@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

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

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

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

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

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

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

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

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

@article {pmid40778304,
year = {2025},
author = {Zhang, K and Wen, M and Nan, X and Zhao, S and Li, H and Ai, Y and Zhu, H},
title = {NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1604378},
pmid = {40778304},
issn = {1663-4365},
abstract = {NMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critically contributes to the pathogenesis of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Dysregulated glutamatergic signaling synergizes with pathological protein aggregation (e.g., Aβ, α-synuclein, mutant huntingtin) to drive neuronal loss. We systematically delineate NMDAR-related mechanisms underlying neurodegeneration, highlighting spatial-specific roles (e.g., synaptic NMDAR-mediated neuroprotection versus extrasynaptic NMDAR-mediated excitotoxicity) and crosstalk with mitochondrial dysfunction and oxidative stress. We critically evaluate current therapeutic strategies targeting NMDARs, including subunit-selective modulators, downstream effector modulation, and glutamate transporter modulation designed to restore NMDAR homeostasis. Consequently, NMDARs and their modulators represent promising therapeutic targets for these refractory conditions. This review comprehensively summarizes current research on the involvement of NMDARs and the glutamatergic system in neurodegenerative diseases. Furthermore, we discuss the clinical application of NMDAR-targeting agents and explore emerging therapeutic strategies focused on modulating NMDAR-related pathways. This article aims to provide a reference for elucidating the molecular mechanisms underlying these neurodegenerative disorders and to highlight potential avenues for future drug development.},
}

@article {pmid40779613,
year = {2026},
author = {Chaouch, A and Crook, A and Douglas, AGL and McDermott, CJ and Al-Chalabi, A and McNeill, A and Bedford, J and Howard, J and MacLeod, R},
title = {The use of genetic testing in amyotrophic lateral sclerosis (ALS): a practical approach.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {27},
number = {1-2},
pages = {28-34},
doi = {10.1080/21678421.2025.2539895},
pmid = {40779613},
issn = {2167-9223},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/methods ; Genetic Counseling ; Genetic Predisposition to Disease/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease thought to be precipitated by genetic, environment and lifestyle factors. In the UK, whole genome sequencing has become available to all people living with ALS, regardless of their family history or age of onset of disease. However, there is currently no formal guidance on how to deliver genetic counseling and testing in busy mainstream clinics. This article offers practical suggestions to clinicians who may wish or need to discuss genomic testing. As more clinical trials and targeted gene therapies develop, it is likely that conversations will evolve, reflecting the dynamic nature of this important and complex field.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/diagnosis
*Genetic Testing/methods
Genetic Counseling
Genetic Predisposition to Disease/genetics

@article {pmid40782358,
year = {2026},
author = {St Clair-Sullivan, N and Brighton, LJ and Jha, P and Bone, AE and Sudirman, NA and Maddocks, M and Bayly, J},
title = {Assistive technologies for people with advanced disease and in palliative care: a scoping review.},
journal = {Disability and rehabilitation. Assistive technology},
volume = {21},
number = {1},
pages = {32-48},
doi = {10.1080/17483107.2025.2536175},
pmid = {40782358},
issn = {1748-3115},
mesh = {Humans ; *Self-Help Devices ; *Palliative Care ; Quality of Life ; *Persons with Disabilities/rehabilitation ; Dementia/rehabilitation ; Neoplasms ; Parkinson Disease/rehabilitation ; },
abstract = {Population ageing, multi-morbidity and associated disability is shifting global demand for health and care services. Innovative solutions are required to meet the evolving needs of people with advanced disease, support independent functioning and quality of life. This scoping review aimed to map and examine evidence on the role of assistive technology in adults with advanced disease and those receiving palliative care. A systematic search of Medline, Embase, PsychINFO and Cinahl, was conducted from inception to 31[st] July 2024 for studies investigating use of assistive technologies in people with advanced disease or receiving palliative care. Titles and abstracts were independently screened before full texts retrieved for eligibility review, data extraction, synthesis and descriptive analysis. 23/811 screened papers met eligibility criteria. Participants included ALS/MND (n13/23); palliative care (n4/23); cancer (n2/23); dementia (n2/23); Parkinson's (n1/23) and frailty (n1/23). Studies evaluated assistive technologies supporting ten functional domains; most frequently to support communication and information management (n13/23), least frequently orthoses and prosthesis, and domestic activities and participation in domestic life (n1/23). Outcomes of assistive technology use related to functioning, quality of life, dignity in end-of-life care and health service use. Implications for individual users, device design and delivery are discussed. This review highlights potential benefits of assistive technologies and gaps in research on their use for adults with advanced disease or receiving palliative care. Empirical evidence is limited and focuses on communication enhancing high-tech devices. Future research should explore assistive technology's impact over time on health outcomes, alongside strategies to integrate provision in care.},
}

