ScR guidelines, we systematically searched Scopus and EBSCOhost up to April 2025. Studies were included if they evaluated an intervention targeting teachers’ mental health and reported at least one implementation aspect. Data extraction was guided by leading implementation science frameworks.

RESULTS: Of 4,062 identified records, 16 met the inclusion criteria. Most studies were primarily effectiveness-focused and assessed early-stage implementation rather than long-term implementation or sustainment. Implementation outcomes such as acceptability and feasibility were frequently reported but rarely grounded in implementation frameworks. Implementation determinants appeared in most studies, predominantly as post hoc barriers, with few studies assessing them a priori to guide implementation planning. Implementation strategies were commonly described but seldom explicitly labeled as such. Most studies examined implementation and intervention outcomes separately, limiting insights into how implementation processes influenced effectiveness. Nevertheless, several insights emerged, including the relevance of training and educating stakeholders, tailoring interventions to context, and strengthening relational dynamics, all examples of implementation strategies, as well as the importance of considering intervention content and implementation jointly.

CONCLUSION: Although implementation determinants, strategies, and outcomes were reported in studies on teachers’ mental health interventions, reporting was often fragmented, unsystematic and rarely guided by established frameworks or terminology. Future research should adopt comprehensive, theory-informed approaches that link implementation and intervention content. From a public health perspective, aligning evidence-based interventions, addressing both organizational and individual levels, with context-sensitive implementation strategies is key to sustainably improving teachers’ mental health and strengthening schools as healthy, supportive environments.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-026-26589-w.},
}

@article {pmid41710159,
year = {2026},
author = {Pang, Y and Yang, J and Liu, J and Xie, Z and Wang, J},
title = {Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1731771},
pmid = {41710159},
issn = {1662-4548},
abstract = {This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain's resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.},
}

@article {pmid41709060,
year = {2026},
author = {Yadav, AK and Verma, P and Srivastava, A and Srivastava, P and Rai, R and Rathour, S},
title = {Molecular insights into glial neuroimmune cross reactivity with CNS antigens and its role in neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41709060},
issn = {1568-5608},
abstract = {Neuroinflammation has been increasingly considered a key player of neurodegenerative as well as psychiatric disorders. This review integrates existing knowledge on glial-neuroimmune interactions, emphasizing the roles of cytokine signaling, glial activation, and BBB modulation in neuro-pathogenesis. A systematic review was performed studying peer-reviewed literature on molecular pathways of microglia, astrocytes, endothelial cells, and peripheral immune mediators. A possible explanation of this finding could be that the model is based on the underlying pathophysiology, and this is shared across disease contexts, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. Novel in vitro platforms, including the organ-on-a-chip and brain organoids, were also discussed for their translational potential. Microglia M1/M2 polarization and astrocyte reactivity appeared to be a common feature in neurotoxicity as well as excitotoxicity and chronic inflammation. Cytokine cascade of TNF-α, IL-1β, and IL-6 led to the disrupted BBB, allowing for peripheral immune cells to infiltrate. Both the NLRP3 inflammasome and mitochondrial dysfunction were identified as enhancers of neuroimmune signaling. Comparing across disease models, shared relationships emerged between glia-cytokines-BBB. Advanced in vitro systems proved to be useful to model these interactions and screen prescription drugs. This review highlights existing insights into glia-neuroimmune cross-reactivity and its critical role in CNS disease. The molecular interactions between these molecules could represent promising targets for novel therapeutic options. We suggests integrative systems platforms and AI-driven strategies to expedite clinical translation in neuroinflammation.},
}

@article {pmid41699331,
year = {2026},
author = {Ercin, N and Besli, N and Beker, M and Celik, U},
title = {Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {3},
pages = {72},
pmid = {41699331},
issn = {1573-675X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism/genetics ; *Cell Death/drug effects ; Animals ; Necroptosis/drug effects ; Ferroptosis/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Pyroptosis/drug effects ; Oxidative Stress ; },
abstract = {Neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are defined by progressively increased neuronal loss that lacks curative therapies. Increasing evidence supports that non-canonical regulated cell death pathways including ferroptosis, necroptosis, pyroptosis, and parthanatos, are implicated in pathological mechanisms of neuroinflammation, and oxidative stress, and mitochondrial dysfunction, likely impacting neurodegenerative pathologies. In this review, we summarize the existing literature on the molecular pathways and potential pathogenic implications of these cell death pathways in neurodegenerative diseases, highlighting their upstream triggers, regulatory proteins, and downstream effectors. We also briefly describe representative pharmacological agents, including ferrostatin-1, necrostatin-1, MCC950 and PARP-inhibitors, that have shown neuroprotective effects in experimental studies. Experimental studies provide valuable information, but translation to clinical treatments presents barriers including overlapping regulated cell death mechanisms, constraints of bloodbrain barrier penetrance and concern for safety. Future development may come through concepts such as biomarker-based patient stratification strategies, multivalent interventions, and improved translational models. Identifying these new regulated cell death pathways may eventually provide new avenues to slow the progression of neurodegeneration and develop more targeted therapies.},
}

Humans
*Neurodegenerative Diseases/drug therapy/pathology/metabolism/genetics
*Cell Death/drug effects
Animals
Necroptosis/drug effects
Ferroptosis/drug effects
Neuroprotective Agents/therapeutic use/pharmacology
Pyroptosis/drug effects
Oxidative Stress

@article {pmid41698629,
year = {2026},
author = {Patwekar, F and Patwekar, M and Wei, LS and Rather, GA and Mohammed, A and Hussain, MS and Gupta, G and Fuloria, S and Fuloria, NK},
title = {Marine-Derived bioactive compounds from Aquaculture: Receptor-Mediated neuroprotection in neurodegenerative disorders.},
journal = {Brain research},
volume = {1879},
number = {},
pages = {150208},
doi = {10.1016/j.brainres.2026.150208},
pmid = {41698629},
issn = {1872-6240},
abstract = {Neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke (IS), are a major global health challenge because of their complex, multifactorial pathology, and the lack of effective disease-modifying therapies. In recent years, aquaculture-derived marine bioactive molecules like fucoidan, phlorotannins, fucoxanthin, laminarin, alginate oligosaccharides, and C-phycocyanin have developed as promising agents for neuroprotection with their structural diversity and multi-target biological activity. This review showcase predominantly preclinical evidence, including in silico molecular docking analyses, in vitro functional assays, and in vivo animal models, to critically understand the receptor-mediated mechanisms with the neuroprotective actions of marine bioactives originated from aquaculture systems. Available studies shows these compounds can modulate large neuro-receptor systems, like cholinergic, dopaminergic, GABAergic, glutamatergic, toll-like, and nuclear receptors, leading in attenuation of oxidative stress, lowering of neuro-inflammation, regulation of neurotransmission, and conservation of mitochondrial and synaptic function. However, the positive approach of mechanistic evidence varies across compounds and receptor classes, with large interactions assisted by functional outcomes instead of direct receptor-binding validation. The review even discusses emerging and enabling technologies like brain organoids, multi-electrode array platforms, omics-based profiling, and artificial intelligence assisted drug discovery, which are increasingly utilized to refine mechanistic understanding and optimize marine-derived products. Importantly, current evidence stay largely preclinical, with little human studies and a lack of validated receptor-specific biomarkers. Overall, this review provides a well-balanced, evidence-based assessment of aquaculture-derived marine bioactive as potential neurotherapeutic agents.},
}

@article {pmid41521074,
year = {2026},
author = {Ham, HJ and Lee, JA},
title = {Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.},
journal = {BMB reports},
volume = {59},
number = {2},
pages = {85-100},
pmid = {41521074},
issn = {1976-670X},
mesh = {Humans ; *Aging/metabolism/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Stress Granules/metabolism/physiology ; Animals ; *Organelles/metabolism ; Mitochondria/metabolism ; Neurons/metabolism ; Cytoplasmic Granules/metabolism ; Autophagy ; Stress, Physiological ; },
abstract = {Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics-with an increased propensity to form SGs while displaying reduced efficiency in their clearance-resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging. [BMB Reports 2026; 59(2): 85-100].},
}

Humans
*Aging/metabolism/physiology
*Neurodegenerative Diseases/metabolism/pathology
*Stress Granules/metabolism/physiology
Animals
*Organelles/metabolism
Mitochondria/metabolism
Neurons/metabolism
Cytoplasmic Granules/metabolism
Autophagy
Stress, Physiological

@article {pmid41693708,
year = {2025},
author = {Mudda, NS and Zhang, L and Sampelli, P},
title = {Targeting gut-brain-immune axis in amyotrophic lateral sclerosis.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1637976},
pmid = {41693708},
issn = {1664-3224},
mesh = {*Amyotrophic Lateral Sclerosis/immunology/microbiology/therapy/metabolism ; Humans ; *Gastrointestinal Microbiome/immunology ; Animals ; *Brain/immunology/metabolism ; Dysbiosis/immunology ; *Brain-Gut Axis/immunology ; Cytokines/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron neurodegenerative disorder with a median survival of only 3-5 years. The heterogeneity of the disease and lack of effective therapies highlight the importance of identifying novel pathogenic mechanisms. We hypothesize that dysbiosis of gut microbiota enhances ALS by disrupting intestinal barrier function and altering metabolite profiles to drive systemic inflammation and neuronal stress. Precisely, the decrease in health-promoting bacteria (e.g., Akkermansia muciniphila, Bifidobacterium and Lactobacillus spp.) in ALS can reduce neuroprotective metabolite production (short-chain fatty acids, nicotinamide, GABA, precursors of serotonin) and increase gut permeability, enabling lipopolysaccharide (LPS) and pro-inflammatory cytokines into the circulation. Such changes would activate microglia and impair motor neuron homeostasis by glutamate excitotoxicity and mitochondrial dysfunction. The gut-brain axis operates through immune-mediated mechanisms, where ALS-associated microbiota changes compromise mucosal immunity and trigger peripheral Th1/Th17-biased responses with impaired Treg regulation. Elevated endotoxin levels correlate with TLR4-driven inflammation, promoting pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) that cross into the CNS and prime microglia toward a neurotoxic M1 phenotype, creating a milieu where IL-17A and other mediators directly injure motor neurons. Our hypothesis relies on establishing human and animal evidence of microbiome derangements, barrier dysfunction, and immune deregulation with ALS. We hypothesize that restoration of an "ALS-protective" microbiota consortium or its metabolic by-products can potentially slow disease progression. Testable hypotheses include improvement of ALS model motor deficits by probiotic or fecal-microbiota therapies, and normalization of inflammatory biomarkers. This paradigm recontextualizes ALS as a gut-brain disease and suggests new directions for translational research into this unmet medical indication.},
}

*Amyotrophic Lateral Sclerosis/immunology/microbiology/therapy/metabolism
Humans
*Gastrointestinal Microbiome/immunology
Animals
*Brain/immunology/metabolism
Dysbiosis/immunology
*Brain-Gut Axis/immunology
Cytokines/metabolism

@article {pmid41690071,
year = {2026},
author = {El-Moaty, HIA and Sameh, A and Saber, S and Hamad, RS and Elmorsy, EA and Alsoqih, NS and Farrag, AA and Eissa, H and El-Kott, AF and Negm, S and AlShehri, MA and Ali, MAM and Hasan, WA and Gaafar, A and Khalifa, HS and Ibrahim, EH and Morsy, K and Elnaghy, F},
title = {Adenosine A2A receptor as a dual-acting molecular switch: Glial morphological changes and neurovascular tissue remodeling in neuroinflammation and neurodegeneration.},
journal = {Tissue & cell},
volume = {100},
number = {},
pages = {103389},
doi = {10.1016/j.tice.2026.103389},
pmid = {41690071},
issn = {1532-3072},
abstract = {Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A2A receptor (A2AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A2AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A2AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A2AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A2AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A2AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A2AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A2AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling.},
}

@article {pmid41689968,
year = {2026},
author = {Qaisar, R and Deepa, SS},
title = {A Narrative Review of Necroptosis in Neuromuscular Junction Disorders: Pathogenesis and Therapeutic Strategies.},
journal = {Archives of medical research},
volume = {57},
number = {5},
pages = {103401},
doi = {10.1016/j.arcmed.2026.103401},
pmid = {41689968},
issn = {1873-5487},
abstract = {Necroptosis is a regulated and inflammatory form of cell death that has emerged as a key contributor to neuromuscular junction (NMJ) dysfunction. This narrative review aims to synthesize current evidence on the role of necroptosis in NMJ pathology and its potential therapeutic implications. First, we present the conceptual framework linking necroptosis to NMJ degradation, focusing on core mediators such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL). Second, we summarize the available evidence across NMJ compartments, including motor neurons, Schwann cells, and skeletal muscle. We also describe how necroptosis activation correlates with structural and functional deficits in conditions such as spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. Third, we examine the translational potential of targeting necroptosis, highlighting preclinical studies on RIPK1, RIPK3, and MLKL inhibitors. Although these findings suggest therapeutic value, current evidence is predominantly derived from animal models, and clinical applicability remains uncertain. Rigorous trials are needed to confirm the safety and efficacy of these treatments. Understanding necroptosis as a shared mechanism across NMJ components may inform future strategies to preserve neuromuscular function.},
}

@article {pmid41686369,
year = {2026},
author = {Qaisar, R},
title = {Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.},
journal = {Cell and tissue research},
volume = {403},
number = {2},
pages = {20},
pmid = {41686369},
issn = {1432-0878},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neuromuscular Junction/metabolism/pathology ; Animals ; *Synapses/metabolism ; },
abstract = {Extracellular vesicles (EVs) have emerged as pivotal modulators of neuromuscular junction (NMJ) biology, reshaping our understanding of synaptic communication, maintenance, and degeneration. This review consolidates current insights into the roles of EVs derived from motor neurons, muscle fibers, and Schwann cells in regulating NMJ integrity. In healthy states, EVs deliver trophic factors, structural proteins, and regulatory RNAs that promote the clustering of acetylcholine receptors, presynaptic stability, and axonal growth. Motor neuron EVs carry Wnt7a, synaptophysin, and PGC-1α, while muscle-derived EVs deliver miR-206, agrin, and caveolin-3. Schwann cell EVs contribute neurotrophic support via NRG1 and GDNF. In contrast, diseased or aged NMJs exhibit EV cargo dysregulation, marked by the presence of misfolded proteins (e.g., SOD1, TDP-43), pro-inflammatory cytokines, and reduced regenerative miRNAs. These changes contribute to synaptic dismantling, neuroinflammation, and impaired repair in conditions such as ALS, SMA, MG, and sarcopenia. The review highlights the bidirectional nature of EV signalling and its dynamic regulation by neuronal activity and stress. Emerging therapeutic strategies include engineering EVs to deliver protective cargo, targeting them to NMJ components, and designing biomaterial-based depots for sustained release. Furthermore, EV signatures in blood and muscle hold promise as non-invasive biomarkers for early detection of NMJ decline in ALS, SMA, MG, and sarcopenia. Despite promising preclinical data, challenges remain in EV characterization, targeting specificity, and clinical translation. This review underscores a paradigm shift: EVs are not passive byproducts but active messengers of neuromuscular health and disease, with realistic applications in diagnostics, regenerative therapy, and personalized medicine.},
}

