@article {pmid42883328,
year = {2026},
author = {Garbarek, J and Hys, O and Woźniak, A and Szewczyk-Golec, K and Nuszkiewicz, J},
title = {Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193564},
pmid = {42883328},
issn = {1420-3049},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidation-Reduction/drug effects ; Antioxidants/pharmacology/chemistry/therapeutic use ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Bees/chemistry ; Propolis/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Royal Jelly ; *Bee Venoms/chemistry/therapeutic use/pharmacology ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Signal Transduction/drug effects ; Honey/analysis ; },
abstract = {Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.},
}

Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidation-Reduction/drug effects
Antioxidants/pharmacology/chemistry/therapeutic use
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use
Bees/chemistry
Propolis/chemistry/therapeutic use
Oxidative Stress/drug effects
Royal Jelly
*Bee Venoms/chemistry/therapeutic use/pharmacology
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Signal Transduction/drug effects
Honey/analysis

@article {pmid42883433,
year = {2026},
author = {Li, P and Qi, ZM and Wu, JZ and Liu, J and Yu, P},
title = {Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.},
journal = {Biology},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/biology15191760},
pmid = {42883433},
issn = {2079-7737},
support = {NO.20250204060YY//Jilin Province Science and Technology Department/ ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.},
}

@article {pmid42880848,
year = {2026},
author = {Martin, LJ},
title = {DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {381-397},
doi = {10.1016/B978-0-443-19043-8.00014-1},
pmid = {42880848},
issn = {0072-9752},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/metabolism/pathology/physiology ; *DNA Methylation/genetics/physiology ; Animals ; *Epigenesis, Genetic/genetics/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*Motor Neurons/metabolism/pathology/physiology
*DNA Methylation/genetics/physiology
Animals
*Epigenesis, Genetic/genetics/physiology

@article {pmid42881132,
year = {2026},
author = {Trucco, AP and Camino, J and Bedford, J and Mioshi, E},
title = {Interventions to support informal carers managing behavioral symptoms in frontotemporal lobar degeneration: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/21678421.2026.2741037},
pmid = {42881132},
issn = {2167-9223},
abstract = {OBJECTIVE: Informal carers of people living with frontotemporal lobar degeneration (FTLD) face significant challenges in managing complex behavioral symptoms, yet disease specific support remains limited. This scoping review explored non-pharmacological interventions developed to support this carer population.

METHODS: Database searches were conducted across Medline, APA PsycINFO, CINAHL, ERIC, E-Journals, and Scopus from January 2011 to November 2025, supplemented by hand searching, identifying nine included studies.

RESULTS: Interventions broadly comprised occupational therapy-based activity programmes, psychoeducational approaches, and web-based self-management tools. The majority of studies were feasibility or acceptability studies, with findings generally positive; however, behavioral symptoms were inconsistently reported, and sample sizes were small, highlighting that evidence remains at an early stage.

CONCLUSION: Despite the promising nature of existing approaches, structured implementation of non-pharmacological interventions to support informal carers manage behavioral symtoms into clinical practice remains absent. Translating feasible and acceptable interventions into accessible, disease-specific support for carers of people living with FTLD is urgently needed.},
}

@article {pmid42882466,
year = {2026},
author = {Burdman, G and Hanna, M and Arias, AY and Vashist, A and Lakshmana, MK},
title = {Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191768},
pmid = {42882466},
issn = {2073-4409},
support = {1R21DA060111, 1R61AG086971, R03AG08475//National Institute of Health (NIH)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Brain/pathology/cytology ; *Organoids/pathology/cytology ; *Nervous System Diseases/pathology ; Animals ; Microphysiological Systems ; Neurons/pathology ; Models, Biological ; },
abstract = {Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.},
}

Humans
*Induced Pluripotent Stem Cells/cytology/metabolism
*Brain/pathology/cytology
*Organoids/pathology/cytology
*Nervous System Diseases/pathology
Animals
Microphysiological Systems
Neurons/pathology
Models, Biological

@article {pmid42882496,
year = {2026},
author = {Morrone, M and Valori, CF and Brambilla, L and Rossi, D},
title = {Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191798},
pmid = {42882496},
issn = {2073-4409},
support = {JPND2022-DC4MND//Ministry of Health/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Motor Neurons/pathology/metabolism ; *Neuroglia/pathology/metabolism ; *Motor Neuron Disease/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Differentiation ; Astrocytes/pathology/metabolism ; },
abstract = {Induced pluripotent stem cells (iPSCs) have revolutionized disease modelling by providing unprecedented opportunities to investigate complex human disorders. Among others, Amyotrophic Lateral Sclerosis (ALS), the most common adult-onset motor neuron disease, clearly embodies this complexity. This disorder remains particularly challenging not only because of its marked clinical and molecular heterogeneity but also as a consequence of the composite interactions between motor neurons and the neighboring non-neuronal cells, especially astrocytes, which contribute to disease progression. The ability to generate patient-specific spinal motor neurons and astrocytes from human iPSCs has enabled the development of in vitro models that recapitulate key pathological features of ALS, offering valuable platforms to investigate disease mechanisms, to identify therapeutic targets, and to support personalized medicine approaches. In this review, we summarize current iPSC-based strategies for modelling ALS, highlighting their applications in studying disease physiopathology and drug development. In addition, advanced human iPSC-derived technologies, including organoids and organ-on-a-chip systems, are discussed highlighting their potential, current limitations, and future perspectives.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism/cytology/pathology
*Motor Neurons/pathology/metabolism
*Neuroglia/pathology/metabolism
*Motor Neuron Disease/pathology
*Amyotrophic Lateral Sclerosis/pathology
Animals
Cell Differentiation
Astrocytes/pathology/metabolism

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42875680,
year = {2026},
author = {Gupta, R and Kumar, R and K S, BS and Modi, DK and Kumari, S and Kumar, N and Singh, P and Ravi, K and Abomughaid, MM},
title = {Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42875680},
issn = {1559-1182},
mesh = {Humans ; *Histone Deacetylases/metabolism ; Animals ; *Homeostasis/drug effects/physiology ; Neurodegenerative Diseases ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; *Neurons/metabolism/drug effects ; Signal Transduction ; },
abstract = {Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.},
}

Humans
*Histone Deacetylases/metabolism
Animals
*Homeostasis/drug effects/physiology
Neurodegenerative Diseases
Histone Deacetylase Inhibitors/pharmacology/therapeutic use
*Neurons/metabolism/drug effects
Signal Transduction

@article {pmid42875960,
year = {2026},
author = {Zhang, W and Sun, Y and Liao, ZY and Xue, B and Ju, SY and Wan, YJ and Wang, YJ},
title = {Recent Advances in Engineering Ammonia Lyase for Biosynthesis of Aromatic Noncanonical Amino Acids.},
journal = {Biotechnology journal},
volume = {21},
number = {10},
pages = {e70321},
doi = {10.1002/biot.70321},
pmid = {42875960},
issn = {1860-7314},
support = {LQN26B060007//Zhejiang Provincial Natural Science Foundation of China/ ; 2025C01097//"Pioneer" and "Leading Goose" Key R&D Program of Zhejiang/ ; 22178318//National Natural Science Foundation of China/ ; 22608515//National Natural Science Foundation of China/ ; 2025M771186//China Postdoctoral Science Foundation/ ; },
mesh = {*Ammonia-Lyases/metabolism/genetics/chemistry ; *Protein Engineering/methods ; *Amino Acids, Aromatic/biosynthesis/chemistry/metabolism ; Biocatalysis ; },
abstract = {Aromatic noncanonical amino acids (aromatic ncAAs) are valuable building blocks for pharmaceuticals, agrochemicals, food additives, and specialty chemicals, yet their sustainable and stereoselective synthesis remains challenging. Ammonia-lyases (ALs) have emerged as powerful biocatalysts for the one-step asymmetric hydroamination of arylacrylic acids, and recent advances in protein engineering have substantially enhanced their catalytic performance including efficiency, selectivity, promiscuity, and productivity. This review integrates catalytic mechanisms with the deployment of engineering strategies to illustrate how aromatic amino acid ammonia-lyases (AALs) have evolved into versatile biocatalysts for aromatic ncAAs synthesis. Particular attention is devoted to the engineering of AALs (including phenylalanine, tyrosine, histidine ammonia lyase) and (methyl)aspartate ammonia lyases, highlighting progress in substrate scope expansion, catalytic promiscuity, selectivity modulation, and hybrid catalytic systems. Current limitations and emerging opportunities are further assessed to delineate future directions for next-generation ALs engineering. The engineering strategies and current states of ALs summarized herein provide a conceptual basis for the efficient development of ALs for sustainable aromatic ncAAs biomanufacturing.},
}

*Ammonia-Lyases/metabolism/genetics/chemistry
*Protein Engineering/methods
*Amino Acids, Aromatic/biosynthesis/chemistry/metabolism
Biocatalysis

@article {pmid42878739,
year = {2026},
author = {Sanghai, N and Tranmer, GK},
title = {Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/14737175.2026.2748281},
pmid = {42878739},
issn = {1744-8360},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease traditionally viewed as a motor neuron disorder in which muscle atrophy occurs secondary to neuronal loss. However, recent clinical proteomic advances have highlighted carbonic anhydrase 3 (CA3), a muscle-enriched enzyme, as a promising biomarker associated with ALS disease progression. Therefore, considering ALS a neurocentric disease is not untenable.

AREAS COVERED: In this review, the authors examined the emergence of CA3 as an ALS biomarker and evaluated evidence from recent large-scale clinical consortium studies supporting its diagnostic and prognostic utility. They also compare CA3 with established biomarkers, neurofilament light chain (NEFL), a surrogate endpoint approved by the FDA.

EXPERT OPINION: Discoveries of CA3 biomarker in ALS highlight that peripheral skeletal muscle is not merely a passive bystander, but an integral participant in ALS disease progression. Unlike NEFL, which primarily reflects neuroaxonal injury, CA3 may capture early neuromuscular dysfunction preceding motor neuron degeneration. CA3's emergence as an ALS biomarker supports a more integrated neuromuscular model of ALS and provides a compelling rationale for incorporating CA3 into multimodal diagnostic, prognostic, and pharmacodynamic biomarker panels to accelerate ALS drug discovery, therapeutic evaluation, and precision clinical trial development, highlighting their complementary roles in early diagnosis, patient stratification, and therapeutic clinical trial design.},
}

@article {pmid42880056,
year = {2026},
author = {Wang, M and Li, J and Wang, X and Chai, X and Luo, J and Zhang, Y and Chang, X and Sun, Y and Wang, H},
title = {Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.},
journal = {Cytokine & growth factor reviews},
volume = {92},
number = {},
pages = {101537},
doi = {10.1016/j.cytogfr.2026.101537},
pmid = {42880056},
issn = {1879-0305},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.},
}