Humans
*Extracellular Vesicles/metabolism
*Neuromuscular Junction/metabolism/pathology
Animals
*Synapses/metabolism

@article {pmid41684011,
year = {2026},
author = {Chico, L and Schirinzi, E and Balestrini, L and Polzella, M and Siciliano, G},
title = {Nrf2-Activating Natural Compounds in Neurodegenerative Diseases: Targeting Oxidative Stress and Protein Aggregation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
pmid = {41684011},
issn = {1422-0067},
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Biological Products/pharmacology/therapeutic use ; Animals ; *Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Signal Transduction/drug effects ; },
abstract = {Neurodegenerative diseases (NDs) are among the leading causes of disability and mortality worldwide and are characterized by multifactorial pathogenesis involving interconnected mechanisms, such as oxidative stress, protein misfolding and aggregation, neuroinflammation, and mitochondrial dysfunction. Dysregulation of transcription factors, governing cellular defense responses, particularly nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and proteostatic pathways, plays a critical role in neurodegenerative processes. Currently, available pharmacological treatments for NDs are largely symptomatic, as no disease-modifying therapies exist. Natural bioactive compounds have emerged as promising multi-target agents, demonstrating antioxidant, anti-aggregative, and anti-apoptotic properties, frequently mediated through activation of the Nrf2 signaling pathways. These compounds may represent valuable supportive strategies alongside conventional drug treatments, potentially contributing to the modulation of multiple pathogenic mechanisms. This review summarizes key oxidative stress- and protein aggregation-driven mechanisms underlying Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. It further examines the neuroprotective potential of plant-, fungi-, and marine-derived natural compounds, with particular emphasis on Nrf2 activation. Beyond redox regulation, the broader role of Nrf2 in maintaining proteostasis is discussed. Overall, the review highlights Nrf2-inducing nutraceuticals as promising complementary, multi-target approaches for neuroprotection in NDs.},
}

Humans
*NF-E2-Related Factor 2/metabolism
*Oxidative Stress/drug effects
*Neurodegenerative Diseases/metabolism/drug therapy
*Biological Products/pharmacology/therapeutic use
Animals
*Protein Aggregates/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Antioxidants/pharmacology/therapeutic use
Signal Transduction/drug effects

@article {pmid41683920,
year = {2026},
author = {Auburger, GWJ and Key, J and Gispert, S and Lastres-Becker, I and Almaguer-Mederos, LE and Bassa, C and Auburger, A and Auburger, G and Arsovic, A and Deller, T and Sen, NE},
title = {Bioinformatic Analyses of the Ataxin-2 Family Since Algae Emphasize Its Small Isoforms, Large Chimerisms, and the Importance of Human Exon 1B as Target of Therapies to Prevent Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
pmid = {41683920},
issn = {1422-0067},
support = {AU96/21-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Ataxin-2/genetics/metabolism/chemistry ; *Computational Biology/methods ; *Exons ; Protein Isoforms/genetics/metabolism ; Peptides/genetics/metabolism ; Animals ; *Neurodegenerative Diseases/genetics/prevention & control ; Phylogeny ; },
abstract = {Polyglutamine expansion in Ataxin-2 (ATXN2) is responsible for rare, dominantly inherited Spinocerebellar Ataxia type 2 (SCA2). Together with its paralog Ataxin-2-like (ATXN2L), both proteins have received much interest, since the deletion of their yeast and fly orthologs alleviates TDP-43-triggered neurotoxicity in Amyotrophic Lateral Sclerosis models. Their typical structure across evolution combines LSm with LSm-Associated Domains and a PAM2 motif. To understand the physiological regulation and functions of Ataxin-2 homologs, the phylogenesis of sequences was analyzed. Human ATXN2 harbors multiple alternative start codons, e.g., from an intrinsically disordered sequence (IDR) present since armadillo, or from the polyQ sequence that arose since amphibians, or from the LSm domain since primitive eukaryotes. Multiple smaller isoforms also exist across the C-terminus. Therapeutic knockdown of polyQ expansions in human ATXN2 should selectively target exon 1B. PolyQ repeats developed repeatedly, usually framed and often interrupted by (poly)Pro, originally near PAM2. The LSmAD sequence appeared in algae as the characteristic Ataxin-2 feature with strong conservation. Frequently, Ataxin-2 has added domains, likely due to transcriptional readthrough of neighbor genes during cell stress. These chimerisms show enrichment of rRNA processing; nutrient store mobilization; membrane strengthening via lipid, protein, and glycosylated components; and cell protrusions. Thus, any mutation of Ataxin-2 has complex effects, also affecting membrane resilience.},
}

Humans
*Ataxin-2/genetics/metabolism/chemistry
*Computational Biology/methods
*Exons
Protein Isoforms/genetics/metabolism
Peptides/genetics/metabolism
Animals
*Neurodegenerative Diseases/genetics/prevention & control
Phylogeny

@article {pmid41683564,
year = {2026},
author = {Jamerlan, A and Hulme, J},
title = {From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
pmid = {41683564},
issn = {1422-0067},
support = {RS-2025-02292973//Ministry of Oceans and Fisheries/ ; RS-2021-NR060117//Ministry of Education/ ; },
mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Proteostasis ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Autophagy ; Animals ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Protein Folding ; Kinetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation).},
}

Humans
*DNA-Binding Proteins/metabolism/genetics/chemistry
*Proteostasis
*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
Autophagy
Animals
*Frontotemporal Dementia/metabolism/genetics/pathology
Protein Folding
Kinetics

@article {pmid41683467,
year = {2026},
author = {Czaj, PV and Szewczyk-Golec, K and Nuszkiewicz, J and Woźniak, A},
title = {Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
pmid = {41683467},
issn = {1420-3049},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Dysbiosis/metabolism/microbiology ; *Neurodegenerative Diseases/metabolism/microbiology ; Animals ; *Brain/metabolism ; Oxidative Stress ; Signal Transduction ; Parkinson Disease/metabolism/microbiology ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key molecular features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss. Increasing evidence indicates that gut dysbiosis and alterations in microbiota-derived metabolites are involved in these processes through multiple pathways along the gut-brain axis. However, while broad compositional changes are well-documented, a critical knowledge gap remains regarding the specific biochemical signal transduction pathways translating dysbiosis into pathology. This narrative review addresses this gap by synthesizing current human and experimental studies addressing gut microbiota alterations in AD, PD, and ALS, with particular emphasis on the biochemical and molecular mechanisms mediated by gut-derived metabolites. Dysbiosis in neurodegenerative diseases is frequently associated with reduced abundance of short-chain fatty acid (SCFA)-producing bacteria and altered metabolism of SCFAs, bile acids, tryptophan-derived indoles, trimethylamine-N-oxide (TMAO), and lipopolysaccharides (LPS). These microbial metabolites have been shown to modulate intestinal and blood-brain barrier integrity, influence Toll-like receptor- and G protein-coupled receptor-dependent signaling, regulate microglial activation, and affect molecular pathways related to protein aggregation in experimental models. In addition, emerging evidence highlights the involvement of oxidative and nitrosative stress, immune-metabolic crosstalk, and altered xenobiotic metabolism in microbiota-host interactions during neurodegeneration. By integrating microbiological, metabolic, and molecular perspectives, this review underscores the important and emerging role of microbiota-derived molecules in neurodegenerative disorders and outlines key chemical and metabolic pathways that may represent targets for future mechanistic studies and therapeutic strategies.},
}

Humans
*Gastrointestinal Microbiome
*Dysbiosis/metabolism/microbiology
*Neurodegenerative Diseases/metabolism/microbiology
Animals
*Brain/metabolism
Oxidative Stress
Signal Transduction
Parkinson Disease/metabolism/microbiology

@article {pmid40960388,
year = {2026},
author = {Jhilal, S and Marchesotti, S and Thirion, B and Soudrie, B and Giraud, AL and Mandonnet, E},
title = {Implantable Neural Speech Decoders: Recent Advances, Future Challenges.},
journal = {Neurorehabilitation and neural repair},
volume = {40},
number = {2},
pages = {157-172},
doi = {10.1177/15459683251369468},
pmid = {40960388},
issn = {1552-6844},
mesh = {Humans ; *Speech/physiology ; *Locked-In Syndrome/rehabilitation/physiopathology ; *Brain-Computer Interfaces ; },
abstract = {The social life of locked-in syndrome (LIS) patients is significantly impacted by their difficulties to communicate. Consequently, researchers have started to explore how to decode intended speech from neural signals directly recorded from the cortex. The first studies in the late 2000s reported modest decoding accuracies. However, thanks to fast advances in machine learning, the most recent studies have reached decoding accuracies high enough to be optimistic about the clinical benefit of neural speech decoders in the near future. We first discuss the selection criteria for implanting a neural speech decoder in LIS patients, emphasizing the advantages and disadvantages associated with conditions such as brainstem stroke and amyotrophic lateral sclerosis. We examine the key design considerations for neural speech decoders, demonstrating how successful implantation requires careful optimization of multiple interrelated factors including language representation, cortical recording areas, neural features, training paradigms, and decoding algorithms. We then discuss current approaches and provide arguments for potential improvements in decoder design and implementation. Finally, we explore the crucial question of who should learn to use the neural speech decoder-the patient, the machine, or both. In conclusion, while neural speech decoders present promising avenues for improving communication for LIS patients, interdisciplinary efforts spanning neurorehabilitation, neuroscience, neuroengineering, and ethics are imperative to design future clinical trials.},
}

Humans
*Speech/physiology
*Locked-In Syndrome/rehabilitation/physiopathology
*Brain-Computer Interfaces

@article {pmid40735987,
year = {2025},
author = {Ergin, AD},
title = {Nanotechnological Approaches for Mitochondrial Targeting in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {25},
number = {28},
pages = {3251-3266},
pmid = {40735987},
issn = {1873-4294},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; *Nanotechnology ; *Drug Delivery Systems ; Animals ; Nanoparticles/chemistry ; *Neuroprotective Agents/chemistry/pharmacology ; },
abstract = {OBJECTIVES: Mitochondria are dynamic organelles essential for energy metabolism and cellular homeostasis, playing critical roles in ATP production, calcium regulation, redox balance, and apoptosis. However, mitochondrial dysfunction is a central factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Given the essential role of mitochondria in neuronal survival, targeted therapeutic strategies that restore mitochondrial function have gained significant attention. This review explores the latest advances in mitochondrial-targeted therapies and their potential applications in neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted on mitochondrial-targeted therapeutic strategies, with a focus on nanotechnology-based drug delivery systems. The analysis includes various nanoparticle-based approaches, such as liposomes, DQAsomes, and polymeric nanoparticles, which have demonstrated high biocompatibility, controlled drug release, and enhanced mitochondrial targeting efficiency. Additionally, mitochondria-penetrating peptides and delocalized lipophilic cations (DLCs) are discussed for their role in improving drug localization within mitochondria and overcoming biological barriers, including the blood-brain barrier (BBB).

RESULTS: Recent research shows the potential of mitochondrial-targeted antioxidants, peptides, and biocompatible nanocarriers in arranging mitochondrial dysfunction and protecting neurons from oxidative damage. Various nanoparticle-based drug delivery systems have demonstrated the ability to selectively target mitochondria, improving drug bioavailability, therapeutic efficacy, and neuroprotective outcomes in neurodegenerative diseases.

CONCLUSION: Mitochondria-targeted therapies provide promising avenues for disease-modifying treatments aimed at preserving neuronal integrity and delaying disease progression. The unique properties of nanoparticles, such as their ability to enhance drug stability, facilitate controlled release, and achieve precise mitochondrial localization, make them valuable tools for neurodegenerative disease therapy. Future research should focus on optimizing delivery systems, validating clinical applicability, and exploring interdisciplinary approaches to accelerate translation into effective treatments.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Mitochondria/drug effects/metabolism
*Nanotechnology
*Drug Delivery Systems
Animals
Nanoparticles/chemistry
*Neuroprotective Agents/chemistry/pharmacology

@article {pmid41678537,
year = {2026},
author = {Helal, MM and Almosilhy, NA and Abo-Elnour, DE and Jaffal, RSY and Allam, EG and Almosilhy, MA and Batarseh, SF and Meshref, M},
title = {Targeting metabolic dysfunction in amyotrophic lateral sclerosis: therapeutic potential of GLP-1 receptor agonists.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/21678421.2026.2627901},
pmid = {41678537},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and profound systemic metabolic dysfunction, including hypermetabolism, weight loss, insulin resistance, and altered glucose and lipid homeostasis. Increasing recognition of these metabolic abnormalities has driven interest in repurposing antidiabetic therapies, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs), for ALS. Beyond their established metabolic actions, GLP-1RAs exert pleiotropic effects relevant to neurodegeneration, including modulation of neuroinflammation, mitochondrial function, oxidative stress, excitotoxicity, and cell-survival signaling, with selected agents demonstrating central nervous system penetration. This narrative review summarizes current knowledge on metabolic impairment in ALS and critically evaluates the mechanistic rationale, preclinical evidence, and emerging clinical data supporting or opposing the use of GLP-1-based therapies in this disease. Preclinical studies suggest that GLP-1 signaling can provide neuroprotective and neurotrophic effects in ALS models, although findings are heterogeneous and highly dependent on compound selection, delivery strategy, and experimental design. In contrast, available clinical evidence is limited and does not demonstrate therapeutic benefit in ALS, while raising important safety concerns, particularly related to weight loss, lean mass reduction, and altered glucose regulation, factors associated with a worse prognosis in ALS. Collectively, current data indicate that although GLP-1-based therapies may have compelling biological plausibility and beneficial effects in other neurodegenerative disorders (NDGs), their role in ALS remains uncertain and potentially harmful. Well-designed, ALS-specific clinical studies are required to clarify safety, efficacy, and patient selection before GLP-1RAs can be considered for therapeutic use in this vulnerable population.},
}

@article {pmid41678108,
year = {2026},
author = {Umesh, SB and Sadanandan, B and Marabanahalli Yogendraiah, K and Vijayalakshmi, V},
title = {The Impact of Zinc on Cellular Dynamics, Brain Function, and its Therapeutic Potential in Neuronal Regeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {436},
pmid = {41678108},
issn = {1559-1182},
mesh = {Humans ; *Zinc/pharmacology/metabolism/therapeutic use ; Animals ; *Nerve Regeneration/drug effects/physiology ; *Brain/physiology/drug effects ; *Neurons/drug effects/metabolism ; Neurogenesis/drug effects ; },
abstract = {Zinc is a vital trace element that plays a central role in maintaining brain function, regulating cellular dynamics, and promoting neuronal repair. As the second most abundant transition metal in the central nervous system, zinc is essential for neurotransmission, synaptic plasticity, and neurogenesis, processes that underlie higher cognitive functions such as learning and memory. Its homeostasis is tightly controlled, as dysregulation contributes to the onset and progression of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At the cellular level, zinc serves as a critical regulator of proliferation, differentiation, and survival, influencing the behavior of neural and mesenchymal stem cells. Through modulation of signaling pathways such as PI3K/Akt and MAPK, zinc governs cell growth, maturation, and neuroprotection. Physiological levels support axonal sprouting, neurite extension, and synaptic connectivity, whereas excessive release under pathological conditions exacerbates oxidative stress and excitotoxicity. Emerging evidence highlights zinc's therapeutic role in neuronal regeneration. Controlled supplementation enhances neurogenesis, reduces apoptosis, restores synaptic activity, and improves memory outcomes in experimental models of neural injury. Zinc-enriched biomaterials and scaffolds are also being developed for neural tissue engineering, where the incorporation of zinc enhances neurite outgrowth, cell adhesion, and network repair. Beyond neuroregeneration, zinc-based nanomaterials are gaining biomedical significance. Zinc oxide nanoparticles (ZnO NPs) exhibit potent anticancer activity against human cancer cell lines by inducing reactive oxygen species generation, DNA damage, and apoptosis. Additionally, other zinc nanoparticles, including zinc sulfide and zinc-doped biomaterials, show potential in tissue repair, wound healing, and drug delivery applications. Collectively, these findings underscore zinc's multifaceted role in neural function, regenerative biology, and nanomedicine. Advancing our understanding of zinc-mediated mechanisms may enable the development of novel zinc-targeted therapeutic strategies for treating neurodegenerative diseases and promoting functional recovery after brain injury.},
}

Humans
*Zinc/pharmacology/metabolism/therapeutic use
Animals
*Nerve Regeneration/drug effects/physiology
*Brain/physiology/drug effects
*Neurons/drug effects/metabolism
Neurogenesis/drug effects

@article {pmid41677614,
year = {2026},
author = {Salamotas, I and Stavropoulou De Lorenzo, S and Stachtiari, A and Taxiarchis, A and Tsolaki, M and Michailidou, I and Preza, E},
title = {From Dish to Trial: Building Translational Models of ALS.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
pmid = {41677614},
issn = {2073-4409},
mesh = {*Amyotrophic Lateral Sclerosis/pathology/therapy ; Humans ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Translational Research, Biomedical ; Clinical Trials as Topic ; Animals ; *Models, Biological ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell-cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies.},
}

*Amyotrophic Lateral Sclerosis/pathology/therapy
Humans
Induced Pluripotent Stem Cells/metabolism/cytology
*Translational Research, Biomedical
Clinical Trials as Topic
Animals
*Models, Biological

@article {pmid41675725,
year = {2026},
author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N},
title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1441-1453},
pmid = {41675725},
issn = {2049-0801},
abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

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

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

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

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.},
}

@article {pmid41674784,
year = {2025},
author = {Yashooa, RK and Nabi, AQ and Smail, SW and Azeez, SS and Nooh, WA and Mustafa, SA and Al-Farha, AA and Capitanio, N and Shekha, MS},
title = {CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1737468},
pmid = {41674784},
issn = {1664-2295},
abstract = {CRISPR-Cas genome-editing technologies have emerged as powerful tools for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review critically evaluates current CRISPR/Cas applications in neurodegeneration, with emphasis on mechanistic insights, therapeutic outcomes, and translational feasibility. Preclinical and early translational studies demonstrate that CRISPR-Cas platforms can correct pathogenic mutations, suppress toxic gene expression, and restore neuronal function. Advanced modalities, including base and prime editing, CRISPRi/a, and RNA-targeting Cas systems, improve precision and reduce genomic damage, which is particularly advantageous in post-mitotic neurons. Emerging CRISPR-based diagnostics (e.g., SHERLOCK and DETECTR), AI-assisted sgRNA design, and machine-learning approaches for predicting off-target effects further enhance the safety, stratification, and monitoring of CRISPR therapeutics. In parallel, patient-derived brain organoids and assembloids provide scalable human-relevant platforms for mechanistic studies and preclinical validation. Despite this progress, major challenges remain, including efficient delivery across the blood-brain barrier, immune responses, long-term safety, and ethical and regulatory considerations. Overall, CRISPR-Cas technologies hold strong potential as disease-modifying interventions for neurodegenerative disorders, provided that advances in delivery systems, artificial intelligence integration, and regulatory oversight continue to evolve toward clinical translation.},
}

@article {pmid41673769,
year = {2026},
author = {Sharma, S and Vandenakker, A and Cortés-Pérez, C and Milne, S and Douville, RN},
title = {Implications of virus-induced stress granules in tauopathies.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {4},
pmid = {41673769},
issn = {2047-9158},
support = {#2401-3152//St. Boniface Hospital Foundation/ ; RGPIN-2016-05761//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Humans ; *Tauopathies/metabolism/virology/pathology ; *Stress Granules/metabolism/virology ; Animals ; *tau Proteins/metabolism ; *Virus Diseases/metabolism/complications ; },
abstract = {Tauopathies are characterized by aberrant tau structure and function, which is associated with neurodegenerative dementias, such as Alzheimer's disease, Pick's disease, and frontotemporal dementia, as well as the motor neuron disease amyotrophic lateral sclerosis. Consistent association of these neurodegenerative conditions with viruses suggests an interplay between viral activity and the development of tauopathy. In this review, we explore how tau dysregulation may facilitate viral activity, and conversely, how viruses may drive tauopathy. We further discuss how stress granules (SGs) are a likely hub for the interactions between tau and viral components, leading to tau deregulation. Within the network of SG proteins analyzed, 15 proteins were identified to be both tau interactors and implicated in viral processes, having dual functionality. These SG proteins are further discussed in terms of their relationship with tauopathy, viral replication, and neurodegeneration. Concrete examples of synergistic and competing effects between tau and viruses are highlighted, revealing both pathological and protective mechanisms. This dichotomy underscores a complexity that is both disease- and virus-specific, within the context of SG biology and tau pathology. While the viral involvement in tauopathies could be considered detrimental, it may provide insights into antiviral therapeutics to target the accumulation and misfolding of tau in these neurodegenerative diseases.},
}

Humans
*Tauopathies/metabolism/virology/pathology
*Stress Granules/metabolism/virology
Animals
*tau Proteins/metabolism
*Virus Diseases/metabolism/complications

@article {pmid41672134,
year = {2026},
author = {Maneu, V and García, AG},
title = {P2X7 receptors as targets for neuroprotection.},
journal = {Neuropharmacology},
volume = {289},
number = {},
pages = {110877},
doi = {10.1016/j.neuropharm.2026.110877},
pmid = {41672134},
issn = {1873-7064},
abstract = {In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.},
}

@article {pmid41564770,
year = {2026},
author = {Lee, H and Jo, Y and Jung, M and Lee, JH and Kim, TH and Lee, J and Kim, DJ and Rahmati, M and Smith, L and Pizzol, D and Son, Y and Park, J and Ahn, SH and Yon, DK and Choi, DW and Kang, J},
title = {Heavy metal exposure and all health outcomes: An umbrella review of meta-analyses.},
journal = {Journal of hazardous materials},
volume = {503},
number = {},
pages = {141141},
doi = {10.1016/j.jhazmat.2026.141141},
pmid = {41564770},
issn = {1873-3336},
mesh = {Humans ; *Metals, Heavy/toxicity ; *Environmental Exposure/adverse effects ; Meta-Analysis as Topic ; *Environmental Pollutants/toxicity ; Female ; Arsenic ; },
abstract = {We aimed to systematically evaluate the strength and credibility of evidence linking exposure to five major heavy metals, including arsenic, cadmium, lead, mercury, and chromium, with health outcomes (PROSPERO, CRD420251169899). Literature searches of PubMed/Embase, CINAHL, and Google Scholar up to April 20, 2025, identified meta-analyses of observational studies assessing these associations. Effect sizes were recalculated using random-effects models and expressed as equivalent odds ratios (eOR) with 95 % confidence intervals (CIs). The methodological quality of the included reviews was assessed using the AMSTAR2, and the credibility of associations was graded according to predefined criteria: Class I (convincing), Class II (highly suggestive), Class III (suggestive), Class IV (weak), and non-significant (NS). A total of 35 meta-analyses encompassing 103 health outcomes were included. Arsenic exposure was associated with melanoma (eOR 1.50 [95 % CI, 1.0-2.24], CE=IV), digestive cancers (1.23 [1.07-1.41], CE=III), gestational diabetes mellitus (1.47 [1.11-1.95], CE=III), hypertension (1.15 [1.06-1.24], CE=III), and preterm birth (1.12 [1.04-1.21], CE=III). Lead exposure showed significant associations with autistic disorder in children (12.70 [3.93-41.10], CE=IV), hearing loss (7.55 [6.69-8.53], CE=III), age-related eye disease (9.80 [1.72-55.85], CE=IV), and amyotrophic lateral sclerosis (1.46 [1.16-1.83], CE=III). Mercury exposure was linked to increased risk in membranous nephropathy (5.75 [1.54-21.44], CE=IV) and thyroid cancer (1.90 [1.55-2.33], CE=IV). Cadmium exposure was associated with renal cancer (1.47 [1.26-1.71], CE=II), cardiovascular disease (1.33 [1.05-1.69], CE=IV), stroke (1.36 [1.10-1.68], CE=III), diabetes mellitus (1.27 [1.07-1.52], CE=III), fracture risk (1.30 [1.13-1.49], CE=III), and age-related eye disease (113.26 [16.86-760.68], CE=III). Chromium exposure was associated with stomach cancer (1.28 [1.16-1.41], CE=I), supporting convincing evidence. Overall, exposures to these metals were consistently associated with diverse diseases across organ systems and life stages, suggesting proactive implications against heavy metal exposures.},
}

Humans
*Metals, Heavy/toxicity
*Environmental Exposure/adverse effects
Meta-Analysis as Topic
*Environmental Pollutants/toxicity
Female
Arsenic

@article {pmid41666800,
year = {2026},
author = {Maidi, AZM and Suram, RP and Deniz, Y and An, SL and Hong, Y},
title = {Heart rate variability as a non-invasive biomarker of autonomic dysfunction in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {Autonomic neuroscience : basic & clinical},
volume = {264},
number = {},
pages = {103393},
doi = {10.1016/j.autneu.2026.103393},
pmid = {41666800},
issn = {1872-7484},
abstract = {OBJECTIVE: This study assessed heart rate variability (HRV) alterations in amyotrophic lateral sclerosis (ALS) patients compared to healthy control groups using both frequency-domain and time-domain HRV parameters.

METHODS: A systematic review and meta-analysis were conducted using studies retrieved from PubMed, Embase, Web of Science, and Cochrane Library databases up to November 13, 2024. Fourteen studies were included in the qualitative synthesis and eight in the quantitative analysis.

RESULTS: ALS patients exhibited significantly reduced Low Frequency (LF) and High Frequency (HF) HRV parameters compared to healthy controls (p < 0.001 and p = 0.02, respectively). Time-domain parameters also showed significant reductions: RMSSD (p < 0.001), SDNN (p < 0.001), and pNN50% (p = 0.01). Despite an overall decrease in HRV, the LF/HF ratio did not show a statistically significant difference (p = 0.12).

CONCLUSION: Patients with ALS demonstrate autonomic dysfunction, evidenced by significant reductions in key time-domain (RMSSD, SDNN, pNN50%) and frequency-domain (LF, HF) parameters, suggesting impaired parasympathetic modulation. HRV may serve as a valuable, non-invasive biomarker for the early detection and management of cardiorespiratory complications in ALS.},
}

@article {pmid41665706,
year = {2026},
author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É},
title = {Eye tracking as a digital biomarker in neurodegenerative diseases.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {133},
pmid = {41665706},
issn = {1432-1459},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology/complications ; Biomarkers ; *Eye-Tracking Technology ; *Eye Movements/physiology ; },
abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.},
}

Humans
*Neurodegenerative Diseases/diagnosis/physiopathology/complications
Biomarkers
*Eye-Tracking Technology
*Eye Movements/physiology

@article {pmid41663779,
year = {2026},
author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S},
title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41663779},
issn = {2240-2993},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.},
}

@article {pmid41657419,
year = {2026},
author = {Wang, Z and Huang, J and Yun, D},
title = {Current and emerging therapeutic strategies for amyotrophic lateral sclerosis: from pharmacological approaches to gene and stem cell therapies.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1729302},
pmid = {41657419},
issn = {1664-2295},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that involves upper and lower motor neurons, severely impairing patients' quality of life. The complex interaction of genetic and environmental factors in ALS pathophysiology complicates therapeutic development. Currently available disease-modifying pharmacological therapies for ALS offer limited efficacy, only slowing disease progression to a modest degree. The recent market withdrawal of a previously approved therapy (AMX0035) further underscores the challenges in this field. Biological targets for ALS and related neurodegenerative diseases offer a unique avenue for therapeutic intervention. With the advancement of genetic engineering technology, innovative therapies such as Stem cell therapy and gene therapy are also discussed, offering a promising horizon for ALS treatment. In addition, the management of ALS symptoms plays a key role in improving the daily lives of people with the disease. In this review, we summarize various strategies for treating ALS, providing an overview of the disease.},
}

@article {pmid41653014,
year = {2026},
author = {Abrahao, A and Ciepielewska, M and Zinman, L},
title = {Value of Clinical Evidence and Health Economics and Outcomes Research (HEOR) Studies.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S7-S12},
pmid = {41653014},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Outcome Assessment, Health Care/economics ; *Economics, Medical ; Randomized Controlled Trials as Topic ; Amyotrophic Lateral Sclerosis/therapy/economics ; *Evidence-Based Medicine/economics ; Cost-Benefit Analysis ; },
abstract = {Randomized controlled trials (RCTs) remain the gold standard for establishing the efficacy and safety of new treatments. However, clinical evidence derived from the systematic analysis of real-world data generated through routine clinical practice can complement RCT data by offering insights into treatment performance in broader, more heterogeneous patient populations and clinical care settings. The integration of high-quality clinical evidence into health economics and outcomes research (HEOR) is increasingly important, as it supports healthcare decision-making across multiple stakeholders, including regulatory agencies, payers, clinicians, and patients. Multiple study designs, such as pragmatic trials, hybrid RCTs, external control arms, and observational studies, can provide valuable clinical evidence beyond the controlled trial setting. These data can enhance understanding of comparative effectiveness, patient-reported outcomes, treatment safety, and healthcare utilization and costs. The field of amyotrophic lateral sclerosis offers a compelling example of how clinical evidence derived from global registries and clinical studies has advanced understanding of disease epidemiology, treatment patterns, and the effectiveness of therapies, including riluzole and edaravone. Consequently, this review and the associated supplementary articles are meant to serve as a primer to inform clinicians of the potential contribution of clinical evidence to HEOR studies.},
}