@article {pmid42880226,
year = {2026},
author = {DeAngelo, JD and Silverstein, AM and Shechter, D},
title = {Protein arginine methylation rewires molecular interactions.},
journal = {Cell chemical biology},
volume = {33},
number = {10},
pages = {1404-1421},
doi = {10.1016/j.chembiol.2026.09.011},
pmid = {42880226},
issn = {2451-9448},
mesh = {*Arginine/metabolism/chemistry ; Methylation ; *Protein-Arginine N-Methyltransferases/metabolism/chemistry ; Humans ; Protein Binding ; *Intrinsically Disordered Proteins/metabolism/chemistry ; },
abstract = {Protein arginine methyltransferases (PRMT1-9) catalyze monomethylation and dimethylation of arginine residues in RNA- and DNA-associated proteins. Protein arginine methylation can weaken or strengthen nucleic acid binding, recruit or exclude protein partners, and promote or suppress higher-order assembly, making its molecular consequences highly context dependent. Methylation preserves the cationic character of the guanidinium group, while altering hydrogen-bond donor topology, steric accessibility, and interaction geometry. These effects are particularly consequential in intrinsically disordered regions (IDRs), where arginine-rich motifs mediate multivalent protein-protein and protein-nucleic acid interactions. Here, we propose an interaction-equilibrium framework in which arginine methylation redistributes binding capacity among the competing protein, nucleic acid, and assembly states. This framework integrates reader-dependent and reader-independent effects of methylarginine and provides a chemical basis for understanding how a charge-preserving modification can reweight molecular interactions across diverse cellular contexts.},
}

*Arginine/metabolism/chemistry
Methylation
*Protein-Arginine N-Methyltransferases/metabolism/chemistry
Humans
Protein Binding
*Intrinsically Disordered Proteins/metabolism/chemistry

@article {pmid42865955,
year = {2026},
author = {Long, Z and Guo, H and Sun, L},
title = {Mesenchymal stromal cells in age-related neurodegenerative disorders: mechanisms, translational barriers, and precision strategies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1965598},
pmid = {42865955},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism/etiology ; *Mesenchymal Stem Cells/metabolism/immunology ; Animals ; *Aging/immunology ; Extracellular Vesicles/metabolism/transplantation ; *Mesenchymal Stem Cell Transplantation/methods ; Precision Medicine ; Translational Research, Biomedical ; },
abstract = {Ageing remodels the neuroimmune, metabolic, and vascular environment in ways that accelerate neuronal vulnerability and constrain tissue repair. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are therefore attractive candidates for neurodegenerative disorders because their effects extend beyond cell replacement to coordinated paracrine, immunomodulatory, trophic, and vascular regulation. This critical review evaluates the biological rationale, disease-specific evidence, translational limitations, and precision-development strategies for MSC-based interventions in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, and vascular dementia, whilst using selected rare hereditary neurodegenerative disorders as exploratory boundary cases. Current evidence supports three interconnected modes of action: reprogramming maladaptive neuroimmune responses; preserving neuronal homeostasis through trophic support, mitochondrial rescue, and proteostasis regulation; and restoring the neurovascular unit and blood-brain barrier. However, reproducible clinical efficacy remains limited by variation in tissue source, donor age, manufacturing, potency, dose, route, and outcome selection, as well as poor central nervous system exposure and inadequate patient stratification. Ageing-related changes in both the recipient microenvironment and the cellular product further complicate translation. Future development should replace empirical cell administration with mechanism-defined products, validated potency assays, quantitative biodistribution, biomarker-guided enrolment, engineered cells or vesicles, rational combinations, and trials using disease-modifying endpoints. MSC-based therapies are best positioned not as universal regenerative agents, but as mechanism-defined, biomarker-matched products-potentially engineered at the cell or EV level-that regulate biologically active and potentially reversible disease states.},
}

Humans
*Neurodegenerative Diseases/therapy/metabolism/etiology
*Mesenchymal Stem Cells/metabolism/immunology
Animals
*Aging/immunology
Extracellular Vesicles/metabolism/transplantation
*Mesenchymal Stem Cell Transplantation/methods
Precision Medicine
Translational Research, Biomedical

@article {pmid42869255,
year = {2026},
author = {Zhang, ZY and Qin, BQ and Wu, SZ and Zhang, H},
title = {Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118545},
doi = {10.1016/j.bcp.2026.118545},
pmid = {42869255},
issn = {1873-2968},
abstract = {Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.},
}

@article {pmid42869990,
year = {2026},
author = {Castro, J and de Carvalho, M and Swash, M},
title = {Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {478},
number = {11},
pages = {},
pmid = {42869990},
issn = {1432-2013},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; Animals ; *Muscle Spindles/physiopathology/physiology ; *Motor Neurons/physiology ; Motor Neurons, Gamma/physiology ; *Spinal Cord/physiopathology ; Interneurons/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.},
}

*Amyotrophic Lateral Sclerosis/physiopathology/pathology
Humans
Animals
*Muscle Spindles/physiopathology/physiology
*Motor Neurons/physiology
Motor Neurons, Gamma/physiology
*Spinal Cord/physiopathology
Interneurons/physiology

@article {pmid42862306,
year = {2026},
author = {Sahu, S and Jain, P and Dharme, KK and Yadav, K},
title = {CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42862306},
issn = {1420-908X},
support = {Probecell/Res/2026/124//Probecell Scientific Pvt. Ltd./ ; },
mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/genetics/therapy ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Nanoparticles/administration & dosage ; },
abstract = {BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.

PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.

METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.

RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.

CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.},
}

Humans
Animals
*Neuroinflammatory Diseases/genetics/therapy
*Gene Editing/methods
*CRISPR-Cas Systems
Nanoparticles/administration & dosage

@article {pmid42862794,
year = {2026},
author = {Hawas, Y and Abdelmageed, A and Messak, M and Ziada, A and Gamal, M and Ghanem, TIE and Abdelwahab, MM and Meshref, M and Kashbour, MO},
title = {History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag050},
pmid = {42862794},
issn = {1423-0208},
abstract = {BACKGROUND: Head injury has been proposed as a potential modifiable risk factor for amyotrophic lateral sclerosis (ALS); however, prior studies have yielded inconsistent findings. We aimed to re-evaluate this association through an updated systematic review and meta-analysis, incorporating the latest evidence and exploring the influence of injury severity, frequency, timing, and definition.

METHODS: A systematic search of PubMed, Scopus, Web of Science, Embase, EBSCO, and ProQuest from inception to January 2026 was conducted. Observational studies (cohort and case-control) reporting the association between head injury and ALS risk were included. Pooled effect estimates were generated using random-effects models. Subgroup, sensitivity, cumulative, and publication bias analyses were performed.

RESULTS: Twenty-nine studies encompassing 5,033,215 participants were included. These comprised 22 case-control studies and seven cohort studies. Case-control meta-analysis showed that head injury was associated with 36% higher odds of ALS (AOR = 1.36; 95% CI: 1.24-1.48; I² = 20.4%). Cohort studies showed a positive but non-significant association (RR = 1.59; 95% CI: 0.93-2.71). Subgroup analyses showed significant associations within mild, moderate, and severe injury categories and among studies with clearly defined traumatic brain injury exposure. Single head injury was associated with higher odds of ALS (AOR = 1.22; 95% CI: 1.11-1.34).

CONCLUSION: Head injury was associated with an increased risk of ALS across multiple analyses, including different injury severity levels and exposure definitions. However, the observational nature of available evidence and the possibility of reverse causation and residual confounding limit causal interpretation. Further prospective studies and mechanistic investigations are required to clarify the potential relationship between head injury and ALS development.},
}

@article {pmid42864786,
year = {2026},
author = {Hokkoku, K},
title = {[Lumbar Spinal Disease or Peripheral Nerve Disorder? The Role of Neurological Examination in Differential Diagnosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {10},
pages = {1089-1096},
doi = {10.11477/mf.188160960780101089},
pmid = {42864786},
issn = {1881-6096},
mesh = {Humans ; Diagnosis, Differential ; *Peripheral Nervous System Diseases/diagnosis ; *Neurologic Examination ; Nerve Conduction Studies ; *Spinal Diseases/diagnosis ; },
abstract = {Lower-limb numbness, pain, and weakness are common clinical complaints that require differentiation between cauda equina or radicular lesions associated with lumbar spinal disease and peripheral nerve disorders. Because degenerative findings on lumbar imaging are common, particularly among older adults, the responsible lesion should not be determined based on imaging findings alone. In this context, neurological examination contributes to anatomical localization and is central to the differential diagnosis. Particular emphasis is placed on interpreting muscle weakness and sensory disturbance according to myotomal, dermatomal, and peripheral nerve distributions. Other neurological findings, including gait disturbance, neurogenic claudication, bladder or bowel dysfunction, nerve stretch signs, and reflex changes, also provide important clues for localization. This review further addresses common diagnostic challenges encountered in daily practice, including differentiation of L5 radiculopathy from fibular neuropathy in patients with foot drop, distinction between cauda equina lesions and polyneuropathy, recognition of immune-mediated polyradiculoneuropathies, and identification of amyotrophic lateral sclerosis when it mimics lumbar spinal disease. Ancillary tests such as nerve conduction studies, needle electromyography, somatosensory evoked potentials, nerve ultrasound, and imaging should be interpreted in relation to the lesion localization suggested by neurological examination.},
}

Humans
Diagnosis, Differential
*Peripheral Nervous System Diseases/diagnosis
*Neurologic Examination
Nerve Conduction Studies
*Spinal Diseases/diagnosis

@article {pmid42865281,
year = {2026},
author = {Pini, A and Cobel, C and Moretti, F and Governatori, G and Bonamici, M and Gobbato, T and Buonaccorso, L and Sireci, F and Ghirotto, L},
title = {Mapping the evidence on dignity therapy in amyotrophic lateral sclerosis: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2742818},
pmid = {42865281},
issn = {2167-9223},
abstract = {Objective: To systematically map and synthesize the existing literature on the use of Dignity Therapy (DT) in amyotrophic lateral sclerosis (ALS), with particular attention to feasibility, acceptability, therapeutic outcomes, and clinical adaptations required for patients and caregivers. Methods: A systematic scoping review was conducted searching PubMed/MEDLINE, CINAHL, PsycINFO, and Scopus for studies published in the last ten years examining DT in individuals with ALS. Eligible studies were charted and compared qualitatively due to heterogeneity in design, outcomes, and measurement tools. Results: A total of 237 records were identified, of which five met the eligibility criteria. DT was generally feasible in ALS, including in advanced disease stages, when adapted with augmentative communication devices, email correspondence, or videoconferencing. Acceptability was high across studies, with participants frequently reporting meaningful engagement with the narrative process and positive perceptions of the generativity document. Qualitative evidence indicated potential benefits in existential well-being, emotional adjustment, maintenance of identity, and family communication. Quantitative outcomes were inconsistent, showing variable effects on dignity-related distress, mood symptoms, and spiritual well-being. Caregiver responses were mixed, with some reporting perceived support and others noting limited immediate impact. Conclusions: DT appears to be a promising intervention for addressing existential and relational needs in ALS, though current evidence is limited by small sample sizes and methodological variability. Larger, methodologically rigorous studies are needed to clarify therapeutic effects, optimize delivery adaptations, and evaluate outcomes for both patients and caregivers.},
}

@article {pmid42636000,
year = {2026},
author = {Benatar, M and Barmada, S and Jicha, GA and Lagier-Tourenne, C and Gregory, J and Al-Chalabi, A and Boeve, BF and Jack, CR and Seeley, WW and Maragakis, NJ and Wuu, J and Zeier, Z and Onyike, C and Lewcock, J and Hovinga, C and Jafar-Nejad, P and Uspenskaya, O and Simmons, A and Browne, SE and Rohrer, J and Petrucelli, L and Shapiro, J and Scharper, D and Boxer, A and Ostrow, LW and Staffaroni, AM and Dacks, P and Turner, MR and Dave, KD and de Majo, M and Mitic, L and Fradette, S and Budd Haeberlein, S and Simuni, T and Dunn, B and McMillan, CT and Lee, EB},
title = {TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.},
journal = {JAMA neurology},
volume = {83},
number = {10},
pages = {1013-1022},
doi = {10.1001/jamaneurol.2026.2812},
pmid = {42636000},
issn = {2168-6157},
mesh = {Humans ; *Neurodegenerative Diseases/classification/pathology/genetics/metabolism/diagnosis ; *DNA-Binding Proteins/metabolism/genetics ; Biomarkers/metabolism ; *TDP-43 Proteinopathies/classification/pathology ; },
abstract = {IMPORTANCE: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.