Humans
*Outcome Assessment, Health Care/economics
*Economics, Medical
Randomized Controlled Trials as Topic
Amyotrophic Lateral Sclerosis/therapy/economics
*Evidence-Based Medicine/economics
Cost-Benefit Analysis

@article {pmid41653010,
year = {2026},
author = {Abrahao, A and Zinman, L and Apple, S},
title = {Current and Ongoing Clinical Studies.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S26-S28},
pmid = {41653010},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; *Clinical Trials as Topic ; *Free Radical Scavengers/therapeutic use/administration & dosage ; },
abstract = {This article provides a comprehensive overview of current and ongoing studies evaluating intravenous (IV) edaravone and edaravone oral suspension in the treatment of amyotrophic lateral sclerosis (ALS). In addition to data from clinical practice and post hoc analyses, multiple observational and interventional studies are underway to better understand the efficacy, safety, and biological impact of edaravone in clinical settings. Key studies include SUNRISE Japan, a long-term postmarketing surveillance study of IV edaravone in Japanese patients with ALS; the ALS/Motor Neuron Disease Natural History Study, a longitudinal registry designed to inform clinical trial design and track ALS progression; and the REFINE-ALS study, which is actively collecting biomarker data to elucidate the pathophysiologic mechanisms influenced by edaravone. For edaravone oral suspension, United States Food and Drug Administration approval was supported by Study MT-1186-A01, a phase 3 trial assessing safety and tolerability over 48 weeks, with extension Study MT-1186-A03. Study MT-1186-A02, conducted as an FDA postmarketing commitment, and its extension, Study MT-1186-A04, evaluated whether investigational once daily dosing showed superior efficacy vs. the approved on/off dosing regimen. Collectively, these studies contribute to a growing body of evidence supporting the use of edaravone as a therapeutic option for ALS. They also underscore the importance of continued data collection from both clinical trials and clinical settings to inform optimal treatment strategies and combination therapy approaches as more agents become available in an evolving ALS treatment landscape.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Edaravone/therapeutic use
*Clinical Trials as Topic
*Free Radical Scavengers/therapeutic use/administration & dosage

@article {pmid41646005,
year = {2026},
author = {Peng, J and Fan, T and Wang, J and Deng, Y and Xu, R},
title = {Current potential biomarkers for Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: review of literature.},
journal = {Dialogues in clinical neuroscience},
volume = {28},
number = {1},
pages = {17-39},
pmid = {41646005},
issn = {1958-5969},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/diagnosis/blood/metabolism/cerebrospinal fluid ; *Parkinson Disease/diagnosis/blood/metabolism/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are several common neurodegenerative diseases (NDs). At present, is the lack of effective diagnosis, progression, prognosis and therapeutic biomarkers. it is a urgent demand to search the relevant confident biomarkers.

AREA COVERED: This review systematically analysed the potential biomarkers of blood, cerebrospinal fluid, neuroimaing and emerging non-invasive indicators, and synthesises current evidences on the biomarkers of AD, PD and ALS about diagnosis, progression, prognosis and therapeutic, especially diagnosis biomarkers.

EXPERT COMMENTARY: In this review, we focus on discussing relevant diagnosis, progression, prognosis and therapeutic biomarkers for AD, PD and ALS in recent years, and prospecting the possible future directions of relevant biomarkers.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/diagnosis/blood/metabolism/cerebrospinal fluid
*Parkinson Disease/diagnosis/blood/metabolism/cerebrospinal fluid

@article {pmid41645941,
year = {2026},
author = {Iammeechai, W and Srikulmontri, T and White, BAA},
title = {Emotional intelligence development in medical education: A scoping review of educational interventions.},
journal = {Medical teacher},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/0142159X.2026.2621214},
pmid = {41645941},
issn = {1466-187X},
abstract = {Background and aims: Emotional intelligence (EI) is an essential competency for physicians. Medical educators seek educational interventions to cultivate EI in their learners. This scoping review aimed to conceptualize current knowledge about educational interventions for developing EI in medical education. Methods: This study adopted the first five stages of Levac et al.'s scoping review framework, which builds on Arksey and O'Malley's scoping review methodology. The authors accessed three databases-PubMed, CINAHL, and PsycINFO-to review the literature from 2014 to February 2025. Two authors (WI and TS) independently screened the literature for eligibility. A third author (BAAW) resolved any discrepancies. Two authors (WI and BAAW) charted the eligible articles. Results: Of the 638 studies, 64 were eligible. Approximately one-third of eligible studies focused on interventions for medical students. Stress management, leadership, communication, and professionalism were key topics integrated into EI development interventions. Various methods were employed, such as small-group discussions, case-based discussions, and simulations. Most studies used self-rating questionnaires as assessment tools. Half of the studies (56.25%) reported positive impacts from their interventions. Conclusions: The findings could serve as a guide for educators and researchers seeking to implement or study such interventions.},
}

@article {pmid41642483,
year = {2026},
author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS},
title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01674-1},
pmid = {41642483},
issn = {1573-6830},
abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.},
}

@article {pmid41640615,
year = {2026},
author = {Wang, G and Pan, SJ},
title = {Integrative acupoint stimulation within enhanced recovery after endoscopic procedures: Harnessing the neuroimmune axis for enhanced gastrointestinal recovery.},
journal = {World journal of gastroenterology},
volume = {32},
number = {3},
pages = {114048},
pmid = {41640615},
issn = {2219-2840},
mesh = {Humans ; *Acupuncture Points ; Recovery of Function ; *Enhanced Recovery After Surgery ; *Gastrointestinal Tract/innervation/surgery/immunology ; Neuroimmunomodulation ; Randomized Controlled Trials as Topic ; *Perioperative Care/methods ; Hypothalamo-Hypophyseal System/immunology ; *Transcutaneous Electric Nerve Stimulation/methods ; Pituitary-Adrenal System ; *Endoscopy, Gastrointestinal/adverse effects ; Treatment Outcome ; },
abstract = {Enhanced recovery after surgery (ERAS) programs have transformed perioperative care, yet delayed gastrointestinal function and excessive neuroendocrine stress remain major obstacles to optimal recovery. Hong et al's randomized controlled trial embedded acupoint-based neuromodulation - meridian-timed acupoint application combined with transcutaneous electrical acupoint stimulation - within an ERAS framework and demonstrated accelerated gastrointestinal recovery accompanied by endocrine attenuation. This article offers a structured critical appraisal of the trial, emphasizing methodological rigor, mechanistic plausibility, and alignment with ERAS core principles of stress mitigation, functional restoration, and patient experience. The observed reductions in norepinephrine, cortisol, and aldosterone suggest modulation of the hypothalamic-pituitary-adrenal axis as a key mediator of benefit. Future research priorities include multicenter, sham-controlled validation; integration of autonomic and inflammatory biomarkers (heart rate variability, interleukin-6, tumor necrosis factor-α, C-reactive protein); and pragmatic evaluation of cost-effectiveness and acceptability. Positioning acupoint stimulation within precision-integrative perioperative care could advance ERAS from a recovery protocol to a system of host-response modulation. Integrative acupoint neuromodulation thus represents a biologically coherent, low-risk, and scalable strategy for enhancing resilience, accelerating gastrointestinal recovery, and improving surgical outcomes worldwide.},
}

Humans
*Acupuncture Points
Recovery of Function
*Enhanced Recovery After Surgery
*Gastrointestinal Tract/innervation/surgery/immunology
Neuroimmunomodulation
Randomized Controlled Trials as Topic
*Perioperative Care/methods
Hypothalamo-Hypophyseal System/immunology
*Transcutaneous Electric Nerve Stimulation/methods
Pituitary-Adrenal System
*Endoscopy, Gastrointestinal/adverse effects
Treatment Outcome

@article {pmid41640104,
year = {2026},
author = {Karros, M and DiFulco, M and Nogid, A},
title = {Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.},
journal = {The Annals of pharmacotherapy},
volume = {},
number = {},
pages = {10600280251408862},
doi = {10.1177/10600280251408862},
pmid = {41640104},
issn = {1542-6270},
abstract = {OBJECTIVE: This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).

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

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

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

CONCLUSION: Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.},
}

@article {pmid41639687,
year = {2026},
author = {Zhang, N and Su, WM and Chen, T and Zhang, Q and Cao, B and Wang, Y and Chen, YP},
title = {From pathogenesis to therapy: the emerging role of regulatory T cells in amyotrophic lateral sclerosis.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {50},
pmid = {41639687},
issn = {1742-2094},
support = {82371422//National Natural Science Fund of China/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023HXFH032//1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; },
abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord, with a pathogenesis that remains incompletely understood. Increasing evidence in recent years has highlighted the pivotal role of neuroinflammation in ALS, in which regulatory T cells (Tregs) emerge as key modulators of the neuroimmune response. This review systematically summarizes recent advances in understanding Treg biology in ALS, including their dynamic alterations across different disease stages and their potential immunoregulatory mechanisms, while also highlighting ongoing clinical trials and emerging cellular therapeutic strategies targeting Tregs. Current evidence suggests that Tregs not only participate in the immunopathology of ALS but also represent a promising target for therapeutic intervention. Nevertheless, there are still significant challenges, including incomplete mechanistic insights, limited clinical validation and obstacles to the implementation of Treg-based therapies. Overall, Treg research in ALS provides valuable directions for elucidating disease mechanisms and developing novel immune-based interventions.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid41635116,
year = {2026},
author = {Wang, Y and Lipton, SA},
title = {Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.},
journal = {Journal of neurochemistry},
volume = {170},
number = {2},
pages = {e70365},
doi = {10.1111/jnc.70365},
pmid = {41635116},
issn = {1471-4159},
support = {DP1 DA041722/DA/NIDA NIH HHS/United States ; R01 DA048882/DA/NIDA NIH HHS/United States ; ReMIND-L DISC4 16292//California Institute for Regenerative Medicine/ ; R01 AG056259/AG/NIA NIH HHS/United States ; R01 AG078756/AG/NIA NIH HHS/United States ; R35 AG071734/AG/NIA NIH HHS/United States ; R56 AG065372/AG/NIA NIH HHS/United States ; RF1 AG057409/AG/NIA NIH HHS/United States ; U01 AG088679/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; /NH/NIH HHS/United States ; },
mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; *Mutation/genetics ; *Protein Processing, Post-Translational/genetics ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.},
}

Humans
*Neurodegenerative Diseases/genetics/metabolism
Animals
*Mutation/genetics
*Protein Processing, Post-Translational/genetics

@article {pmid41633676,
year = {2025},
author = {Šoša, I and Sergi, CM},
title = {Genomics for Sudden Cardiac Death: A Review of the Topic and Call for Increased Professionalism in Clinico-Molecular Autopsy and Forensic Laboratory Sciences.},
journal = {Annals of clinical and laboratory science},
volume = {55},
number = {6},
pages = {859-868},
pmid = {41633676},
issn = {1550-8080},
mesh = {Humans ; *Death, Sudden, Cardiac/pathology ; *Genomics/methods ; Autopsy ; *Professionalism ; Gene Frequency ; *Forensic Genetics ; Genome, Human/genetics ; },
abstract = {In 2001, the first draft sequence of the human genome was released, the culmination of a decade-long, multibillion-dollar effort. Since then, an OMICs platform has been proposed to further evaluate and edit the human genome for diagnostic and therapeutic purposes. The Human Genome Project opened a Pandora's box, expanding the forensic laboratory physicians' toolbox. Kinship analysis has been used extensively for parentage testing and identifying cases of human remains and missing persons. The Combined DNA Index System has played a significant role in forensic DNA databases. Nanopore sequencing and improved genomic tools aid enormously in identifying amplicons from degraded samples. The application of genomics in determining the potential channelopathies of sudden cardiac death (SCD) has been an enormous step forward in recent years in forensic histopathology. We reviewed the literature. Kong et al.'s meta-analysis of the mean allele frequencies of SCN5A, NOS1AP, KCNH2, KCNE1, and KCNQ1 genes across Black, Caucasian, Asian, and Hispanic ethnicities has been pivotal to forensic science in the last decade. The authors used sequenced genomic data from the Exome Aggregation Consortium to compare allele frequencies between different ethnicities. They found that Asians had the highest overall mean allele frequencies for NOS1AP and SCN5A, Caucasians had the highest KCNH2 frequency, and Hispanics had the highest KCNQ1 frequency. In 2026, the call for increased professionalism in clinico-molecular autopsy and forensic laboratory sciences is driven by rapid technological advancements (e.g., forensic molecular genomic autopsies), critical workforce shortages in some geographical areas, and the increasing complexity of death investigations. This professionalization focuses on standardizing molecular protocols, enhancing ethical frameworks, and addressing the need for specialized interdisciplinary expertise.},
}

Humans
*Death, Sudden, Cardiac/pathology
*Genomics/methods
Autopsy
*Professionalism
Gene Frequency
*Forensic Genetics
Genome, Human/genetics

@article {pmid41629214,
year = {2026},
author = {Malard, F},
title = {Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {27},
number = {2},
pages = {e202500774},
pmid = {41629214},
issn = {1439-7633},
mesh = {Humans ; *N-Acetylglucosaminyltransferases/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy ; *Aging/metabolism/genetics ; RNA, Messenger/metabolism/genetics ; RNA Splicing ; Animals ; },
abstract = {The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.},
}

Humans
*N-Acetylglucosaminyltransferases/genetics/metabolism
*Neurodegenerative Diseases/metabolism/genetics/drug therapy
*Aging/metabolism/genetics
RNA, Messenger/metabolism/genetics
RNA Splicing
Animals

@article {pmid41569095,
year = {2026},
author = {Charbonnel, T and Richard, E and Dupuis, A and Palla, M and Vourc'h, P and Corcia, P and Al Ojaimi, Y and Blasco, H},
title = {The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt?.},
journal = {Expert opinion on drug discovery},
volume = {21},
number = {2},
pages = {147-160},
doi = {10.1080/17460441.2026.2619067},
pmid = {41569095},
issn = {1746-045X},
mesh = {*Edaravone/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; Animals ; *Neuroprotective Agents/pharmacology/administration & dosage ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/administration & dosage/pharmacokinetics ; Drug Development/methods ; Drug Discovery/methods ; Oxidative Stress/drug effects ; Mice, Transgenic ; Mice ; Drug Evaluation, Preclinical ; Blood-Brain Barrier/metabolism ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with limited therapeutic options. Among the few approved drugs, edaravone, a free radical scavenger developed originally for ischemic stroke, has attracted particular attention for its ability to counteract oxidative stress, a key driver of neurodegeneration. Its amphipathic structure and ability to cross the blood-brain barrier support its potential neuroprotective action.

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

EXPERT OPINION: Clinically, edaravone provides modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges in ALS drug discovery, including limited model predictivity, methodological variability, and lack of patient stratification. The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS.},
}

*Edaravone/pharmacology/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology
Humans
Animals
*Neuroprotective Agents/pharmacology/administration & dosage
Disease Models, Animal
Free Radical Scavengers/pharmacology/administration & dosage/pharmacokinetics
Drug Development/methods
Drug Discovery/methods
Oxidative Stress/drug effects
Mice, Transgenic
Mice
Drug Evaluation, Preclinical
Blood-Brain Barrier/metabolism

@article {pmid41622338,
year = {2026},
author = {Salehcheh, M and Nikravesh, M and Aghebat-Bekheir, S and Matin, M},
title = {Manganese concentrations in biological matrices and amyotrophic lateral sclerosis (ALS): a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {2},
pages = {216},
pmid = {41622338},
issn = {1590-3478},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/blood ; Humans ; *Manganese/blood/metabolism/analysis ; },
abstract = {BACKGROUND: Manganese (Mn) is an essential but neurotoxic trace element implicated in neurodegenerative disorders. Its association with amyotrophic lateral sclerosis (ALS) remains uncertain. We conducted a systematic review and meta-analysis to evaluate whether Mn concentrations differ between ALS patients and healthy controls.

METHODS: We systematically searched PubMed, EMBASE, Web of Science, and Scopus for observational studies comparing Mn concentrations between ALS patients and healthy controls. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Heterogeneity was assessed with the I² statistic, and publication bias was evaluated by Egger's test.

RESULTS: Twelve studies (446 ALS cases, 652 controls) measuring Mn in blood, serum, cerebrospinal fluid (CSF), hair, urine, toenail, plasma, or tissue were included. The pooled SMD was 0.05 (95% CI: - 0.20 to 0.30; p = 0.68; I² = 71.7%), indicating no significant difference in Mn concentrations. Subgroup analyses by biological matrix and analytical method showed no consistent pattern; meta-regression identified analytical method as a significant source of heterogeneity.

CONCLUSION: No publication bias was detected (Egger's p = 0.53). Peripheral Mn concentrations do not differ significantly between ALS patients and controls. Future research should employ longitudinal and CNS-targeted approaches, incorporating occupational exposure assessment and standardized analytical protocols.},
}

*Amyotrophic Lateral Sclerosis/metabolism/blood
Humans
*Manganese/blood/metabolism/analysis

@article {pmid41621017,
year = {2026},
author = {Aynaashe, A and Kursula, P},
title = {Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.},
journal = {Amino acids},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00726-026-03500-w},
pmid = {41621017},
issn = {1438-2199},
abstract = {Amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT) are two distinct neurodegenerative disorders. While ALS is characterised by rapidly progressive motor neuron degeneration, leading to severe complications and death, CMT as a peripheral neuropathy is less severe, and patients have a longer life span, although with a compromised quality of life. Despite their clinical differences, current knowledge suggests that familial ALS (fALS) and CMT may share common genetic and molecular mechanisms. We aimed to identify shared genes mutations and molecular pathways between fALS and CMT through a literature and database search. Thirteen genes were identified, involved in distinct cellular processes: axonal transport (DYNC1H1, KIF5A, SPG11, DCTN1), protein homeostasis (NEFH, VCP, SOD1), RNA metabolism (GARS, SETX), cellular stress response (HSPB1, FIG4), and mitochondrial function (MFN2, CHCHD10). While these linkages to the two diseases are rare for each gene, understanding possible mechanistic commonalities at the molecular level can initiate new research directions, help in identifying additional common genes between neurodegenerative disorders, and improve diagnostics.},
}

@article {pmid41619791,
year = {2026},
author = {Yazdani, S and Seitz, C and Andersson, J and Ingre, C and Fang, F and Lovik, A},
title = {Methodological considerations in the analysis of survival data in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/21678421.2026.2615111},
pmid = {41619791},
issn = {2167-9223},
abstract = {Survival outcomes are commonly analyzed in studies with data from patients with progressive, neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Given the fast progression of ALS, survival analyses are, however, often difficult to perform and interpret. In this methodological article we demonstrate on real-world data how the choices we make in the study design, data collection, and analysis could influence the results. The factors we consider in this study are length of follow-up, sample size, timing of sample collection, and choice of covariables adjusted for in the models. We further discuss the importance of each of these contributing factors and about how to avoid mistakes in interpreting and reporting survival data in ALS and other rare, progressive diseases.},
}

@article {pmid41558230,
year = {2026},
author = {Ye, J},
title = {Beyond binary diagnosis: Key questions on AI accuracy, real-world applicability, and safety in clinical decision support.},
journal = {International journal of medical informatics},
volume = {209},
number = {},
pages = {106292},
doi = {10.1016/j.ijmedinf.2026.106292},
pmid = {41558230},
issn = {1872-8243},
mesh = {*Artificial Intelligence ; *Decision Support Systems, Clinical ; Humans ; *Patient Safety ; },
abstract = {This comment relates to Kücking et al.'s (2026) study on the bidirectional effects of artificial intelligence recommendations and healthcare provider related factors on the accuracy of wound impregnation diagnosis. While acknowledging the valuable contributions of this research, including distinguishing between correct/incorrect artificial intelligence outputs, rigorous simulation design, and emphasis on clinical safety, we have raised key questions to enhance the interpretation of results and real-world translation. The main focuses include the moderating role of artificial intelligence system accuracy in automation bias, external effectiveness in real clinical environments, potential mechanisms for gender differences in diagnostic performance, the impact of visual cue design on decision-making, and the potential of explainable artificial intelligence (XAI) in risk mitigation. This review aims to promote further research and facilitate the safe and effective integration of artificial intelligence based clinical decision support systems (CDSS) into clinical practice.},
}

*Artificial Intelligence
*Decision Support Systems, Clinical
Humans
*Patient Safety

@article {pmid40740123,
year = {2026},
author = {Giacomelli, E and Scirocco, E and Higgins, M and Pilja, A and Paganoni, S and Ho, D},
title = {Research access barriers in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {27},
number = {1-2},
pages = {207-214},
doi = {10.1080/21678421.2025.2539900},
pmid = {40740123},
issn = {2167-9223},
mesh = {*Amyotrophic Lateral Sclerosis/therapy/epidemiology ; Humans ; *Biomedical Research ; *Health Services Accessibility ; },
abstract = {As the general population ages, amyotrophic lateral sclerosis (ALS) incidence and prevalence are expected to rise, and the barriers that limit participation in ALS clinical research studies may increase. In this report, we highlight key challenges and available resources for accessing clinical research. We emphasize the importance of education and engagement among individuals with ALS and their families, clinicians, and researchers. Addressing accessibility and fostering trust in ALS research participation is essential to advance treatments for this devastating disease. We propose practical strategies to overcome participation barriers, including decentralized trial models, remote participation options, and expanded outreach through patient navigators, advisory committees, and digital tools. Strengthening partnerships among individuals with ALS, caregivers, researchers, ALS organizations, regulators, and industry, will help align research efforts with community needs and accelerate therapeutic development.},
}

*Amyotrophic Lateral Sclerosis/therapy/epidemiology
Humans
*Biomedical Research
*Health Services Accessibility

@article {pmid40517187,
year = {2026},
author = {Haro-Martínez, E and Muscolino, E and Moral, N and Duran, J and Fornaguera, C},
title = {Crossing the blood-brain barrier: nanoparticle-based strategies for neurodegenerative disease therapy.},
journal = {Drug delivery and translational research},
volume = {16},
number = {3},
pages = {797-824},
pmid = {40517187},
issn = {2190-3948},
support = {2021 SGR 00537//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 2024-LLAV-00042//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; ICREA Acadèmia 2024//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 202207-31//Fundació la Marató de TV3/ ; PID2020-118699GB-100//Agencia Estatal de Investigación/ ; Not specified//Fundación Ramón Areces/ ; FISDUR-2024//Departament d'Universitats, Recerca i Societat de la Informació/ ; },
mesh = {Humans ; *Blood-Brain Barrier/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Nanoparticles/administration & dosage/chemistry ; Drug Delivery Systems ; Drug Carriers/chemistry ; },
abstract = {Neurodegenerative conditions, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease, represent a critical medical challenge due to their increasing prevalence, severe consequences, and absence of curative treatments. Beyond the need for a deeper understanding of the fundamental mechanisms underlying neurodegeneration, the development of effective treatments is hindered by the blood-brain barrier, which poses a major obstacle to delivering therapeutic agents to the central nervous system. This review provides a comprehensive analysis of the current landscape of nanoparticle-based strategies to overcome the blood-brain barrier and enhance drug delivery for the treatment of neurodegenerative diseases. The nanocarriers reviewed in this work encompass a diverse array of nanoparticles, including polymeric nanoparticles (e.g. micelles and dendrimers), inorganic nanoparticles (e.g. superparamagentic iron oxide nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, selenium and cerium oxide nanoparticles), lipid nanoparticles (e.g. liposomes, solid lipid nanoparticles, nanoemulsions), as well as quantum dots, protein nanoparticles, and hybrid nanocarriers. By examining recent advancements and highlighting future research directions, we aim to shed light on the promising role of nanomedicine in addressing the unmet therapeutic needs of these diseases.},
}

Humans
*Blood-Brain Barrier/metabolism
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Nanoparticles/administration & dosage/chemistry
Drug Delivery Systems
Drug Carriers/chemistry

@article {pmid41619021,
year = {2026},
author = {Dressler, D and Frevert, J and Johnson, EA and Fink, K and Pellett, S and Pandey, S and Walter, U and Tacik, P and Kanovsky, P and Shahidi, GA and Brüggemann, N and Rosales, RL and Relja, M and Jin, L and Rodriguez, JAS and Pan, L and Francisco, GE and Shang, H and Bai, X and Adib Saberi, F},
title = {Iatrogenic botulism: a risk for botulinum toxin's medical use?.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41619021},
issn = {1435-1463},
abstract = {Botulinum toxin (BT) is infamous for its extreme toxicity. If it enters the bloodstream, it can cause botulism presenting with a typical pattern of motor and autonomic dysfunction. An international expert panel organised by IAB-Interdisciplinary Working Group for Movement Disorders explored iatrogenic botulism after BT's medical use (IB), reached conclusions and formulated recommendations. When injected into its target tissue, BT binds to gangliosides on cholinergic nerve terminals before it is internalised permanently. Small amounts of BT, however, are circulating within the bloodstream. When BT type B is applied, IB-B occurs frequently, typically affecting the autonomic nervous system. When BT type A is applied, IB-A only occurs in special circumstances, even when high doses are used. We identified 236 patients with IB-A in the literature. All IB-A was mild or moderate and fully reversible. In 212 patients, it occurred with unapproved BT use. In 116 of them, unapproved BT preparations were used, in 81, unapproved indications were treated and in 15, underlying neuromuscular impairment including myasthenia gravis, Lambert-Eaton myasthenic syndrome, amyotrophic lateral sclerosis and spinal muscle atrophy were contraindications for BT use. In 24 patients, IB-A occurred in approved BT use. Their evaluation was frequently incomplete, so that causes for IB-A often remain unclear. They may include presence of differential diagnosis, subclinical neuromuscular impairment and interference with additional diseases. When IB is suspected, proper evaluation is necessary to verify it and to identify its causes. Off-label use is common in BT therapy. However, it should be performed with caution, especially in children and when high doses are applied. High BT doses should not be applied to low volumes of target tissues, in order not to exceed the BT binding capacity.},
}

@article {pmid41618645,
year = {2026},
author = {Verhoeff, MC and van Selms, MKA and Lobbezoo, F},
title = {A Personal Exploration of Oral Health in Amyotrophic Lateral Sclerosis (ALS) Through the Eyes of a Multifaceted Authority.},
journal = {Journal of oral rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1111/joor.70157},
pmid = {41618645},
issn = {1365-2842},
abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that impairs motor function, including oral musculature, complicating oral hygiene and care. Despite its impact, oral health in ALS patients remains under-addressed. This personal scoping review explores oral health in ALS through the dual lens of Dr. Maurits K.A. van Selms-a dental researcher and ALS patient-highlighting care, research, and education priorities.

METHODS: Semi-structured interviews were conducted via email with Dr. van Selms, using a topic guide adapted from a prior personal scoping review. The interview covered personal experiences and professional insights into oral health care, research, and education in ALS. Responses were analysed and synthesised into thematic agendas.

RESULTS: Dr. van Selms emphasised the neglect of oral hygiene in ALS care. He advocated for patient-informed, tailored guidelines based on functional capacity, interdisciplinary collaboration, and improved accessibility to dental services. In research, he called for ethically sensitive, patient-centered studies that reduce the burden of oral care. Educationally, he stressed the need for inclusive training across disciplines and stakeholder levels, promoting self-advocacy and awareness. Instructional materials, such as videos, were recommended to support caregivers and patients.

CONCLUSION: This personal scoping review underscores the importance of integrating oral health into ALS management. Dr. van Selms' unique perspective reveals gaps in care delivery, research ethics, and education, advocating for interdisciplinary collaboration and proactive guideline development. His insights offer a roadmap for improving oral health outcomes and quality of life in ALS and similar neurodegenerative conditions.},
}

@article {pmid41613186,
year = {2025},
author = {An, W and Jin, Z and Li, Y},
title = {Dual role of exosomes in neurodegenerative diseases: a molecular bridge between neuroinflammation and transmission of pathological proteins.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1708655},
pmid = {41613186},
issn = {1664-2295},
abstract = {Neurodegenerative diseases (NDDs) are complex disorders characterized by the progressive loss of neuronal function. Their pathological mechanisms involve multiple levels, including neuroinflammation, abnormal protein aggregation, and disrupted cell signaling. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis (MS), and prion diseases not only severely impact patients' quality of life but also pose significant challenges for medical research due to their complex pathogenesis and the lack of effective treatments. In recent years, extracellular vesicles (EVs), particularly exosomes, have garnered increasing attention for their critical role in cell-to-cell communication. Exosomes are membrane-enclosed nanovesicles approximately 30-150 nm in diameter that can carry proteins, lipids, nucleic acids, and other bioactive molecules, influencing recipient cells through paracrine or distant signaling. This review aims to summarize the roles of exosomes as mediators of neuroinflammation and as vehicles for intercellular transmission of pathogenic proteins in neurodegenerative diseases.},
}

@article {pmid40908696,
year = {2025},
author = {Paul, S and Tiwari, P and Dubey, S},
title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.},
journal = {Protein and peptide letters},
volume = {32},
number = {8},
pages = {539-556},
pmid = {40908696},
issn = {1875-5305},
mesh = {Humans ; *Drug Discovery/methods ; *Neurodegenerative Diseases/drug therapy/enzymology ; Molecular Docking Simulation ; *Enzyme Inhibitors/chemistry/therapeutic use/pharmacology ; Animals ; },
abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management.