OBSERVATIONS: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.

CONCLUSIONS AND RELEVANCE: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.},
}

Humans
*Neurodegenerative Diseases/classification/pathology/genetics/metabolism/diagnosis
*DNA-Binding Proteins/metabolism/genetics
Biomarkers/metabolism
*TDP-43 Proteinopathies/classification/pathology

@article {pmid42858164,
year = {2026},
author = {Vocelle, A and Ensrud, E and Howard, IM},
title = {Prognostication in Amyotrophic Lateral Sclerosis: A Narrative Review of Pre-Diagnosis and Functional Outcomes.},
journal = {NeuroRehabilitation},
volume = {},
number = {},
pages = {10538135261490936},
doi = {10.1177/10538135261490936},
pmid = {42858164},
issn = {1878-6448},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a very heterogeneous disease, yet some of the most common questions received by physicians in the ALS clinic are "how much time do I have?" and "what can I expect to happen next?" This line of inquiry is not strictly limited to patients; clinicians also need an idea of prognosis to appropriately plan for treatment decisions and prepare the patient and caregiver for future care needs. This narrative review synthesizes current evidence on prognostic indicators in ALS, organized across three temporal phases: factors preceding diagnosis, factors present at diagnosis, and factors emerging after diagnosis. Pre-diagnosis predictors include age at onset, sex, socioeconomic status, genetic background, premorbid Body Mass Index (BMI) and nutritional status, and comorbid disease. At diagnosis, clinical phenotype and site of onset, diagnostic delay, baseline Amyotrophic Lateral Sclerosis Functional Rating Score-Revised (ALSFRS-R) and forced vital capacity, cognitive involvement, fluid biomarkers, and electrophysiologic measures carry prognostic weight. Post-diagnosis, the trajectory is refined by the rate of ALSFRS-R decline, serial respiratory measures, and weight loss, and is actively modified by clinical interventions including noninvasive ventilation, enteral nutrition, disease-modifying therapy, and multidisciplinary care. Notably, quality of life does not track with physical decline, consistent with the disability paradox described in other severe neurological conditions. For neurorehabilitation, these indicators support a shift from reactive to anticipatory practice: timing equipment provision, communication support, respiratory intervention, and goals-of-care discussions to the predicted trajectory rather than to established deficit. Refinement of prognostic models may also improve stratification in ALS clinical trials.},
}

@article {pmid42859482,
year = {2026},
author = {Sharma, T and Krishna, H and Dixit, A and Dixit, SG and Shukla, KK and Banerjee, M and Nayak, P},
title = {Aluminium as a Metalloestrogen: Toxicological Pathways, Endocrine Disruption and Systemic Health Implications.},
journal = {Maedica},
volume = {21},
number = {3},
pages = {759-766},
pmid = {42859482},
issn = {1841-9038},
abstract = {Aluminium (Al) is the most abundant metal in the Earth's crust and a common environmental contaminant due to industrial processes, recycling and consumer goods. Aluminium can enter the human body via the gastrointestinal, respiratory, and skin routes, as well as through injection, although this is not essential for biological function. It can then accumulate in different organs. Its physicochemical properties enable it to displace vital metals, bind to biomolecules and interfere with cellular processes, leading to genotoxicity, oxidative stress and protein misfolding. Aluminium toxicity impacts various body systems, such as neurodegeneration, bone disorders, heart conditions, endocrine disruption and reproductive issues. Notably, Al acts as a metalloestrogen, mimicking or disrupting estrogen receptor signaling. This interference affects the hypothalamic-pituitary-gonadal axis and changes estrogen-dependent processes in both males and females. This review explores Al's systemic toxicology and its emerging function as an endocrine disruptor, highlighting its dual nature as both a sustainable industrial resource and a common biological toxin. The findings highlight important public health issues and suggest the need for further research into how Al interacts with estrogen receptors to improve prevention and treatment.},
}

@article {pmid42862029,
year = {2026},
author = {Santos Silva, C and de Carvalho, M},
title = {Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70782},
doi = {10.1111/ene.70782},
pmid = {42862029},
issn = {1468-1331},
mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis ; Humans ; *Carbon Dioxide ; *Blood Gas Monitoring, Transcutaneous/methods ; *Hypoventilation/diagnosis/etiology ; *Respiratory Insufficiency/diagnosis/etiology ; },
abstract = {BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Conventional pulmonary function tests are effort-dependent and may fail to detect early nocturnal hypoventilation. Transcutaneous carbon dioxide (PtcCO2) measurement is a non-invasive method for assessing ventilation, but its role in ALS remains unclear. We performed a scoping review to map the current evidence.

METHODS: PubMed, Web of Science, Scopus, and Google Scholar were searched from inception to April 2026. Original studies evaluating PtcCO2 monitoring in ALS were included. Due to heterogeneity in study designs, populations, and outcomes, a narrative synthesis was performed, categorized by study characteristics, measurement protocols, and clinical endpoints.

RESULTS: Twenty-one studies were included. Most were observational and conducted in tertiary centres. Twelve studies evaluated PtcCO2 as a surrogate marker for nocturnal hypoventilation, mainly to guide initiation or titration of non-invasive ventilation. Definitions of hypoventilation and reported PtcCO2 metrics varied widely. Only three studies evaluated PtcCO2 in relation to respiratory impairment or hypercapnia, but none reported formal measures of diagnostic accuracy. Evidence regarding the prognostic value was limited and inconsistent. Three studies showed that nocturnal hypercapnia preceded abnormalities in spirometry or daytime hypercapnia.

CONCLUSIONS: PtcCO2 monitoring shows promise as a non-invasive method for assessing nocturnal ventilatory abnormalities in ALS, including nocturnal hypoventilation. However, due to methodological heterogeneity, its diagnostic and prognostic roles remain uncertain. Current evidence is insufficient to support PtcCO2 as a standalone criterion for NIV initiation. Large-scale prospective studies with standardized protocols are essential to delineate its clinical utility.},
}

*Amyotrophic Lateral Sclerosis/complications/diagnosis
Humans
*Carbon Dioxide
*Blood Gas Monitoring, Transcutaneous/methods
*Hypoventilation/diagnosis/etiology
*Respiratory Insufficiency/diagnosis/etiology

@article {pmid42862052,
year = {2026},
author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT},
title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03262a},
pmid = {42862052},
issn = {1364-548X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.},
}

@article {pmid42855762,
year = {2026},
author = {Wang, HF and Sun, B and Pan, J and Pang, XY and Bai, JM and Feng, JL},
title = {[The role of the GSTP1/JNK signaling pathway in regulating oxidative stress and programmed cell death in amyotrophic lateral sclerosis].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {10},
pages = {1122-1129},
doi = {10.3760/cma.j.cn112138-20260501-00268},
pmid = {42855762},
issn = {0578-1426},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Oxidative Stress ; *Glutathione S-Transferase pi/metabolism ; Humans ; *Apoptosis ; Animals ; *MAP Kinase Signaling System ; Signal Transduction ; JNK Mitogen-Activated Protein Kinases/metabolism ; },
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Oxidative Stress
*Glutathione S-Transferase pi/metabolism
Humans
*Apoptosis
Animals
*MAP Kinase Signaling System
Signal Transduction
JNK Mitogen-Activated Protein Kinases/metabolism

@article {pmid42855802,
year = {2026},
author = {Zheng, X and Yu, X},
title = {A Comprehensive Review and Future Prospects of Aluminum-Sulfur Batteries: From Material Design to Practical Challenges.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e06181},
doi = {10.1002/adma.202506181},
pmid = {42855802},
issn = {1521-4095},
support = {2019-01 07-00-07-E00028//Innovation Program of the Shanghai Municipal Education Commission/ ; 51971065//National Science Foundation of China/ ; },
abstract = {Aluminum-sulfur (Al-S) batteries are promising next-generation energy storage systems owing to the high abundance, low cost, and multi-electron redox capability of Al, combined with the high theoretical capacity and environmental friendliness of S. This review systematically compares the dual electrochemical mechanisms based on S reduction (S[0]/S[2-]) and S oxidation (S[0]/S[4+]), highlighting their distinct advantages in energy density and safety. Key strategies for cathode design-including carbon-based, anchoring-functional, and catalytic-functional hosts-are discussed, alongside electrolyte engineering using ionic liquids, deep eutectic solvents, inorganic molten salts, and aqueous systems. Recent advances in dendrite suppression, anode protective layers, and functional separators are also summarized. A central challenge identified is the sluggish Al[3+] solvation/desolvation kinetics, which limits rate capability and low-temperature performance. The application of in situ/operando characterization techniques (XANES, Raman, UV-vis) to unravel complex reaction pathways is emphasized. By integrating multidisciplinary innovations, this review provides a comprehensive perspective and a phased commercialization roadmap, aiming to accelerate the transition of Al-S batteries from laboratory research to practical green energy storage.},
}

@article {pmid42852066,
year = {2026},
author = {Duarte, ML and Iared, W and Oliveira, ABS and Dos Santos, LR and da Silva, MSP},
title = {Comparison between ultrasound and electromyography for detection of fasciculations in amyotrophic lateral sclerosis: an updated systematic review and meta-analysis.},
journal = {Radiologia brasileira},
volume = {59},
number = {},
pages = {e20260011},
pmid = {42852066},
issn = {0100-3984},
abstract = {Fasciculations are a key manifestation of lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). Al-though electromyography is considered the gold-standard method for the detection of fasciculations, its sensitivity for that purpose depends on the muscle sampled and the examination time. Muscle ultrasound has emerged as a dynamic, noninvasive technique with high sensitivity for detecting spontaneous muscle activity. This updated system-atic review compares ultrasound and electromyography in terms of their performance for the detection of muscle fas-ciculations in ALS, with stratification by muscle group and observation time. A comprehensive search of the literature identified studies evaluating both techniques. Data were synthesized descriptively and, when possible, quantitatively. Ultrasound demonstrated higher or comparable detection rates across most muscle groups, particularly in muscles that are large or deep, such as the biceps brachii, tibialis anterior, and vastus lateralis. Longer ultrasound observation times, especially 60 s, were associated with substantially higher detection rates without a loss of specificity. Although electromyography is still essential for electrophysiological characterization, ultrasound offers broader muscle cover-age, excellent reproducibility, and a noninvasive approach. These findings support muscle ultrasound as a valuable complementary tool for the detection and assessment of fasciculations in patients with motor neuron disease.},
}

@article {pmid42852552,
year = {2026},
author = {Choudhury, A and Prabha, S and Saeed, MU and Sulaimani, MN and Hassan, MI},
title = {Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2747518},
pmid = {42852552},
issn = {1744-7631},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.

AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.

EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.},
}

@article {pmid42847522,
year = {2026},
author = {Donlin-Asp, PG and Clayton, EL},
title = {Synaptic Proteostasis in Health and Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70565},
pmid = {42847522},
issn = {1471-4159},
support = {309570/Z/24/Z/WT_/Wellcome Trust/United Kingdom ; ARUK-SRF2022A-005//Alzheimer's Research UK/ ; //CureSynGAP/ ; 571/ALZS_/Alzheimer's Society/United Kingdom ; //Simons Initiative for the Developing Brain/ ; },
mesh = {Humans ; *Proteostasis/physiology ; *Synapses/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Autophagy/physiology ; *Neurons/metabolism/pathology ; Proteotoxic Stress ; },
abstract = {Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.},
}

Humans
*Proteostasis/physiology
*Synapses/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Autophagy/physiology
*Neurons/metabolism/pathology
Proteotoxic Stress

@article {pmid42849148,
year = {2026},
author = {Freischmidt, A and Weishaupt, JH},
title = {Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.},
journal = {Current opinion in genetics & development},
volume = {101},
number = {},
pages = {102549},
doi = {10.1016/j.gde.2026.102549},
pmid = {42849148},
issn = {1879-0380},
abstract = {Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.},
}

@article {pmid42850529,
year = {2026},
author = {Reilich, P and Schöberl, F},
title = {[Amyotrophic lateral sclerosis: Specific considerations in palliative care].},
journal = {MMW Fortschritte der Medizin},
volume = {168},
number = {17},
pages = {51-54},
doi = {10.1007/s15006-026-6225-z},
pmid = {42850529},
issn = {1613-3560},
}

@article {pmid42851615,
year = {2026},
author = {Ohara, M and Ishigaki, S and Watts, JK and Yamada, K and Ikezu, T and Ikezu, S},
title = {Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {41},
pmid = {42851615},
issn = {3059-4944},
abstract = {Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.},
}

@article {pmid42851749,
year = {2026},
author = {Li, M and Li, R and Deng, Z and Zhang, L and Lv, S and Shi, J and Ma, H and Guan, W and Zhang, H and Li, J and Teng, J},
title = {Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1918967},
pmid = {42851749},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with limited therapeutic options, highlighting the need for multi-target interventions. Traditional Chinese botanical medicine (TCBM) interventions have attracted increasing attention as potential multi-target pharmacological candidates for ALS. In addition, a separate body of evidence derived from selected plant-derived bioactive compounds directly investigated in ALS-specific models provides complementary mechanistic insights into ALS-related pathways. However, the pharmacological mechanisms and translational potential of these two distinct evidence categories remain insufficiently summarized. This review systematically summarizes ALS-related pathological mechanisms and the molecular actions reported within these two distinct evidence categories, together with translational challenges and future research directions.

METHODS: A structured literature search was conducted in PubMed, Web of Science, and ScienceDirect up to May 2026. A total of 198 publications were retained, including 48 ALS-specific original intervention studies forming the core pharmacological evidence set.

RESULTS: ALS involves interconnected pathological processes, including neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxicity, and neuromuscular junction injury. Evidence across these two categories suggests modulation of multiple ALS-related pathological processes. Reported effects include regulation of inflammatory signaling, enhancement of Nrf2-mediated antioxidant responses, improvement of PGC-1α/MFN2-associated mitochondrial homeostasis, and promotion of protein clearance pathways.

CONCLUSION: Together, these distinct but complementary evidence categories highlight the potential for multi-target modulation of ALS-related pathology. However, current evidence remains predominantly preclinical, and clinical efficacy and translational feasibility require further validation.},
}

@article {pmid42851781,
year = {2026},
author = {Smeyers, J and Mordes, DA},
title = {Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1941293},
pmid = {42851781},
issn = {1662-4548},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum characterized by TDP-43 pathology and overlapping genetic risk factors. Loss-of-function variants in TBK1 (TANK-binding kinase 1) represent one of the most common genetic causes of ALS/FTD, highlighting haploinsufficiency for TBK1 as a major contributor to disease pathogenesis. Emerging evidence from iPSC and mouse models suggests that reduced TBK1 activity disrupts interconnected autophagy, endo-lysosomal, and innate immune pathways through both cell-autonomous and non-cell-autonomous mechanisms. In this review, we discuss the multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways, highlight its critical role in maintaining microglial homeostasis, and explore how these convergent functions inform therapeutic strategies for ALS/FTD.},
}

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42843275,
year = {2026},
author = {Adrita, N and Claassen, I and Huerta, M and Black, SM and Estevez, AG and Roberts, BR and Beckman, JS and Franco, MC},
title = {Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.},
journal = {Redox biology},
volume = {97},
number = {},
pages = {104423},
doi = {10.1016/j.redox.2026.104423},
pmid = {42843275},
issn = {2213-2317},
abstract = {Protein tyrosine nitration is a post-translational modification associated with conditions of oxidative and inflammatory stress, driven by the production of reactive oxygen and nitrogen species (ROS and RNS). Once considered primarily a footprint of oxidative damage, tyrosine nitration is increasingly recognized as a selective modification that, in specific biological contexts, can alter protein structure, stability, enzymatic activity, and interaction networks. Mechanistically, nitration occurs through peroxynitrite-dependent and heme-peroxidase-dependent pathways and preferentially targets specific tyrosine residues based on local protein structure, solvent accessibility, and microenvironmental chemistry. Accumulating evidence has identified disease-specific nitration signatures across multiple pathological contexts. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, nitration of proteins such as tau, α-synuclein, manganese superoxide dismutase, ATP synthase, glyceraldehyde-3-phosphate dehydrogenase, heat shock proteins, and cytoskeletal components contributes to mitochondrial dysfunction, protein aggregation, metabolic failure, and neuronal loss. Similarly, in cardiovascular and pulmonary diseases, protein tyrosine nitration disrupts vascular and epithelial homeostasis by impairing endothelial signaling, fibrinolysis, lipid metabolism, and barrier integrity through modification of key regulatory proteins. By influencing phosphorylation-dependent signaling, enzymatic function, and protein-protein interactions, tyrosine nitration contributes to the connection between redox imbalance and progressive cellular and tissue dysfunction. This review summarizes current mechanistic insights into site-specific protein tyrosine nitration, highlights the emerging disease-associated nitroproteome, and discusses how advances in analytical and structural approaches are redefining nitration as a functional regulatory modification. Understanding the molecular determinants and consequences of tyrosine nitration may enable the development of targeted diagnostics and therapeutic strategies across diverse human diseases.},
}

@article {pmid42844308,
year = {2026},
author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU},
title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42844308},
issn = {1432-1912},
abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.},
}

@article {pmid40947692,
year = {2026},
author = {Manubolu, K and Peeriga, R},
title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.},
journal = {Current aging science},
volume = {19},
number = {3},
pages = {285-302},
pmid = {40947692},
issn = {1874-6128},
mesh = {Humans ; *Artificial Intelligence ; *Neurodegenerative Diseases/drug therapy/diagnosis/genetics ; *Precision Medicine ; Drug Discovery ; Medication Adherence ; Drug Repositioning ; },
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.},
}

Humans
*Artificial Intelligence
*Neurodegenerative Diseases/drug therapy/diagnosis/genetics
*Precision Medicine
Drug Discovery
Medication Adherence
Drug Repositioning

@article {pmid42649099,
year = {2026},
author = {, and Kassardjian, CD and Desai, U and Živković, SA and Simmons, Z and Narayanaswami, P},
title = {It's Virtually Here: Telemedicine, Virtual Care, and Neuromuscular Disease.},
journal = {Muscle & nerve},
volume = {74},
number = {5},
pages = {1318-1327},
doi = {10.1002/mus.70382},
pmid = {42649099},
issn = {1097-4598},
mesh = {Humans ; *Neuromuscular Diseases/therapy/diagnosis ; *Telemedicine/trends ; *COVID-19/epidemiology ; Digital Health ; SARS-CoV-2 ; },
abstract = {The COVID-19 pandemic forced a partial shift in neuromuscular clinical practice away from in-person care to remote means. However, this shift was unexpected, abrupt, reactive to the emergency of a pandemic, and disruptive to the usual manner of care, without adequate time to adapt or study the optimal manner to provide care remotely. While traditionally associated with hub-and-spoke telemedicine models, the pandemic popularized direct-to-home virtual care, mostly unsupported by on-site examiners or standardized platforms. In chronic neuromuscular disorders such as amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG), virtual care has demonstrated feasibility, patient satisfaction, and potential cost savings, particularly for geographically or functionally disadvantaged populations. Disease-specific adaptations such as the Myasthenia Gravis Core Exam and wearable-based assessments (e.g., home spirometry, grip strength monitoring, and digital outcome measures) have enabled more structured remote evaluations. However, diagnostic accuracy may be compromised by the inability to perform detailed neurological examinations or electrodiagnostic studies. Equity concerns persist due to variability in digital literacy, internet and digital device access, and socioeconomic status. Post-pandemic, patients with disabilities may continue to benefit in a combined virtual/in-person paradigm of care. More evidence is required to evaluate the impact of virtual care on neuromuscular practice quality of care and outcomes. We outline some of the questions that require further study, hoping to spur research and quality improvement investigations of these new care models.},
}

Humans
*Neuromuscular Diseases/therapy/diagnosis
*Telemedicine/trends
*COVID-19/epidemiology
Digital Health
SARS-CoV-2

@article {pmid42833594,
year = {2026},
author = {Dahlhaus, R and Yalcin, I and Tischer, J and Braun, RJ},
title = {TDP-43 and ALS - what's wrong with my membranes?.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107630},
doi = {10.1016/j.nbd.2026.107630},
pmid = {42833594},
issn = {1095-953X},
abstract = {In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.},
}

@article {pmid42837018,
year = {2026},
author = {de Azevedo, EM and Bernardo, VS and Lima, MMS and Eleutherio, ECA and Outeiro, TF},
title = {SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42837018},
issn = {1432-0533},
support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88887.169657/2025-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88881.986154/2024-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 300367/2026-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 210.034/2026//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; },
mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; *Brain/pathology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/pathology ; },
abstract = {Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.},
}

Humans
*Superoxide Dismutase-1/metabolism
*Brain/pathology/metabolism
*Neurodegenerative Diseases/pathology/metabolism
Animals
Amyotrophic Lateral Sclerosis/pathology

@article {pmid42840744,
year = {2026},
author = {Mouraux, C and Santana, MM and Rosenthal, LS and Cortese, A and Santorelli, FM and Opal, P and Coarelli, G},
title = {The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag313},
pmid = {42840744},
issn = {2632-1297},
abstract = {The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich's ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich's ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.},
}

@article {pmid42826718,
year = {2026},
author = {Cha, Y and Kim, KS},
title = {From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {103104},
doi = {10.1016/j.xcrm.2026.103104},
pmid = {42826718},
issn = {2666-3791},
abstract = {Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological "black box" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.},
}

@article {pmid42826647,
year = {2026},
author = {Esmaeili, H and Das, S and Rytel, K and Sidransky, E and Chen, Y},
title = {CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.},
journal = {Molecular genetics and metabolism},
volume = {149},
number = {3},
pages = {110265},
doi = {10.1016/j.ymgme.2026.110265},
pmid = {42826647},
issn = {1096-7206},
abstract = {Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.},
}