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

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

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

CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.},
}

Humans
*Drug Discovery/methods
*Neurodegenerative Diseases/drug therapy/enzymology
Molecular Docking Simulation
*Enzyme Inhibitors/chemistry/therapeutic use/pharmacology
Animals

@article {pmid41612406,
year = {2026},
author = {Bigi, A and Chiti, F},
title = {Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.},
journal = {Genome biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13059-026-03956-9},
pmid = {41612406},
issn = {1474-760X},
support = {#NEXTGENERATIONEU (NGEU) - National Recovery and Resilience Plan (NRRP), Investment PE8─Project Age-It: "Ageing Well in an Ageing Society" (D.R. 1557 11.10.2022).//Ministero dell'Università e della Ricerca/ ; Fondi di Ateneo RICATEN 2024 and RICATEN 2025//Università degli Studi di Firenze/ ; Fondi di Ateneo RICATEN 2023, RICATEN 2024 and RICATEN 2025//Università degli Studi di Firenze/ ; },
abstract = {Phase separation is an important process in biology associated with formation of membraneless organelles but possibly related to the emergence of solid inclusions. TDP-43 is a largely studied paradigmatic case, as it forms neuronal cytoplasmic inclusions in neurodegenerative diseases and is an essential component of many membraneless organelles. Here, we review the physicochemical fundamentals of liquid-liquid phase separation (LLPS) of TDP-43 and its fragments in vitro, showing that full-length TDP-43 requires RNA or chaperones to form stable liquid droplets. We describe TDP-43-containing membraneless organelles and the debate on whether these assemblies represent reservoirs for pathological solid inclusion formation.},
}

@article {pmid41605610,
year = {2026},
author = {Oreskovic, E and Petzold, A and Petropoulos, IN and Hau, S},
title = {Corneal confocal microscopy as a paraclinical test in neurodegenerative disease: a scoping review.},
journal = {The British journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1136/bjo-2025-328181},
pmid = {41605610},
issn = {1468-2079},
abstract = {Corneal confocal microscopy (CCM) is a non-invasive imaging technique that enables quantification of the corneal sub-basal nerve plexus and has emerged as a potential surrogate biomarker for peripheral neurodegeneration. This scoping review evaluated current evidence on the use of CCM in assessing corneal nerve fibre changes across neurodegenerative diseases (NDDs) and explored its potential as a paraclinical diagnostic and monitoring tool. A comprehensive search of PubMed and Scopus was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines to identify studies reporting quantitative CCM metrics, including corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL). Both cross-sectional and longitudinal studies of patients with NDDs were included, and findings were narratively synthesised. 50 studies were included: Parkinson's disease (n=13), multiple sclerosis (n=11), cerebrovascular accidents (n=7), post-COVID-19 neuropathy (n=5), amyotrophic lateral sclerosis (n=4), chronic inflammatory demyelinating polyneuropathy (n=4), Alzheimer's disease (n=3), Fabry disease (n=2) and neurofibromatosis type 1 (n=1). CNFL and CNFD were consistently reduced in Parkinson's disease, multiple sclerosis, cerebrovascular accidents, amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy and post-COVID-19 neuropathy, whereas CNBD results were inconsistent. The strongest evidence supported the role of CCM in Parkinson's disease and multiple sclerosis. CNFL and CNFD emerged as the most reliable CCM-derived metrics across NDDs, supporting their potential as objective biomarkers for neurodegeneration. While findings support the potential of CCM as a paraclinical diagnostic tool, methodological heterogeneity in image acquisition, analysis software and study design limited comparability. Standardised imaging and analysis protocols are needed to enable broader clinical application and validation across NDDs.},
}

@article {pmid41604971,
year = {2026},
author = {Ahamad, S and Akshinthala, P and Fazal, F and Sah, GK and Khan, MH and Upadhyay, A and Bhat, SA and Hussain, MK},
title = {Small-molecule-based activation of Wnt/β-catenin signaling: An underexplored yet promising strategy for neuroprotection.},
journal = {Bioorganic chemistry},
volume = {170},
number = {},
pages = {109540},
doi = {10.1016/j.bioorg.2026.109540},
pmid = {41604971},
issn = {1090-2120},
abstract = {The Wnt/β-catenin pathway regulates key processes such as neurogenesis, synaptic plasticity, and neuroinflammation, each disrupted in neurodegenerative disorders like AD, PD, ALS, and stroke. Small molecules have shown potential to restore this signaling axis and confer neuroprotection. While these molecules modulate Wnt activity, none has achieved FDA approval, primarily due to poor brain permeability, off-target effects, and insufficient biomarker-based validation. Moreover, current strategies remain disproportionately focused on GSK-3β, with other viable targets, such as DKK1, NOTUM, SFRP-1, sclerostin, and Dvl-CXXC5 or Axin-β-catenin interactions, largely underexplored. Natural products, particularly flavonoids and diterpenoids, offer valuable scaffolds; however, their SAR remain poorly characterized, and promising synthetic leads often lack further development. This review highlights recent pharmacological advances, emerging molecular targets, and key translational barriers. Future success will depend on optimizing pharmacokinetics, improving brain-targeted delivery, and integrating biomarker-driven strategies into clinical trial design.},
}

@article {pmid41604235,
year = {2026},
author = {Al-Ameer, HJ and Basheer, NM and H, M and Shankhyan, A and Panigrahi, R and Arora, V and Azizjanov, K and Eshchanov, E and Ataullaev, Z},
title = {Neuroimmune Cross-Talk and Multilevel Cascades in Fentanyl Toxicity: Interplay of Hypoxic Stress, Glial Activation, and Synaptic Dysregulation in Systems-Level Neurodegeneration.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70069},
pmid = {41604235},
issn = {1099-1263},
abstract = {Fentanyl, an ultra-potent synthetic opioid, has traditionally been characterized by its acute toxic effects, particularly respiratory depression. However, accumulating research indicates that its neurobiological influence extends far beyond its short pharmacological window, intersecting with several core mechanisms implicated in major neurodegenerative disorders. This review integrates multiscale evidence to propose a unified conceptual framework in which fentanyl may function not only as an acute neurotoxin but also as a putative accelerator of long-term neurodegenerative vulnerability. Drawing from molecular signaling, cellular stress pathways, glial-neuronal cross-talk, neurovascular regulation, synaptic architecture, and large-scale neural networks, we highlight fentanyl's capacity to trigger a convergent cascade encompassing hypoxic-metabolic reprogramming, mitochondrial fragmentation, TLR4-NF-κB-driven inflammation, NLRP3 inflammasome activation, complement-mediated synaptic pruning, astrocytic EAAT2 downregulation, and blood-brain barrier compromise. These alterations propagate through recursive cross-talk loops that progressively diminish neuronal resilience, destabilize oscillatory coherence, and weaken circuit-level adaptability. Importantly, mechanistic overlaps with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis suggest that fentanyl exposure may be mechanistically associated with processes capable of accelerating disease onset, exacerbating progression, or unmasking latent vulnerabilities, particularly in genetically or metabolically predisposed individuals. By reframing fentanyl as a systems-level destabilizer capable of imprinting persistent neurobiological changes, this model underscores the need for comprehensive biomarker development, longitudinal risk assessment, and targeted neuroprotective interventions. The integrative framework presented herein offers a foundation for predicting the long-term neurological consequences of fentanyl exposure and calls for urgent reconsideration of its role in population-level neurodegenerative risk.},
}

@article {pmid41601803,
year = {2025},
author = {An, X and Hou, D and Miao, MY and Zhou, YM and Qi, S and Zhang, L and Li, H and Zhou, JX},
title = {Noninvasive monitoring of inspiratory effort in mechanical ventilation: a dual-database bibliometric analysis from 1990 to 2025.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1747437},
pmid = {41601803},
issn = {2296-858X},
abstract = {INTRODUCTION: This study conducts a bibliometric analysis to map the intellectual structure, evolution, and emerging trends in research on airway pressure-based indexes for monitoring inspiratory effort.

METHODS: Systematic searches of the Web of Science Core Collection (WOSCC) and Pubmed were performed for publications dated between 1990 and 2025. Bibliometric parameters, including publication trends, country and affiliation contributions, author influence, journal distribution, keyword co-occurrence, and reference co-citation networks, were analyzed using Bibliometrix and CiteSpace.

RESULTS: The analysis included 291 publications from WOSCC. The annual publication output showed a near U-shaped trend, with an initial decline after the 1990s, followed by a strong resurgence after 2011. Italy was the most productive country, followed by the USA and France. The Institut National de la Sante et de la Recherche Medicale emerged as the leading institution. The journal Chest published the most articles, while the American Journal of Respiratory and Critical Care Medicine had the highest total citations. Laurent Brochard was identified as the most prolific and influential author. Keyword analysis highlighted "occlusion pressure" and "mechanical ventilation" as core themes. Reference co-citation clustering revealed major research domains, including "acute respiratory distress syndrome," "self-inflicted lung injury," and "nasal high flow." Burst detection analysis indicated that "respiratory drive," "lung injury," and "critically ill patients" are emerging research frontiers. Complementary analysis of 242 PubMed clinical studies confirmed these trends and highlighted growing clinical focus on "fluid responsiveness" and "amyotrophic lateral sclerosis."

CONCLUSION: Research on airway pressure-based indices has evolved from physiological studies into a crucial clinical tool for respiratory monitoring. The field exhibits strong international collaboration and emphasizes core areas, including acute respiratory failure and lung-protective ventilation. Analysis of clinical study data confirms these trends and highlights emerging applications in the assessment of fluid responsiveness and neuromuscular disorders. These findings support the ongoing development of personalized ventilation strategies based on monitoring respiratory effort.},
}

@article {pmid41601624,
year = {2025},
author = {Yang, J and Song, X and Yan, S and Li, Q and Yang, W},
title = {The gut microbiota influences neurodegenerative diseases through the gut-brain axis: molecular mechanisms and effects on immune function.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1739329},
pmid = {41601624},
issn = {1664-3224},
mesh = {Humans ; *Gastrointestinal Microbiome/immunology ; *Neurodegenerative Diseases/immunology/microbiology/therapy/metabolism/etiology ; Animals ; *Brain/immunology/metabolism ; *Brain-Gut Axis/immunology ; Fecal Microbiota Transplantation ; Probiotics/therapeutic use ; Prebiotics ; },
abstract = {The pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is complex and multifactorial. Recent studies indicate that the microbiota-gut-brain axis (MGBA) plays a crucial role in the development and progression of NDDs. The MGBA concept reveals a complex bidirectional regulatory network between the gut microbiota and the central nervous system (CNS), linking them through immune, neural, endocrine, and metabolic pathways. This review summarizes the components of the MGBA, communication pathways between gut microbiota and the brain, and mechanisms by which gut microbiota influence the onset and progression of NDDs. Finally, preclinical therapeutic approaches for NDDs are discussed, evaluating preclinical trial data for probiotics, prebiotics, and fecal microbiota transplantation.},
}

Humans
*Gastrointestinal Microbiome/immunology
*Neurodegenerative Diseases/immunology/microbiology/therapy/metabolism/etiology
Animals
*Brain/immunology/metabolism
*Brain-Gut Axis/immunology
Fecal Microbiota Transplantation
Probiotics/therapeutic use
Prebiotics

@article {pmid41599691,
year = {2026},
author = {Zhao, X and Zheng, Y and Cai, X and Yao, Y and Qin, D},
title = {The Expanding Role of Non-Coding RNAs in Neurodegenerative Diseases: From Biomarkers to Therapeutic Targets.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
pmid = {41599691},
issn = {1424-8247},
support = {Y202248634//Zhejiang Provincial Department of Education Project/ ; Y202454271//Zhejiang Provincial Department of Education Project/ ; },
abstract = {Non-coding RNAs have emerged as central regulators of gene expression in neurodegenerative diseases, offering new opportunities for diagnosis and therapy. This review synthesizes current knowledge on microRNAs, long non-coding RNAs, and circular RNAs in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, emphasizing their roles in synaptic function, proteostasis, mitochondrial biology, and neuroinflammation. We evaluate evidence supporting non-coding RNAs as circulating and tissue-based biomarkers for early detection, disease monitoring, and patient stratification, and we compare analytical platforms and biofluid sources. Mechanistic insights reveal how non-coding RNAs modulate pathogenic protein aggregation, neuronal excitability, immune cell crosstalk, and blood-brain barrier integrity. Translational efforts toward RNA-targeted interventions are reviewed, including antisense oligonucleotides, small interfering RNAs, miRNA mimics and inhibitors, circular RNA decoys, and extracellular vesicle-mediated delivery systems. We discuss pharmacological modulation, delivery challenges, safety concerns, and strategies to enhance specificity and CNS penetration. Finally, we outline emerging computational and multi-omics approaches to prioritize therapeutic targets and propose a roadmap for advancing non-coding RNA research from preclinical models to clinical trials. Addressing biological heterogeneity and delivery barriers will be pivotal to realizing the diagnostic and therapeutic promise of the non-coding transcriptome in neurodegenerative disease. Collaboration across disciplines and rigorous clinical validation are urgently needed.},
}

@article {pmid41599368,
year = {2026},
author = {Niziński, P and Szalast, K and Makuch-Kocka, A and Paruch-Nosek, K and Ciechanowska, M and Plech, T},
title = {Experimental Models and Translational Strategies in Neuroprotective Drug Development with Emphasis on Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {2},
pages = {},
pmid = {41599368},
issn = {1420-3049},
support = {2022/47/O/NZ7/00155//National Science Centre/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drug Development ; Animals ; *Translational Research, Biomedical ; Disease Models, Animal ; Induced Pluripotent Stem Cells ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002-2012) estimated ~99.6% attrition, while PD programs (1999-2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron-glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood-brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Neuroprotective Agents/pharmacology/therapeutic use
*Drug Development
Animals
*Translational Research, Biomedical
Disease Models, Animal
Induced Pluripotent Stem Cells

@article {pmid41599225,
year = {2026},
author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K},
title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
pmid = {41599225},
issn = {1999-4923},
support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; },
abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.},
}

@article {pmid41599185,
year = {2026},
author = {Benech, H and Flament, V and Lhotellier, C and Roucairol, C and Joudinaud, T},
title = {New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
pmid = {41599185},
issn = {1999-4923},
abstract = {Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.},
}

@article {pmid41596533,
year = {2026},
author = {Bogus, K and Marchesi, N and Campagnoli, LIM and Pascale, A and Pałasz, A},
title = {Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
pmid = {41596533},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; },
abstract = {Neurodegenerative disorders are characterized by progressive neuronal loss and dysfunction, yet increasing evidence indicates that glial cells are central mediators of both disease initiation and progression. Astrocytes, microglia, and oligodendrocyte lineage cells modulate neuronal survival by regulating neuroinflammation, metabolic support, synaptic maintenance, and proteostasis. However, dysregulated glial responses, including chronic microglial activation, impaired phagocytosis, altered cytokine production, and mitochondrial dysfunction, contribute to persistent inflammation and structural degeneration observed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis. Recent advances in single-cell and spatial omics have revealed extensive glial heterogeneity and dynamic shifts between neuroprotective and neurotoxic phenotypes, emphasizing the context-dependent nature of glial activity. This review summarizes current knowledge regarding the multifaceted involvement of glial cells in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/pathology/metabolism/physiopathology
*Neuroglia/metabolism/pathology
Animals
Microglia/metabolism/pathology
Astrocytes/metabolism/pathology

@article {pmid41596063,
year = {2025},
author = {Herbert, A},
title = {G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
pmid = {41596063},
issn = {2076-3921},
abstract = {Expansion of d(GGGGC)n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer's Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.},
}

@article {pmid41595662,
year = {2026},
author = {Stoian, II and Nistor, D and Levai, MC and Popa, DI and Popescu, R},
title = {Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
pmid = {41595662},
issn = {2227-9059},
abstract = {Background and Objectives: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. Methods: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34-PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. Results: Twelve studies met the criteria across tauopathies and Alzheimer's disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington's disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer's hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. Conclusions: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation.},
}

@article {pmid41594924,
year = {2026},
author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C},
title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.},
journal = {Biology},
volume = {15},
number = {2},
pages = {},
pmid = {41594924},
issn = {2079-7737},
abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.},
}

@article {pmid41594611,
year = {2026},
author = {Dong, C and Lv, D and Dong, Y and Zhang, Z and Li, Q and Chen, Z},
title = {Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.},
journal = {Biomolecules},
volume = {16},
number = {1},
pages = {},
pmid = {41594611},
issn = {2218-273X},
support = {2022CXPT037//the Key R&D Program of Shandong Province, China/ ; 5501290015//the Advanced Researcher Fund of Jiangsu University/ ; 202510299087//National Training Program of Innovation and Entrepreneurship for Undergraduates/ ; },
mesh = {*Cardiolipins/metabolism/analysis ; Humans ; *Central Nervous System Diseases/metabolism/diet therapy ; Animals ; Mitochondria/metabolism ; },
abstract = {Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes recent advances in the analytical techniques employed for CL analysis. The principles and applications of mass spectrometry-based platforms, nuclear magnetic resonance, Fourier-transform infrared spectroscopy, atomic force microscopy-infrared spectroscopy, and fluorescent probes were discussed, with an emphasis on their strengths in revealing the structure, composition, dynamics, and spatial distribution of CL. Furthermore, the evidence of CL abnormalities in various CNS disorders was assessed, often showing decreased CL levels, loss of polyunsaturated species, and increased oxidation associated with mitochondrial dysfunction and neuronal apoptosis. Furthermore, the nutritional interventions for CL modulation were discussed, such as polyunsaturated fatty acids, polyphenols, carotenoids, retinoids, alkaloids, and triterpenoids, which summarize their potential health-beneficial effects in remodeling the CL acyl chain, preventing oxidation, and regulating mitochondrial homeostasis. Overall, this review provided insight into integrating CL analysis and dietary modulation in understanding CL-related pathologies in CNS disorders.},
}

*Cardiolipins/metabolism/analysis
Humans
*Central Nervous System Diseases/metabolism/diet therapy
Animals
Mitochondria/metabolism

@article {pmid41593859,
year = {2026},
author = {Pathak, K and Kumari, T and Aggarwal, L and Singh, V},
title = {Preventive dietary and lifestyle strategies for neurodegenerative diseases: a comprehensive review.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/1028415X.2026.2615456},
pmid = {41593859},
issn = {1476-8305},
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, are rising sharply across the globe. These incurable and progressive conditions lead to severe cognitive and motor impairments, diminish the quality of life, and place a substantial burden on healthcare systems. In response to this growing challenge, the present review offers an integrative and forward-thinking perspective focused on modifiable daily habits that have the potential to preserve brain health and reduce the risk of neurodegeneration. Mounting evidence reveals that everyday lifestyle choices, including food habits, physical activity, sleep, and stress, profoundly shape long-term cognitive outcomes. Neuroprotective diets such as the Mediterranean and ketogenic diets reduce oxidative stress, enhance mitochondrial efficiency, and promote neurogenesis, whereas the Western diet accelerates cognitive decline. Intermittent fasting and caloric restriction trigger autophagy and ketone production, offering metabolic resilience. Functional foods such as berries, walnuts, and leafy greens combat inflammation and oxidative damage. Physical activity and resistance training boost synaptic plasticity and neurotransmitter balance. In addition, high-quality sleep and effective stress control help preserve neuronal integrity and lower neuroinflammatory markers. By integrating insights from neuroscience, nutrition, and behavioral medicine, this review highlights how multiple modifiable factors, when adopted consistently, can work in synergy to preserve cognitive health, delay disease onset, and reduce progression.},
}

@article {pmid41592170,
year = {2026},
author = {Allen, MD and Diab, V and Lezaic, N and Binet, M and Gentil, BJ and Blanchard, O and Genge, A and Massie, R},
title = {The genetics of autosomal recessive ALS: a review of the common forms and their phenotypes.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2615110},
pmid = {41592170},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of upper and lower motor neurons. Most forms of ALS associated with a suspected causal variant are inherited in an autosomal dominant manner. However, there is an important subset of autosomal recessive (AR) variants, often associated with early-onset or atypical clinical features. Advances in genetic sequencing have led to increased recognition of AR ALS. In this review, we focus on four key confirmed AR ALS-associated genes, which appear to be most common-ALS2, SPG11, OPTN, and the D90A variant of SOD1-reviewing their pathophysiology and unique clinical manifestations. We also highlight very rare AR mutations implicated in ALS, including SYNE1, ATP13A2, and FUS, and some associated with overlap syndromes or debated pathogenicity including SIGMAR1, ERLIN1, and ERLIN2. These genes are involved in an array of processes including axonal transport, endosomal trafficking, oxidative stress response, and autophagy, suggesting distinct mechanisms of motor neuron degeneration. Some forms of AR ALS more frequently present with juvenile onset and slower progression, but other genes are associated with broader phenotypic spectra. This includes overlap with hereditary spastic paraplegia (HSP) and hereditary ataxias. Understanding these AR forms of ALS may enhance diagnostic precision, improve prognostication, and may pave the way for targeted gene therapies. This review underscores the emerging significance of AR inheritance in ALS and calls for deeper investigation into its molecular and clinical dimensions.},
}

@article {pmid41585268,
year = {2025},
author = {Srivastav, J and Sharma, S},
title = {Viral and non-viral cellular therapies for neurodegeneration.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1718669},
pmid = {41585268},
issn = {2296-858X},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.},
}

@article {pmid41581940,
year = {2026},
author = {Behera, P and Rangappa, N and Chandrashekar, M and Mishra, A and Chinnathambi, S and Mishra, M},
title = {The multifaceted role of antimicrobial peptides in neurodegeneration: Insights from Drosophila and beyond.},
journal = {Advances in protein chemistry and structural biology},
volume = {149},
number = {},
pages = {419-444},
doi = {10.1016/bs.apcsb.2025.08.003},
pmid = {41581940},
issn = {1876-1631},
mesh = {Animals ; Humans ; *Neurodegenerative Diseases/immunology/metabolism/pathology ; *Antimicrobial Peptides/metabolism/immunology ; *Drosophila ; Disease Models, Animal ; Immunity, Innate ; },
abstract = {Antimicrobial peptides (AMPs) are tiny proteins essential for innate immunity in various taxa, including mammals and insects. They provide defence against a wide range of pathogens, including bacteria, viruses, fungi, and parasites. Apart from their antimicrobial properties, new studies have revealed the roles of AMPs in brain ageing, neurodegeneration, and neuroinflammation. With an emphasis on their dysregulation in glial and neuronal tissues and their role in neuroinflammation, mitochondrial dysfunction, and neuronal loss, we reviewed the new function of AMPs beyond their antimicrobial activity. Findings from Drosophila models of Huntington's disease, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Ataxia-telangiectasia show that immune pathways, like Toll and immune deficiency, drive persistent or ectopic AMP expression, which is similar to the inflammatory processes seen in human neurodegenerative diseases. Furthermore, the dual function of AMPs as mediators of sterile inflammation and protective immunological agents reveals a universal paradox. The translational relevance of these findings is further supported by comparisons with human AMPs, such as LL-37 and β-defensins. LL-37 and β-defensins levels were found to be increased in the cerebrospinal fluid of patients suffering from meningitis. LL-37 is released from neurons and activates glial cells, boosting the production of inflammatory cytokines and decreasing neuronal survival. This chapter redefines AMPs as not only sentinels of microbial defence but also as important participants in preserving or disturbing brain homeostasis by establishing them as a link between immunity and neurobiology.},
}

Animals
Humans
*Neurodegenerative Diseases/immunology/metabolism/pathology
*Antimicrobial Peptides/metabolism/immunology
*Drosophila
Disease Models, Animal
Immunity, Innate

@article {pmid41575675,
year = {2026},
author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M},
title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {42},
pmid = {41575675},
issn = {1573-6768},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/therapy/microbiology ; *Aging/physiology ; Animals ; Probiotics/therapeutic use ; },
abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Dysbiosis/therapy/microbiology
*Aging/physiology
Animals
Probiotics/therapeutic use

@article {pmid41572495,
year = {2026},
author = {Zaman, A and Drake, SS and Fournier, AE},
title = {Extracellular Vesicle-Derived microRNAs as Fluid Biomarkers in Neurodegenerative Diseases: A Systematic Review.},
journal = {Journal of neurochemistry},
volume = {170},
number = {1},
pages = {e70323},
pmid = {41572495},
issn = {1471-4159},
support = {//MS Canada/ ; /CAPMC/CIHR/Canada ; //Fonds de Recherche du Québec - Santé/ ; //Myelin Repair Foundation/ ; //Fonds de recherche du Québec/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics/cerebrospinal fluid/blood/metabolism ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/cerebrospinal fluid/metabolism/blood ; Biomarkers/cerebrospinal fluid/blood/metabolism ; Animals ; },
abstract = {Given the absence of curative treatments for neurodegenerative diseases, early detection and therapeutic intervention are critical to slowing disease progression. Extracellular vesicles (EVs) have emerged as promising biomarkers for neurodegeneration, owing to their accessibility in bodily fluids and dynamic molecular cargo, including microRNAs (miRNAs). The last decade has seen accumulating evidence for miRNA dysregulation in circulating EVs from people with neurodegenerative diseases; however, assessing reproducibility between studies remains challenging, largely due to clinical and methodological heterogeneity. In this systematic review, we comprehensively searched the MEDLINE database for studies investigating miRNA expression in biofluids from people with neurodegenerative diseases. We extracted miRNA expression data from 185 peer-reviewed publications, published until June of 2025, reporting altered miRNA levels in fluid-derived EVs from people with neurodegenerative diseases. We consolidated results between studies to identify the most frequently dysregulated miRNAs across diseases, with a focus on Alzheimer's disease, Parkinson's disease, mild cognitive impairment, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, stroke, traumatic brain injury, and schizophrenia. Evaluating tissue specificity of frequently dysregulated miRNAs revealed enrichment of select miRNAs in the nervous system relative to blood and immune compartments. Summarizing miRNA regulation across biofluids emphasized consistencies between cerebrospinal fluid and plasma, but not serum. We highlight circulating miRNAs that may be reflective of neuropathology, including miR-143-3p, miR-127-3p, miR-9-5p, miR-15a-5p, and miR-125b-5p. Finally, we provide a repository of miRNA expression data from over 30 neurodegenerative conditions which can be exploited to further investigate miRNA regulation in diseases of interest.},
}

Humans
*Neurodegenerative Diseases/diagnosis/genetics/cerebrospinal fluid/blood/metabolism
*Extracellular Vesicles/metabolism/genetics
*MicroRNAs/cerebrospinal fluid/metabolism/blood
Biomarkers/cerebrospinal fluid/blood/metabolism
Animals

@article {pmid41571168,
year = {2026},
author = {Malvandi, AM and Gerosa, L and Maroni, P and Orlando, ME and Mohammadipour, A and Lombardi, G},
title = {miRNA-206 in muscle and central nervous system crosstalk during exercise: A double-edged sword with therapeutic potential.},
journal = {Neuroscience and biobehavioral reviews},
volume = {183},
number = {},
pages = {106569},
doi = {10.1016/j.neubiorev.2026.106569},
pmid = {41571168},
issn = {1873-7528},
abstract = {Physical activity triggers complex molecular responses in skeletal muscle, with increasing evidence showing systemic signaling roles for muscle-derived microRNAs (myomiRs). Among these, miR-206 has attracted attention for its dual function: promoting muscle regeneration but potentially harming the central nervous system (CNS). This review examines how miR-206 expression is regulated during exercise and its effects on muscle biology-such as fiber-type specification, mitochondrial changes, and neuromuscular junction (NMJ) repair. It also explores the paradoxical effects of high miR-206 levels in the CNS, where it targets brain-derived neurotrophic factor (BDNF), reducing neuroplasticity and increasing vulnerability to neuropsychiatric and neurodegenerative diseases. The review highlights disease-specific aspects, showing miR-206 as harmful in Alzheimer's, stroke, and depression, but potentially protective in amyotrophic lateral sclerosis (ALS). We discuss its potential as a biomarker and therapeutic target, stressing tissue-specific regulation approaches. Overall, miR-206 plays a key role in muscle-brain communication, with important implications for exercise, aging, and CNS disorders.},
}