@article {pmid41762671,
year = {2026},
author = {Gaur, N and Angerer, C and Gunes, ZI and Ancau, M and Wang, M and Riemenschneider, H and Hurler, CA and Mungwa, S and Lüningschrör, P and Zhiti, A and Steinbach, R and Briese, M and Srivastava, M and Plaas, M and Hermann, A and Sendtner, M and Jäkel, S and Edbauer, D and Herms, J and Liebscher, S and Grosskreutz, J and Brill, MS},
title = {Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {149},
number = {10},
pages = {3457-3474},
doi = {10.1093/brain/awag083},
pmid = {41762671},
issn = {1460-2156},
support = {//German Ministry for Education and Research/ ; //JPND/ ; 01ED1202B//SOPHIA/ ; 01ED15511A//SOPHIA/ ; //E-RARE/ ; 01GM1304//PYRAMID/ ; //Boris Canessa foundation/ ; 450131873//Deutsche Forschungsgemeinschaft/ ; ANR-21-CE37-0033-01//Deutsche Forschungsgemeinschaft/ ; 413668513//Deutsche Forschungsgemeinschaft/ ; 390857198//Excellence Cluster SyNergy/ ; //Deutsche Gesellschaft für Muskelkranke/ ; //Friedrich Schiller University/ ; PSG471//Estonian Research Council/ ; //Transregional Collaborative Research Centre/ ; //The Graduate School of Systemic Neurosciences/ ; //Agence Nationale de la Recherche/ ; //German Research Foundation/ ; //Hermann and Lilly Schilling Stiftung für medizinische Forschung im Stifterverband/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/enzymology ; Humans ; *Chitinases/metabolism/genetics/biosynthesis ; Animals ; Up-Regulation ; *Neurons/metabolism/enzymology ; Mice ; Chitinase-3-Like Protein 1/metabolism ; Hexosaminidases/metabolism ; Female ; Mice, Transgenic ; Male ; },
abstract = {Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signalling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including chitotriosidase-1 (CHIT1), chitinase-3-like protein 1 (CHI3L1), and human-specific chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of aetiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1 and CHI3L2 levels are elevated in the CSF of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the role of chitinases in ALS disease burden remain: namely, (i) which cell types in the CNS are chitinase sources under physiological conditions; (ii) which of these display chitinase upregulation in ALS; and (iii) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize preclinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS versus non-ALS controls, while CHI3L1 was more closely associated with inflammation and ageing across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins, we posit that their expression profiles can inform the optimization of biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.},
}

*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/enzymology
Humans
*Chitinases/metabolism/genetics/biosynthesis
Animals
Up-Regulation
*Neurons/metabolism/enzymology
Mice
Chitinase-3-Like Protein 1/metabolism
Hexosaminidases/metabolism
Female
Mice, Transgenic
Male

@article {pmid42012311,
year = {2026},
author = {Erol, ZY and Quintanilla, C and Ozdinler, PH},
title = {Bringing cellular clarity to the cortical component of ALS with a high-density multi-electrode array system.},
journal = {The FEBS journal},
volume = {293},
number = {19},
pages = {5686-5695},
pmid = {42012311},
issn = {1742-4658},
support = {R01 AG061708/AG/NIA NIH HHS/United States ; R01AG061708//NIH-NIA/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism ; Microelectrodes ; Animals ; *Single-Cell Analysis/methods/instrumentation ; Neurons/pathology ; },
abstract = {There is selective vulnerability in diseases, requiring the understanding of cell-type specific aspects of neurodegeneration with cellular resolution. Single-cell electrophysiology enables direct investigation of neuronal excitability, ion-channel dynamics, and synaptic transmission with high temporal precision, which is crucial in understanding neuronal circuitries and how they are affected in diseases. Microelectrode arrays (MEAs) have emerged as powerful platforms enabling long-term, parallel, and non-invasive extracellular measurements. The advent of complementary-metal-oxide-semiconductor (CMOS)-based and high-density microelectrode arrays (HD-MEAs) has expanded the spatial and temporal resolution attainable both in vitro and ex vivo. Combined with acute slices, novel cell-culture approaches and three-dimensional (3D) brain organoids, these tools now expedite translational research in disease modeling, neurotoxicity, and pharmacology. Here, we summarise the significance of single-cell electrophysiology, the advantages of the MEA systems, and the latest biomedical and technological advances in this area of research.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism
Microelectrodes
Animals
*Single-Cell Analysis/methods/instrumentation
Neurons/pathology

@article {pmid42817633,
year = {2026},
author = {Morley, JF},
title = {Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817633},
issn = {1471-2970},
mesh = {*Proteostasis ; Humans ; *Neurodegenerative Diseases/physiopathology/pathology ; Animals ; Proteotoxic Stress ; Protein Folding ; },
abstract = {Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
Humans
*Neurodegenerative Diseases/physiopathology/pathology
Animals
Proteotoxic Stress
Protein Folding

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

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

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

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

@article {pmid42826575,
year = {2026},
author = {Tripathi, A and Yadav, AK and Kumar, N},
title = {AI-driven transcriptomics for neurodegenerative disease research: A systematic review.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109448},
doi = {10.1016/j.compbiolchem.2026.109448},
pmid = {42826575},
issn = {1476-928X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.

OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.

METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.

SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.

LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.},
}

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

@article {pmid42811116,
year = {2026},
author = {Brooker, SM and Coukos, R and Krainc, D},
title = {Lysosomal dysfunction in neurodegenerative disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42811116},
issn = {1759-4766},
abstract = {Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.},
}

@article {pmid42812195,
year = {2026},
author = {Tao, R and Zheng, W and Peng, L and Lv, S and Wang, Q},
title = {Multistage pathogenesis and disease associations of Mycobacterium avium subsp. paratuberculosis.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1948490},
pmid = {42812195},
issn = {1664-3224},
mesh = {*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics ; Animals ; *Paratuberculosis/microbiology/immunology/epidemiology/transmission ; Humans ; Macrophages/immunology/microbiology ; Host-Pathogen Interactions ; },
abstract = {Mycobacterium avium subsp. paratuberculosis (MAP) is the primary causative agent of Johne's disease (JD) in ruminants and bears potential public-health implications. Cumulative epidemiological and molecular evidence implies MAP may contribute to Crohn's disease (CD), whereas its links to multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), and amyotrophic lateral sclerosis (ALS) remain associative without proven causality. This narrative review synthesizes MAP environmental distribution, strain genotyping, transmission routes, and multistage pathogenic mechanisms. MAP breaches the intestinal barrier via fibronectin attachment protein (FAP)-mediated invasion of microfold cells and establishes intracellular persistence within macrophages. It deploys virulence factors including protein kinase G (PknG) to inhibit phagosome-lysosome fusion, the stringent response regulator RelA for metabolic reprogramming, and the ESX-3 secretion system for iron acquisition, while subverting host immunity through M2 macrophage polarization and interleukin-10 (IL-10)/interleukin-6 (IL-6)-mediated anti-inflammatory responses, ultimately driving chronic granulomatous inflammation and tissue injury. We also critically assess diagnostic limitations-particularly the inability of polymerase chain reaction (PCR) to distinguish viable from non-viable organisms-and highlight major research challenges, including extrapolation of virulence mechanisms from other mycobacterial species. This work provides a theoretical framework for prevention, diagnosis, and targeted intervention of MAP-associated disorders.},
}

*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics
Animals
*Paratuberculosis/microbiology/immunology/epidemiology/transmission
Humans
Macrophages/immunology/microbiology
Host-Pathogen Interactions

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

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

@article {pmid42814303,
year = {2026},
author = {Nakamura, Y and Moriyama, H and Yokota, T},
title = {Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3065},
number = {},
pages = {161-170},
pmid = {42814303},
issn = {1940-6029},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy ; Humans ; *Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; Biomarkers ; },
abstract = {Advances in genetics and RNA biology have transformed the therapeutic landscape for neurodegenerative disease. Antisense oligonucleotide (ASO) therapies-particularly RNase H-activating "gapmers"-now enable sequence-specific suppression of pathogenic transcripts in the central nervous system. In amyotrophic lateral sclerosis (ALS), tofersen, a 2'-MOE-modified phosphorothioate ASO targeting SOD1 mRNA, has entered clinical use. By promoting RNase H-mediated degradation of SOD1 transcripts after intrathecal delivery, tofersen lowers SOD1 protein in cerebrospinal fluid and plasma neurofilament light chain, demonstrating robust target engagement and neurodegeneration biomarker improvement. Although pivotal trials did not meet primary functional endpoints (ALSFRS-R) at 28 weeks, longer-term and real-world observations suggest potential clinical benefit with earlier initiation, a hypothesis now being tested in presymptomatic SOD1 variant carriers. This chapter reviews the development of gapmer ASOs for ALS with a focus on tofersen-covering chemistry and mechanism, preclinical validation, clinical efficacy and safety, biomarker readouts, and ongoing trials-while outlining key challenges (CNS delivery, adverse event monitoring, endpoint sensitivity) and future directions, including earlier intervention guided by biomarkers and extension to additional genetic forms of ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy
Humans
*Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry
Animals
Superoxide Dismutase-1/genetics/metabolism
Biomarkers

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

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

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

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

@article {pmid42805693,
year = {2026},
author = {Li, H and Gao, WY},
title = {Comparison of the catalysis of ThDP-dependent enzymes AHAS, ALS, and DXPS.},
journal = {Methods in enzymology},
volume = {736},
number = {},
pages = {127-156},
doi = {10.1016/bs.mie.2026.07.004},
pmid = {42805693},
issn = {1557-7988},
mesh = {*Acetolactate Synthase/metabolism/chemistry ; *Thiamine Pyrophosphate/metabolism ; Chromatography, High Pressure Liquid/methods ; *Transferases/metabolism/chemistry ; *Enzyme Assays/methods ; Catalysis ; Biocatalysis ; },
abstract = {Thiamine diphosphate (ThDP)-dependent enzymes are primarily classified into lyases, transferases, and oxidoreductases, catalyzing various biologically important reactions such as keto transfer, dehydrogenation, decarboxylation, and stereoselective C-C bond formation/cleavage in chiral natural products biosynthesis. They constitute one of the largest superfamilies of biocatalysts, operate basically in all forms of living systems. In this chapter, the research progress on three ThDP enzymes are reviewed, including acetohydroxyacid synthase (AHAS) which is a key enzyme in the anabolic pathway for the biosynthesis of branched chain amino acids, acetolactate synthase (ALS) that belongs to the catabolic pathway for the biosynthesis of platform compounds acetoin and 2,3-butanediol, and 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) which is a rate-limiting enzyme in the MEP terpenoid biosynthetic pathway and is also involved in the biosynthesis of ThDP and pyridoxal phosphate in certain bacteria, with the emphasis on comparing the catalysis of the three enzymes. Furthermore, two precolumn derivatization-HPLC protocols using 4-nitro-o-phenylenediamine and 2,4-dinitrophenylhydrazine as respective derivatizing reagents are also described in detail. The methods can not only be utilized to measure the activities of the above enzymes, supplementing the deficiencies of the classic spectrophotometry, but also be used to comprehensively elucidate the consumption of the substrate(s) and the formation of the products in the reactions catalyzed by AHAS, ALS, or DXPS.},
}

*Acetolactate Synthase/metabolism/chemistry
*Thiamine Pyrophosphate/metabolism
Chromatography, High Pressure Liquid/methods
*Transferases/metabolism/chemistry
*Enzyme Assays/methods
Catalysis
Biocatalysis