@article {pmid41570741,
year = {2026},
author = {Genin, EC and Paquis-Flucklinger, V},
title = {ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies.},
journal = {Current opinion in neurobiology},
volume = {97},
number = {},
pages = {103163},
doi = {10.1016/j.conb.2025.103163},
pmid = {41570741},
issn = {1873-6882},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often overlaps clinically and pathologically with frontotemporal dementia (FTD), the second most common form of dementia. Like many neurodegenerative disorders, both ALS and FTD share a crucial pathological hallmark, the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. This process is referred to as proteinopathy. This review focuses on the proteinopathies associated with ALS, including aggregates of TDP-43, SOD1, FUS, and CHCHD10, which disrupt critical cellular processes such as RNA metabolism, mitochondrial function, and protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10-related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating ALS, as they directly target fundamental pathogenic mechanisms.},
}

@article {pmid41567979,
year = {2025},
author = {Hamdalla, RH and Bhaskar, VB and Tian, C},
title = {Brain-derived extracellular vesicles potentially mediate crosstalk with peripheral organs in neurodegenerative diseases.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1710150},
pmid = {41567979},
issn = {2296-634X},
abstract = {Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.},
}

@article {pmid41565509,
year = {2026},
author = {Lee, NC and Lin, CH and Chien, YH and Hwu, WL},
title = {Genetic testing for adult-onset neurodegenerative diseases: A clinical perspective.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.01.021},
pmid = {41565509},
issn = {0929-6646},
abstract = {Adult-onset neurodegenerative diseases (AOND), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, severely affect patients' quality of life. Pathogenic single-nucleotide variations (SNVs) and small insertions and deletions (indels) can disrupt genes involving ANOD, and expansion of short tandem repeats such as trinucleotide repeats is an important etiology of hereditary ataxia. Variations in more than one gene combined to create polygenic risk scores (PRS) for multifactorial types of AOND. Recently, genome structural variations (SVs) like copy number variations (CNVs) and expansion of long repeats are increasingly identified as the etiologies of AOND. Tools for molecular diagnosis of AOND have evolved from Sanger sequencing to next-generation sequencing (NGS) such as short-read whole-exome sequencing (WES) and whole-genome sequencing (WGS), and long-read sequencing is especially helpful in solving SVs and expansions of long repeats. Patients might have affected and/or at-risk family members at the time of diagnosis, so genetic counseling for risk handling and birth planning need to be conducted with caution. This review will help readers to better understand the genetic testing for AOND.},
}

@article {pmid41563518,
year = {2026},
author = {Boomsma, A and Doyle, C and Sai, N and Rogers, ML and Lee, SH and Benyamin, B},
title = {The differences in sex ratio between sporadic and familial amyotrophic lateral sclerosis: a systematic review.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {92},
pmid = {41563518},
issn = {1432-1459},
support = {Research Training Program//Australian Government/ ; DIS-202303-00932//FightMND/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; *Sex Ratio ; Male ; Female ; *Sex Characteristics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is more prevalent in males than in females. However, it is unclear whether the difference in sex ratio is observed similarly in sporadic compared to familial ALS. Here, we conducted a systematic review to investigate the differences in sex ratio between familial and sporadic ALS. Following the meta-analysis of observational studies in epidemiology (MOOSE) guidelines, this study searched Ovid MEDLINE, Embase, Emcare, SCOPUS and Cochrane databases. We used a random-effects meta-analysis to estimate sex ratios in a total of 9269 ALS patients (4135 female, 5134 male) across 20 included studies. We confirmed that ALS is more prevalent in males than in females (sex ratio: 1.25 (95%CI 1.14-1.37). However, when we stratified the analyses, the sex ratio was only different in sporadic ALS. Male-to-female ratios were 1.29 (95% CI 1.16-1.42) for sporadic ALS and 1.05 (95% CI 0.93-1.18) for familial ALS. A further analysis showed a pooled risk ratio of 1.07 (95% CI 1.00-1.15), indicating a 7% higher likelihood of males being diagnosed with sporadic rather than familial ALS. These findings highlight the importance of considering sex-specific factors in ALS research and clinical practice.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/genetics
*Sex Ratio
Male
Female
*Sex Characteristics

@article {pmid41562880,
year = {2026},
author = {Fiorella, ML and Ballini, L and Lavermicocca, V and Ragno, MS and Restivo, DA and Marchese-Ragona, R},
title = {Dysphagia and Dysarthria in Neurodegenerative Diseases: A Multisystem Network Approach to Assessment and Management.},
journal = {Audiology research},
volume = {16},
number = {1},
pages = {},
pmid = {41562880},
issn = {2039-4330},
abstract = {Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024), focusing on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included "dysphagia", "dysarthria", "neurodegenerative diseases", "neural networks", "swallowing control" and "speech production." Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life.},
}

@article {pmid41562832,
year = {2026},
author = {Aranda-Abreu, GE and Rojas-Durán, F and Hernández-Aguilar, ME and Herrera-Covarrubias, D and Tlapa-Monge, LR and Mestizo-Gutiérrez, SL},
title = {The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms.},
journal = {NeuroSci},
volume = {7},
number = {1},
pages = {},
pmid = {41562832},
issn = {2673-4087},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis.},
}

@article {pmid41561436,
year = {2025},
author = {Ishaq, SM and Russell, AP},
title = {Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1686230},
pmid = {41561436},
issn = {1662-5099},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.},
}

@article {pmid41553588,
year = {2026},
author = {Bjørklund, G and Butnariu, M and Caunii, A and Peana, M},
title = {Metallothioneins in Neurodegenerative Diseases: Metal Homeostasis, Autoimmunity, and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {373},
pmid = {41553588},
issn = {1559-1182},
mesh = {Humans ; *Homeostasis/physiology ; *Metallothionein/metabolism ; *Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy ; *Autoimmunity/physiology ; Animals ; *Metals/metabolism ; },
abstract = {Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.},
}

Humans
*Homeostasis/physiology
*Metallothionein/metabolism
*Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy
*Autoimmunity/physiology
Animals
*Metals/metabolism

@article {pmid41552817,
year = {2025},
author = {Chen, Y and Xiao, W and Qian, C and Huang, L and Lv, J and Wang, Z and Luo, Y},
title = {System Xc-pathway as a potential regulatory target in neurological disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1701320},
pmid = {41552817},
issn = {1663-9812},
abstract = {The System Xc-pathway is composed of the 12-transmembrane transporter protein SLC7A11 (xCT) and the single-channel transmembrane protein SLC3A2 (CD98hc). We detail the pathway's characteristics and distribution within the central nervous system, as well as its canonical role in maintaining glutathione synthesis and inhibiting ferroptosis, and its emerging non-canonical functions in metabolic coupling and neuroimmunity. A core theme is the pathway's context-dependent and often paradoxical role across major neurological disorders, including ischemic stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Critically, we analyze how pathological activation of N-methyl-D-aspartate receptors (NMDARs) can dysregulate System Xc-through mechanisms involving calcium overload, reactive oxygen species, and specific signaling axes (e.g., Nrf2, PP2A/AMPK/HMGB1), thereby exacerbating excitotoxicity and oxidative damage. Conversely, System Xc-dysfunction can further fuel NMDAR-mediated injury, creating vicious pathogenic cycles. This analysis reveals that System Xc-is not a unitary target but a dynamic node within a complex network. Consequently, effective therapeutic strategies must move beyond broad inhibition and instead aim for nuanced, cell-type-specific, and disease-stage-precise modulation. This approach will selectively correct the dysfunction of System Xc-while preserving its essential physiological roles. It presents both a significant challenge and a promising frontier for future neuroprotective drug development.},
}

@article {pmid41552526,
year = {2026},
author = {Turcatel, GA and Moura, S},
title = {Glutamate Receptor Agonists as Triggers of Neurotoxicity: Decoding Pathways of Five Neurotoxins and Potential Therapeutic Targets.},
journal = {ACS omega},
volume = {11},
number = {1},
pages = {70-81},
pmid = {41552526},
issn = {2470-1343},
abstract = {l-Glutamate (l-Glu) is one of the primary excitatory neurotransmitters in the nervous system, functioning through both ionotropic and metabotropic receptors. The release of l-Glu into the synaptic cleft, its interaction with receptors, and its reuptake are meticulously regulated by excitatory amino acid transporters. The structural similarity of various compounds to l-glutamate is crucial to their ability to interact with NMDA, AMPA, and kainate receptors. These interactions can significantly influence neural communication and function. Overstimulation of these receptors, which operate as ion channels, results in an increased level of calcium ion influx, a phenomenon known as excitotoxicity, which is often linked to neurodegeneration. Many neurodegenerative conditions are linked to both acute and chronic exposures to neurotoxins, whether they originate within the body (endogenous) or from external sources (exogenous). These neurotoxins often function as l-glutamate receptor agonists, potentially contributing to the progression of these diseases. This perspective focuses on key neurotoxins, including β-N-methylamino-l-alanine (l-BMAA), quinolinic acid (QUIN), domoic acid, β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP), homocysteine (Hcy), and l-homocysteate, all of which exhibit complementary mechanisms of action. We will explore their structural characteristics and mechanisms through which they induce neurotoxicity. Understanding the neurotoxic mechanisms of these compounds is essential for elucidating the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis, neurolathyrism, and amnesic shellfish poisoning. This review summarizes the findings of 64 studies to clarify these relationships involving classic events associated with neurodegeneration such as mitochondrial damage, oxidative stress, and activation of proapoptotic pathways. In summary, the distinctive properties of these neurotoxins provide valuable insights that could help in the development of future therapeutic drugs aimed at treating and alleviating the effects of neurodegenerative diseases. Understanding how these neurotoxins interact with neuronal pathways can guide researchers in designing more effective interventions.},
}

@article {pmid41548740,
year = {2026},
author = {Qaisar, R},
title = {Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.},
journal = {Neuroscience},
volume = {597},
number = {},
pages = {13-26},
doi = {10.1016/j.neuroscience.2026.01.015},
pmid = {41548740},
issn = {1873-7544},
abstract = {The neuromuscular junction (NMJ) is a specialized synapse essential for translating neuronal signals into muscle contraction. This review examines the complex structural, functional, and molecular differences in NMJs that innervate fast- and slow-twitch skeletal muscle fibers. Fast-twitch fibers, optimized for rapid and powerful contractions, possess elaborate NMJs with deep folds, high neurotransmitter turnover, and greater vulnerability to synaptic fatigue and degeneration. In contrast, slow-twitch fiber NMJs exhibit simpler but more stable architectures that support sustained, fatigue-resistant activity. These differences are not fixed but subject to activity-dependent plasticity and pathological remodeling. Chronic stimulation, injury, and aging influence NMJ morphology, with fast-twitch junctions more prone to degeneration in conditions such as ALS, myasthenia gravis, and diabetic neuropathy. Slow-twitch NMJs often resist early deterioration due to superior trophic support, metabolic stability, and more robust expression of synaptic organizers, such as agrin and PGC-1α. Several key signaling pathways, including agrin-MuSK-LRP4, Wnt/β-catenin, and neuregulin/ErbB, govern NMJ maintenance with fiber-type-specific nuances. These insights underscore the importance of tailoring therapeutic strategies to the muscle fiber phenotype. Gene therapies, neuromuscular electrical stimulation, and biomaterial scaffolds are emerging as promising modalities for preserving or restoring NMJ integrity, especially in fast-twitch fibers at higher risk of degeneration. Understanding fiber-type-specific NMJ biology enhances our understanding of motor control, muscle aging, and neuromuscular disease progression, and it opens pathways for precision therapeutics that target vulnerable synapses with structural and functional specificity. This review introduces a novel perspective by emphasizing fiber-type-specific NMJ differences and their implications for targeted therapies.},
}

@article {pmid41548719,
year = {2026},
author = {Li, X and Wan, R and Zhao, Y and Wu, Y and Chen, X and Li, Q and Luo, C},
title = {Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103028},
doi = {10.1016/j.arr.2026.103028},
pmid = {41548719},
issn = {1872-9649},
abstract = {Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and age-related neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). This damage emerges prior to the demise of neuronal cell bodies and the manifestation of clinical symptoms, with its location and severity directly shaping disease phenotypes. Importantly, such synaptic dysfunction is closely linked to the pathological proteins specific to each disorder. This review comprehensively synthesizes current research advances regarding synaptic impairment in age-related neurodegenerative diseases. It elaborates on the location-specific pathological features of synaptic damage in AD, PD, HD, and ALS, with particular emphasis on their associations with disease-related pathological markers. Additionally, the work unpacks five core mechanisms driving synaptic dysfunction: the toxic effects of pathological proteins, dysregulated synaptic protein homeostasis, excitotoxicity coupled with disrupted calcium balance, oxidative stress and inflammatory responses, and deficiencies in neurotrophic factors. Ultimately, it summarizes potential biomarkers and targeted intervention strategies, aiming to provide a systematic reference for mechanistic investigations, early diagnosis, and clinical management of neurodegenerative diseases.},
}

@article {pmid41547243,
year = {2026},
author = {Dorothy Wong, ZY and Kang, X and Shi, Y and Fan, R and Zhang, C and Min, D and Sun, N and Ma, Y and Tang, ML},
title = {Autophagy-tethering compounds (ATTECs) as an emerging and potentially transformative drug discovery approach.},
journal = {European journal of medicinal chemistry},
volume = {305},
number = {},
pages = {118585},
doi = {10.1016/j.ejmech.2026.118585},
pmid = {41547243},
issn = {1768-3254},
mesh = {Humans ; *Autophagy/drug effects ; *Drug Discovery ; Lysosomes/metabolism/drug effects ; Proteolysis/drug effects ; Molecular Structure ; Animals ; },
abstract = {Targeted protein degradation (TPD) strategies leveraging the ubiquitin-proteasome system (UPS), such as proteolysis-targeting chimeras (PROTACs), have gained wide recognition. While the UPS predominantly degrades short-lived soluble proteins, the lysosome-mediated system (LMS) excels at processing larger substrates, including protein aggregates, organelles, and macromolecular complexes. Recently, autophagy-tethering compounds (ATTECs) have emerged as a promising strategy for targeted degradation, harnessing the autophagy-lysosome system (ALS) to enable proximity-induced degradation. These heterobifunctional molecules, composed of LC3-binding warheads and TOI (target of interest) ligands linked together, provide therapeutic potential against disease-causing targets. This review outlines the therapeutic applications of ATTECs in human diseases, highlights recent progress in their development, and explores future opportunities for expanding this emerging class of degradation technologies through ALS from medicinal chemistry perspective.},
}

Humans
*Autophagy/drug effects
*Drug Discovery
Lysosomes/metabolism/drug effects
Proteolysis/drug effects
Molecular Structure
Animals