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

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

@article {pmid40660446,
year = {2026},
author = {Singh, D},
title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.},
journal = {Current drug safety},
volume = {21},
number = {2},
pages = {94-107},
doi = {10.2174/0115748863375490250626163609},
pmid = {40660446},
issn = {2212-3911},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles ; *Mitochondrial Diseases/drug therapy ; },
abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/physiopathology/metabolism
*Mitochondria/drug effects/metabolism/pathology
Animals
*Drug Delivery Systems/methods
Nanoparticles
*Mitochondrial Diseases/drug therapy

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

@article {pmid40663766,
year = {2025},
author = {Matthews, AM and Whiteley, AM},
title = {UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.},
journal = {Biochemical Society transactions},
volume = {53},
number = {4},
pages = {823-833},
pmid = {40663766},
issn = {1470-8752},
support = {R01 NS131660/NS/NINDS NIH HHS/United States ; T32 GM142607/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Autophagy-Related Proteins/genetics/metabolism ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/genetics/therapy ; Animals ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy ; Mutation ; Mitochondria/metabolism ; Frontotemporal Dementia/genetics/metabolism ; *Cell Cycle Proteins/genetics/metabolism ; },
abstract = {Ubiquilins (UBQLNs) regulate cellular protein turnover by shuttling proteins, or 'clients', to the proteasome or autophagy pathways for degradation. Of the five different UBQLN genes in humans, UBQLN2 is the most highly expressed in the nervous system and muscle tissue and has been linked to multiple neurodegenerative diseases. In particular, point mutations of UBQLN2 cause an X-linked, dominant form of amyotrophic lateral sclerosis (ALS), ALS with frontotemporal dementia (ALS/FTD), or FTD. Failed protein degradation is a hallmark of many neurodegenerative diseases, including ALS and FTD; however, it is not clear exactly how ALS/FTD-associated UBQLN2 mutations contribute to pathogenesis. Recent studies have revealed the complexity of UBQLN2 biology and allow deeper understanding as to how UBQLN2 dysfunction may contribute to neurodegenerative disease. UBQLN2 is necessary for mitochondrial protein degradation and for regulating mitochondrial turnover, both of which are essential for motor neurons and have been implicated in the pathogenesis of ALS. Stress granule (SG) formation and regulation are also affected by UBQLN2 mutations, and their dysregulation may contribute to the toxic protein aggregation and SG changes observed in neurodegenerative disease. Finally, there are compelling links connecting UBQLN2 dysfunction with changes to downstream neuronal morphology, function, and behavior. This review will detail the emerging consensus on how UBQLN2 protects against neurodegenerative disease and will provide insights into potential therapeutic approaches.},
}

Humans
Autophagy-Related Proteins/genetics/metabolism
*Adaptor Proteins, Signal Transducing/genetics/metabolism
*Neurodegenerative Diseases/metabolism/genetics/therapy
Animals
Amyotrophic Lateral Sclerosis/genetics/metabolism
Autophagy
Mutation
Mitochondria/metabolism
Frontotemporal Dementia/genetics/metabolism
*Cell Cycle Proteins/genetics/metabolism

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

Humans
*Molecular Chaperones/metabolism/chemistry
*RNA/metabolism/chemistry
G-Quadruplexes
Animals
Protein Folding
Protein Aggregates
*RNA-Binding Proteins/metabolism/chemistry
Amyotrophic Lateral Sclerosis/metabolism

@article {pmid40673975,
year = {2025},
author = {Giorgi, A and Heckman, CJ and Perreault, MC},
title = {Spinally projecting serotonergic neurons in motor network modulation.},
journal = {Journal of neurophysiology},
volume = {134},
number = {5},
pages = {1619-1628},
doi = {10.1152/jn.00139.2025},
pmid = {40673975},
issn = {1522-1598},
support = {20153//National Science Foundation (NSF)/ ; },
mesh = {*Serotonergic Neurons/physiology ; Animals ; Humans ; *Spinal Cord/physiology/cytology ; *Motor Neurons/physiology ; *Brain Stem/physiology/cytology ; Serotonin/metabolism ; },
abstract = {Spinally projecting serotonergic (5-HTsp) neurons represent a heterogeneous population of brainstem neurons whose relevance to the control of movement has largely been inferred. Numerous studies across multiple species have suggested that 5-HTsp neurons exert a widespread influence on spinal sensorimotor networks, operating at multiple levels (primary afferents, interneurons, and motoneurons) through various serotonin receptor subtypes. However, despite the anatomical and neurochemical complexity of the 5-HTsp system, supporting evidence has been mostly derived from indirect approaches [e.g., exogenous application of serotonin (5-HT) and agonists/antagonists of 5-HT receptors]. Direct demonstrations of specific anatomical and functional connectivity have been limited, occasionally yielding discrepant results. Consequently, as the primary provider of serotonin to the spinal cord, the exact contributions of 5-HTsp neurons remain to be fully elucidated. For this mini-review, we sifted through the literature of the last six decades, starting after the characterization of brainstem raphe nuclei and monoaminergic systems, to provide a clearer picture of the anatomy and influences of different 5-HTsp neuron populations on sensorimotor circuits and motor behaviors. We focused on studies reporting direct manipulation of brainstem 5-HTsp neurons, excluding those targeting 5-HT neurotransmission by exogenous application of 5-HT. This emphasis aims to highlight the urgency of resolving how 5-HTsp neuron subpopulations differentiate anatomically and functionally so they can be integrated as dedicated components in current models of supraspinal control of movement and motor diseases such as Parkinson's and amyotrophic lateral sclerosis. Along the way, we point out gaps in knowledge that may be filled using newly available research tools.},
}

*Serotonergic Neurons/physiology
Animals
Humans
*Spinal Cord/physiology/cytology
*Motor Neurons/physiology
*Brain Stem/physiology/cytology
Serotonin/metabolism

@article {pmid40675338,
year = {2025},
author = {Shtilbans, A},
title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tjnut.2025.07.004},
pmid = {40675338},
issn = {1541-6100},
abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10, creatine, and N-acetylcysteine, in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of conditions such as Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.},
}

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

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

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

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

@article {pmid40683546,
year = {2025},
author = {Mehboodi, M and Namdari, MP and Abdollahi, Z and Mobarezi, Z and Kiani, M and Chamani, F and Khanbabaie, H and Rabiei, S and Maleki, MH and Sanati, H and Shahedin, GJ and Isaei, E},
title = {The relationship between increased levels of microbiota-derived lipopolysaccharide in obesity and the pathophysiology of neurodegenerative diseases.},
journal = {Microbial pathogenesis},
volume = {207},
number = {},
pages = {107905},
doi = {10.1016/j.micpath.2025.107905},
pmid = {40683546},
issn = {1096-1208},
mesh = {Humans ; *Lipopolysaccharides/metabolism ; *Obesity/microbiology/complications ; *Neurodegenerative Diseases/physiopathology/microbiology/etiology ; *Gastrointestinal Microbiome/physiology ; Animals ; Inflammation ; Blood-Brain Barrier ; Oxidative Stress ; },
abstract = {Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin derived from the outer membrane of Gram-negative bacteria, has been identified as a crucial link between obesity-related systemic inflammation and the onset of neurodegenerative diseases. Modifications in gut microbiota associated with obesity disrupt the integrity of the intestinal barrier, resulting in increased permeability and heightened levels of circulating LPS a phenomenon known as metabolic endotoxemia. The elevated presence of LPS promotes persistent low-grade inflammation and oxidative stress, both of which are critical contributors to neurodegeneration. This review aims to explore the biological pathways through which LPS influences the development and advancement of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). The role of LPS in exacerbating neuroinflammation through the activation of microglia and the impairment of the blood-brain barrier (BBB) is thoroughly examined. Moreover, the review delves into the interrelated effects of obesity-related systemic inflammation, insulin resistance, and mitochondrial dysfunction in enhancing LPS-driven neurodegenerative mechanisms. Special emphasis is placed on the common pathological characteristics present in these disorders, such as protein misfolding, neuronal apoptosis, and disrupted synaptic function, which may be exacerbated by LPS-related processes. By clarifying the relationships between obesity, LPS, and neurodegenerative diseases, this review underscores potential therapeutic approaches aimed at modulating gut microbiota, improving intestinal barrier function, and mitigating systemic inflammation to prevent or decelerate the progression of these debilitating disorders.},
}

Humans
*Lipopolysaccharides/metabolism
*Obesity/microbiology/complications
*Neurodegenerative Diseases/physiopathology/microbiology/etiology
*Gastrointestinal Microbiome/physiology
Animals
Inflammation
Blood-Brain Barrier
Oxidative Stress

@article {pmid40688669,
year = {2025},
author = {Zhu, RK and Shi, J and Zhou, HJ and Ge, L and Yin, WH and Zeng, H and Wang, XW},
title = {Biological applications of graphene-based nanomaterials in neurodegenerative diseases.},
journal = {Materials today. Bio},
volume = {33},
number = {},
pages = {102064},
pmid = {40688669},
issn = {2590-0064},
abstract = {Neurodegenerative diseases (NDDs) have become a major challenge in global public health due to neurotoxicity caused by progressive neuronal degeneration and abnormal protein aggregation, which has attracted widespread attention. Graphene-based nanomaterials provide innovative solutions for the early diagnosis and precise treatment of NDDs by virtue of their ultra-high conductivity, large specific surface area and multifunctional properties. In this paper, we systematically discuss the key applications of these materials in the diagnosis and treatment of NDDs, and deeply analyze the technological breakthroughs and clinical translation challenges. The core of this paper is to illustrate that graphene-based nanomaterials are expected to reshape the paradigm of NDDs diagnosis and treatment through cross-scale technological innovations, promoting the synergistic development of early diagnosis, personalized treatment and real-time monitoring, and providing a transformative strategy for overcoming NDDs.},
}

@article {pmid40694206,
year = {2025},
author = {Mahto, K and Kuwar, OK and Maloo, A and Kalia, N},
title = {Therapeutic potential of luteolin in neurodegenerative disorders: targeting Nrf2, NFĸB, MAPK, and JAK-STAT pathways to combat neuroinflammation and apoptosis.},
journal = {Inflammopharmacology},
volume = {33},
number = {9},
pages = {5011-5021},
pmid = {40694206},
issn = {1568-5608},
mesh = {*Luteolin/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Apoptosis/drug effects ; Signal Transduction/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; Neuroprotective Agents/pharmacology ; STAT Transcription Factors/metabolism ; Janus Kinases/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; },
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's disease, Multiple sclerosis and Amyotrophic Lateral Sclerosis, are characterized by progressive neuronal loss, oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and apoptosis. The Nrf2/ARE, IĸB/NFĸB, MAPK/AP-1, and JAK-STAT signaling pathways play a pivotal role in these pathological processes, making them promising therapeutic targets. Luteolin, a naturally occurring flavonoid, has demonstrated potent antioxidant, anti-inflammatory, and neuroprotective properties by modulating these interconnected pathways. Activation of Nrf2/ARE signaling by luteolin enhances cellular antioxidant defences, while its inhibition of NFĸB, MAPK/AP-1, and JAK-STAT pathways suppresses neuroinflammation and apoptotic signalling, thereby mitigating neuronal damage. Emerging evidences suggest that luteolin effectively reduces neurotoxic effects by regulating inflammatory cytokine production, stabilizing mitochondrial function, and maintaining redox homeostasis. Its ability to interfere with crosstalk between these signaling pathways highlights its potential as a multi-targeted neuroprotective agent. Preclinical studies have provided strong evidence supporting luteolin's role in mitigating neurodegeneration, suggesting its applicability in neurodegenerative disease management. These findings underscore the therapeutic potential of luteolin in neurodegenerative diseases by targeting multiple pathological mechanisms. However, further investigations are needed to fully elucidate its molecular mechanisms and optimize its therapeutic benefits.},
}

*Luteolin/pharmacology/therapeutic use
Humans
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Apoptosis/drug effects
Signal Transduction/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism
NF-E2-Related Factor 2/metabolism
Neuroprotective Agents/pharmacology
STAT Transcription Factors/metabolism
Janus Kinases/metabolism
NF-kappa B/metabolism
Oxidative Stress/drug effects
Anti-Inflammatory Agents/pharmacology

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

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

@article {pmid40702249,
year = {2025},
author = {Sulthana, N and Mittal, P and Goyal, A and Ballal, S and Maharana, L and Rana, AJ and Khan, Y and Goyal, K and Mishra, R and Ali, H and Gupta, G and Hussain, MS},
title = {Targeting ASK1 signaling in neurodegeneration: molecular insights and therapeutic promise.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {30},
number = {9-10},
pages = {2019-2041},
pmid = {40702249},
issn = {1573-675X},
mesh = {Humans ; *MAP Kinase Kinase Kinase 5/metabolism/genetics/antagonists & inhibitors ; *Neurodegenerative Diseases/genetics/metabolism/drug therapy/pathology ; *Signal Transduction ; Animals ; Apoptosis ; Endoplasmic Reticulum Stress ; Oxidative Stress ; },
abstract = {Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensitive member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is a master regulator of neuronal apoptosis as well as neuroinflammation in neurodegenerative disorders (NDs). Under oxidative and endoplasmic reticulum stress conditions, ASK1 sets off a series of pathways, ultimately leading to impairment of cellular functions and the cell's demise. The comprehensive review focuses on the diverse contributions of ASK1 to neurodegeneration driven by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Human and animal evidence links dysregulated ASK1 signaling is related to amyloid deposition, tau hyperphosphorylation, neuroinflammation, abnormal protein folding, and subsequent neurodegeneration. ASK1 plays a role in tau hyperphosphorylation and amyloid-beta-induced neurotoxicity in AD. ASK1-mediated apoptosis of dopaminergic neurons caused by oxidative stress and aggregation of α-synuclein contributes to PD. Furthermore, ASK1 activation is associated with motor neuron degeneration in ALS related to endoplasmic reticulum stress caused by mutant SOD1. Moreover, the pathogenesis of HD involves the activation of ASK1 by the cellular stress caused by mutant huntingtin protein. ASK1 signaling potentiates inflammatory signals in MS because it is involved in demyelination and neuronal injury. Nonetheless, obstacles persist such as developing brain-targeted therapies, reducing adverse systemic effects, and defining disease-stage-specific functions of ASK1. This review aims to comprehensively examine the role of ASK1 signaling in major NDs, discuss its upstream and downstream regulatory mechanisms, and evaluate the current and emerging therapeutic strategies targeting ASK1.},
}

Humans
*MAP Kinase Kinase Kinase 5/metabolism/genetics/antagonists & inhibitors
*Neurodegenerative Diseases/genetics/metabolism/drug therapy/pathology
*Signal Transduction
Animals
Apoptosis
Endoplasmic Reticulum Stress
Oxidative Stress

@article {pmid40702789,
year = {2025},
author = {Zota, I and Calogeropoulou, T and Chanoumidou, K and Charalampopoulos, I and Gravanis, A},
title = {Synthetic microneurotrophins: Neurotrophin receptors for therapeutics of neurodegenerative diseases.},
journal = {British journal of pharmacology},
volume = {182},
number = {19},
pages = {4466-4489},
doi = {10.1111/bph.70143},
pmid = {40702789},
issn = {1476-5381},
support = {Dinnesmin//FP7 Health/ ; //European Regional Development Fund of the European Union and Greek/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Dehydroepiandrosterone/analogs & derivatives/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Receptors, Nerve Growth Factor/metabolism ; Nerve Growth Factors ; Blood-Brain Barrier/metabolism ; },
abstract = {Neurodegenerative disorders are characterised by the chronic progressive degeneration of specific neuronal subtypes, neuroinflammation, myelin damage and synaptic loss. Despite their growing incidence, advancements in effective treatments remain limited, because of lack of knowledge for the aetiology of the diverse pathophysiology to design systematic therapies. Several studies highlight the role of neurotrophic factors (NTFs) as potential neuroprotective, regenerative therapies for these disorders. Although NTFs hold protective and regenerative potential for chronic neuroinflammatory and neurodegenerative conditions, major hurdles impair their clinical use, such as optimising the dosage of NTFs, minimising the invasiveness of delivery methods, overcoming blood-brain-barrier (BBB) impermeability and managing side effects. In the last two decades our group have synthesised and screened a large chemical library of steroidal analogues of dehydroepiandrosterone (DHEA), an endogenous steroid hormone, for their ability to mimic neurotrophin neuroprotective and neurogenic actions. Interestingly, DHEA was shown to interact with all neurotrophin receptors, acting most probably as an ancestral neurotrophin early in evolution. However, its chronic pharmacological use is questioned by its action as a major precursor of steroidogenesis. This review highlights the findings of numerous preclinical studies on these synthetic, non-toxic, BBB permeable DHEA derivatives, named microneurotrophins (MNTs), deprived of endocrine actions, activators of specific neurotrophin receptors. The multimodal actions of MNTs against neuronal death and activation of microglia, in addition to their beneficial effects in synaptogenesis and neurogenesis, place them as interesting lead molecules in the armamentarium of therapeutics for neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Dehydroepiandrosterone/analogs & derivatives/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
*Receptors, Nerve Growth Factor/metabolism
Nerve Growth Factors
Blood-Brain Barrier/metabolism

@article {pmid40708508,
year = {2026},
author = {Rana, A and Malviya, R and Rajput, S and Sridhar, SB and Wadhwa, T},
title = {Trends in Nanoparticle-based Strategies for the Management of Neuroinflammation.},
journal = {CNS & neurological disorders drug targets},
volume = {25},
number = {1},
pages = {39-55},
pmid = {40708508},
issn = {1996-3181},
mesh = {Humans ; *Neuroinflammatory Diseases/drug therapy ; Animals ; *Nanoparticles/therapeutic use ; *Drug Delivery Systems/methods ; *Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/drug effects ; Microglia/drug effects ; },
abstract = {Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.},
}

Humans
*Neuroinflammatory Diseases/drug therapy
Animals
*Nanoparticles/therapeutic use
*Drug Delivery Systems/methods
*Neurodegenerative Diseases/drug therapy
Blood-Brain Barrier/drug effects
Microglia/drug effects

@article {pmid40709087,
year = {2025},
author = {Wang, G and Zhou, X and Pang, X and Ma, K and Li, L and Song, Y and Hou, D and Wang, X},
title = {Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1625821},
pmid = {40709087},
issn = {1663-9812},
abstract = {With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.},
}

@article {pmid40710301,
year = {2025},
author = {Pasqualucci, E and Angeletti, D and Rosso, P and Fico, E and Zoccali, F and Tirassa, P and De Virgilio, A and de Vincentiis, M and Severini, C},
title = {Management of Dysarthria in Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {14},
number = {14},
pages = {},
pmid = {40710301},
issn = {2073-4409},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Dysarthria/therapy/diagnosis/etiology/physiopathology/complications ; Quality of Life ; },
abstract = {Amyotrophic lateral sclerosis (ALS) stands as the leading neurodegenerative disorder affecting the motor system. One of the hallmarks of ALS, especially its bulbar form, is dysarthria, which significantly impairs the quality of life of ALS patients. This review provides a comprehensive overview of the current knowledge on the clinical manifestations, diagnostic differentiation, underlying mechanisms, diagnostic tools, and therapeutic strategies for the treatment of dysarthria in ALS. We update on the most promising digital speech biomarkers of ALS that are critical for early and differential diagnosis. Advances in artificial intelligence and digital speech processing have transformed the analysis of speech patterns, and offer the opportunity to start therapy early to improve vocal function, as speech rate appears to decline significantly before the diagnosis of ALS is confirmed. In addition, we discuss the impact of interventions that can improve vocal function and quality of life for patients, such as compensatory speech techniques, surgical options, improving lung function and respiratory muscle strength, and percutaneous dilated tracheostomy, possibly with adjunctive therapies to treat respiratory insufficiency, and finally assistive devices for alternative communication.},
}

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

@article {pmid40712472,
year = {2025},
author = {Yousef, AM and Cantor-Cutiva, LC and Hunter, EJ},
title = {Mapping 74 years in acoustic analysis of voice disorders: A bibliometric review and future research directions.},
journal = {Journal of communication disorders},
volume = {117},
number = {},
pages = {106555},
pmid = {40712472},
issn = {1873-7994},
support = {R01 DC012315/DC/NIDCD NIH HHS/United States ; },
mesh = {Humans ; *Bibliometrics ; *Voice Disorders/diagnosis/physiopathology ; *Speech Acoustics ; Speech Production Measurement ; },
abstract = {PURPOSE: This paper conducts a bibliometric analysis to identify and examine the strengths, gaps, and trends in research on acoustic voice assessment for voice disorders.

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

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

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

Humans
*Bibliometrics
*Voice Disorders/diagnosis/physiopathology
*Speech Acoustics
Speech Production Measurement

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

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

@article {pmid40717814,
year = {2025},
author = {Righes, G and Semenzato, L and Koutsikos, K and Zanato, V and Pinton, P and Giorgi, C and Patergnani, S},
title = {The role of autophagy in the pathogenesis and treatment of multiple sclerosis.},
journal = {Autophagy reports},
volume = {4},
number = {1},
pages = {2529196},
pmid = {40717814},
issn = {2769-4127},
abstract = {Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.},
}

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

@article {pmid40717894,
year = {2025},
author = {Yu, M and Ma, H and Lai, X and Wu, J and Shen, M and Yan, J},
title = {Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1592578},
pmid = {40717894},
issn = {1663-4365},
abstract = {Mesenchymal stem cell-derived extracellular vesicles, as carriers for intercellular communication, are rich in bioactive substances such as proteins and nucleic acids, and show unique potential in the treatment of neurodegenerative diseases. Their vesicular structure, with a diameter of 30-150 nm, can penetrate the blood-brain barrier and modulate the activity of microglia and astrocytes by delivering functional molecules. This process inhibits the release of pro-inflammatory factors and enhances the expression of anti-inflammatory mediators, thereby alleviating neuroinflammation in the pathological process of neurodegenerative diseases. As natural drug carriers, extracellular vesicles can improve the targeted delivery efficiency of therapeutic molecules. However, their specific anti-inflammatory mechanisms remain not fully understood and require further exploration. This article discusses the anti-inflammatory effects in the context of neurodegenerative diseases and provides a summary and outlook on the anti-inflammatory actions associated with extracellular vesicles from past research.},
}

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

@article {pmid40724820,
year = {2025},
author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T},
title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
pmid = {40724820},
issn = {1422-0067},
mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; },
abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.},
}

Humans
*Cannabinoids/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Animals
*Inflammation/drug therapy
Central Nervous System/drug effects
*Central Nervous System Diseases/drug therapy

@article {pmid40725270,
year = {2025},
author = {Tahri, A and Niccolai, E and Amedei, A},
title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
pmid = {40725270},
issn = {1422-0067},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; },
abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.},
}

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

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

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

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

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

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

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

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

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

@article {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 {pmid40738791,
year = {2025},
author = {Roy, A and Dawson, VL and Dawson, TM},
title = {From metabolism to mind: The expanding role of the GLP-1 receptor in neurotherapeutics.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {22},
number = {5},
pages = {e00712},
pmid = {40738791},
issn = {1878-7479},
mesh = {Humans ; Animals ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; *Brain/drug effects/metabolism ; },
abstract = {GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes and obesity, are now under investigation for neuroprotective effects in a range of neurological disorders. These agents, whose receptors are widely expressed in brain regions involved in cognition and metabolism, modulate neurotransmitter release and promote neurogenesis. While preclinical studies consistently demonstrate benefits in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), clinical trial outcomes have been variable, largely owing to heterogeneity in study populations and trial design. Newer agents, such as NLY01 and tirzepatide, are under development to enhance central nervous system penetration and efficacy. Although GLP-1RAs are generally safe in metabolic conditions, their use in neurological diseases requires careful monitoring and patient selection. Future directions include developing reliable biomarkers, implementing precision medicine strategies, and exploring the use of combination therapies to maximize therapeutic potential.},
}

Humans
Animals
*Glucagon-Like Peptide-1 Receptor Agonists
*Glucagon-Like Peptide-1 Receptor/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy/metabolism
*Brain/drug effects/metabolism

@article {pmid40739673,
year = {2025},
author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X},
title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {690},
pmid = {40739673},
issn = {2047-783X},
mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; },
abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.},
}

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

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

@article {pmid40744389,
year = {2025},
author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK},
title = {Natural bioactive compounds as modulators of autophagy: A herbal approach to the management of neurodegenerative diseases.},
journal = {European journal of pharmacology},
volume = {1005},
number = {},
pages = {178003},
doi = {10.1016/j.ejphar.2025.178003},
pmid = {40744389},
issn = {1879-0712},
mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Animals ; *Biological Products/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.},
}

Humans
*Autophagy/drug effects
*Neurodegenerative Diseases/drug therapy/pathology/metabolism
Animals
*Biological Products/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology

@article {pmid40747386,
year = {2025},
author = {Arnold, WD and Castoro, R and Saxena, S},
title = {Innovations In Physical Medicine and Rehabilitation: Advances in the Diagnosis, Treatment, and Care of Amyotrophic Lateral Sclerosis.},
journal = {Missouri medicine},
volume = {122},
number = {3},
pages = {199-205},
pmid = {40747386},
issn = {0026-6620},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/rehabilitation ; *Physical and Rehabilitation Medicine/trends/methods ; Quality of Life ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that causes loss of upper and lower motor neurons, leading to muscle weakness and ultimately death. This review highlights recent advancements in Neuromuscular Medicine and Physical Medicine and Rehabilitation (PM&R), emphasizing innovations in the diagnosis, treatment, and care delivery for ALS. The field of PM&R emphasizes a multidisciplinary, patient-centered approach, incorporating advanced diagnostic tools, therapeutic strategies, adaptive equipment, and telerehabilitation to optimize function. Neuromuscular PM&R physicians play a key role in managing symptoms and maximizing functional independence. Current disease-modifying therapies include riluzole and edaravone which provide only modest benefits, but emerging gene therapies like tofersen for SOD1-related ALS offer promise for targeted treatment for genetic forms of ALS. Future advancements in regenerative therapies, biotechnologies, and digital health integration hold the potential to improve care and enhance the quality of life and functional independence of individuals living with ALS.},
}

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

@article {pmid40754996,
year = {2025},
author = {Stam, R},
title = {Low frequency magnetic field exposure and neurodegenerative disease: systematic review of animal studies.},
journal = {Electromagnetic biology and medicine},
volume = {44},
number = {4},
pages = {566-580},
doi = {10.1080/15368378.2025.2540435},
pmid = {40754996},
issn = {1536-8386},
mesh = {Animals ; *Magnetic Fields/adverse effects ; *Neurodegenerative Diseases/etiology/pathology/therapy ; Humans ; Disease Models, Animal ; },
abstract = {Epidemiological studies have found an association between occupational exposure to low frequency magnetic fields and the occurrence of motor neuron disease and Alzheimer's disease. No association has been found for Parkinson's disease and the evidence for multiple sclerosis is insufficient. Animal models studying the effects of low frequency magnetic fields on neurodegenerative disease induction or progression could provide more evidence on causation and the underlying mechanisms. A systematic search and review was conducted of peer-reviewed research articles involving animal experiments on the effects of low frequency magnetic field exposure on behavioural and neuroanatomical outcomes relevant for neurodegenerative diseases in humans. Firstly, experimental studies in naive animals do not support a causal relationship between exposure to low frequency magnetic fields and the induction of neuropathology relevant for Alzheimer's disease, but the number of studies relevant for motor neuron disease, multiple sclerosis and Parkinson's disease is too limited to draw conclusions. Secondly, experimental studies in existing animal models for neurodegenerative disease support a therapeutic (beneficial) effect of low frequency magnetic field treatment on behavioural and neuroanatomical abnormalities relevant for dementia (including Alzheimer's disease), multiple sclerosis and Parkinson's disease and no effect on disease progression in models relevant for motor neuron disease.},
}

Animals
*Magnetic Fields/adverse effects
*Neurodegenerative Diseases/etiology/pathology/therapy
Humans
Disease Models, Animal

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

@article {pmid40762148,
year = {2025},
author = {Mascias Cadavid, J and Mena Bravo, A and Barkhaus, P and Barnes, B and Benatar, M and Breevoort, S and Brown, A and Carter, GT and Crayle, J and Foucher, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Mcdermott, C and Pattee, G and Pierce, K and Pioro, E and Ratner, D and Rivner, M and Tito, E and Wicks, P and Bedlack, R},
title = {ALSUntangled #80: ISRIB (Integrated stress response InhiBitor).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {7-8},
pages = {821-824},
doi = {10.1080/21678421.2025.2542919},
pmid = {40762148},
issn = {2167-9223},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Animals ; Stress Granules/drug effects/metabolism ; },
abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we assess ISRIB, a molecule that attenuates the integrated stress response (ISR). The ISR is an intracellular signaling network through which cells normally respond to stress, but in ALS it appears to be overactive, leading to the formation of "stress granules" which some but not all investigators believe can triggerapoptotic cell death. ISRIB can attenuate the formation of these stress granules while still allowing parts of protein synthesis to continue. Pre-clinical data demonstrate that ISRIB is beneficial in cell models of ALS. A small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects, though we have not been able to independently verify these benefits. There are no clinical trials evaluating ISRIB in any condition and questions about its solubility and bioavailability have arisen. Currently, we do not have enough evidence to endorse the use of ISRIB for treating ALS. We support further research in disease models and clinical trials to study pharmacokinetics, safety and efficacy.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/metabolism
Humans
Animals
Stress Granules/drug effects/metabolism

@article {pmid40767546,
year = {2025},
author = {Dupuis, L and Robertson, J},
title = {Is amyotrophic lateral sclerosis less severe in mice than in humans?.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {581-587},
pmid = {40767546},
issn = {1473-6551},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology ; Animals ; Humans ; *Disease Models, Animal ; Mice ; Gene Knock-In Techniques ; Mice, Transgenic ; },
abstract = {PURPOSE OF REVIEW: We review here novel knock-in models of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Knock-in mouse models of various familial forms of ALS generally display a mild motor phenotype, with limited progression, that do not recapitulate the full-blown clinical picture of ALS.

SUMMARY: ALS is a devastating neurodegenerative disease in humans. Typically manifesting in the fifth or sixth decade of life, ALS leads to progressive motor dysfunction and death, usually within 2-5 years from symptom onset. A subset of ALS cases are dominantly inherited. Over the last 30 years, multiple mouse models of ALS have been generated, and recent advances in mouse genome editing techniques have enabled the generation of mouse strains carrying orthologous mutations in endogenous genes that mirror those causing familial forms of ALS. Intriguingly, many of these knock-in mouse models develop much milder phenotypes than patients with ALS carrying the same mutations. A full-blown ALS clinical phenotype seems to be only elicited upon overexpression of mutant genes beyond the endogenous levels. Here, we review these novel models and argue that these models could represent how ALS manifests in the mouse species. We also evaluate how these models could be used for characterizing mechanisms and preclinical drug evaluation.},
}

*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology
Animals
Humans
*Disease Models, Animal
Mice
Gene Knock-In Techniques
Mice, Transgenic

@article {pmid40772638,
year = {2025},
author = {Menge, S and Decker, L and Freischmidt, A},
title = {Genetics of ALS - genes and modifier.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {568-573},
pmid = {40772638},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; Mitochondria/genetics ; },
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a complex genetic disorder, and the pace of discoveries is very rapid. This review aims at briefly summarizing our current knowledge, and at discussing the progress of the last two years.

RECENT FINDINGS: Common variation in numerous genes and variants in some nuclear-encoded mitochondrial genes were linked to an increased or modified risk of ALS, respectively. Mitochondrial function, i.e. specific mitochondrial haplotypes and loss-of-function variants in mitochondria-related genes, was identified as potent modifier of ALS survival, but not risk. Pioneering analyses of copy number variations in ALS-related genes revealed an increased load in ALS, but causality is unclear. A rare hyperactive variant of ER stress associated transcription factor CREB3 was linked to both substantially decreased ALS risk and slower disease progression. Furthermore, variants in IGFBP7 were linked to rare "ALS reversals", but existence of such phenotypes is controversial.

SUMMARY: Common variation increasing ALS risk contributes to our understanding of sporadic ALS, and novel structural variants have the potential to at least partly explain the missing heritability in ALS. Identification of mitochondrial function and ER stress signaling as potent disease modifiers provide valuable starting points for therapeutic approaches beyond targeting single causative genes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Genetic Predisposition to Disease/genetics
Mitochondria/genetics

@article {pmid40772655,
year = {2025},
author = {He, J and Fan, D},
title = {Amyotrophic lateral sclerosis in Mainland China: clinical translational challenges and opportunities.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {596-605},
pmid = {40772655},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis ; China/epidemiology ; *Translational Research, Biomedical ; Biomarkers ; },
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) imposes a growing medical and socioeconomic burden in China. This review synthesizes recent advances in understanding ALS epidemiology, biomarker discovery, therapeutic innovations, and policy frameworks in China. It highlights the urgency of addressing challenges, including fragmented healthcare resources, translational medicine gaps, and regional inequities, while emphasizing China's unique contributions to global ALS research.

RECENT FINDINGS: Chinese ALS cohorts exhibit distinct epidemiological profiles, including a younger mean age of onset and prolonged median survival. Policy initiatives, such as ALS inclusion in rare disease registries and insurance reforms, aim to reduce financial burdens of patients. Multimodal biomarker exploration has advanced integrated diagnostic models combining neurofilament light chain (NfL) and clinical data platforms. Neuroimaging and electrophysiological studies reveal glymphatic dysfunction, white matter degeneration, and neuromuscular junction abnormalities, with novel links to hepatic metabolism. Genomic analyses identify population-specific variants. Therapeutic innovations in China include not only biopharmaceuticals, but also integrative traditional Chinese medicine (TCM) approaches.

SUMMARY: China's ALS landscape is transitioning towards precision medicine through biomarker-guided diagnostics and multidisciplinary care models. Key priorities include establishing a national ALS registry, standardizing biomarker validation, and expanding clinical trials to bridge translational medicine gaps.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis
China/epidemiology
*Translational Research, Biomedical
Biomarkers