Humans
*Self-Help Devices
*Palliative Care
Quality of Life
*Persons with Disabilities/rehabilitation
Dementia/rehabilitation
Neoplasms
Parkinson Disease/rehabilitation

@article {pmid40784657,
year = {2025},
author = {Babcock, KJ and Abdolmohammadi, B and McKee, AC},
title = {Recent Advances in Chronic Traumatic Encephalopathy.},
journal = {The American journal of pathology},
volume = {195},
number = {11},
pages = {2048-2058},
pmid = {40784657},
issn = {1525-2191},
support = {P30 AG072978/AG/NIA NIH HHS/United States ; R01 AG062348/AG/NIA NIH HHS/United States ; R01 NS119651/NS/NINDS NIH HHS/United States ; U54 NS115266/NS/NINDS NIH HHS/United States ; },
abstract = {Exposure to repeated head impacts (RHIs), such as those experienced in contact sports or military service, can lead to the development of chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. CTE cannot be diagnosed during life, only by post-mortem neuropathologic examination. The pathognomonic lesion of CTE consists of a perivascular accumulation of hyperphosphorylated tau as neurofibrillary tangles and dotlike neurites, preferentially at the depths of cortical sulci. The biomechanics of RHI involve acceleration, deceleration, and rotational forces that distort brain tissue and strain fragile structures, such as blood vessels and axons, especially in the crevices of the brain, where these forces are localized. CTE is unique from other tauopathies in its molecular structure, pattern, and regional distribution of tau. Studies in American football, rugby, and ice hockey players demonstrate a dose-response relationship between years of exposure to sport and increased CTE risk and severity. The clinical symptoms associated with CTE are classified as traumatic encephalopathy syndrome. Exposure to RHI also increases the deposition of other pathologic proteins, including β-amyloid, α-synuclein, and transactive response DNA-binding protein (TDP-43), raising the risk for other neurodegenerations, such as Alzheimer disease, Lewy body disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis.},
}

@article {pmid40787733,
year = {2025},
author = {Raaphorst, J and Gullick, NJ and Shokraneh, F and Brassington, R and Min, M and Ali, SS and Gordon, PA},
title = {Non-targeted immunosuppressive and immunomodulatory therapies for idiopathic inflammatory myopathies.},
journal = {The Cochrane database of systematic reviews},
volume = {8},
number = {8},
pages = {CD015855},
pmid = {40787733},
issn = {1469-493X},
mesh = {Humans ; *Myositis/drug therapy ; *Immunosuppressive Agents/therapeutic use/adverse effects ; Randomized Controlled Trials as Topic ; Dermatomyositis/drug therapy ; *Immunomodulating Agents/therapeutic use/adverse effects ; Bias ; Child ; Adult ; Polymyositis/drug therapy ; },
abstract = {BACKGROUND: Idiopathic inflammatory myopathies (IIM) are autoimmune-mediated inflammatory disorders of skeletal muscles with non-muscle involvement in some people, which carry significant morbidity and mortality. Treatment of IIM represents an area of unmet need. This review is an update of a review previously published in 2012, as new and promising data on non-targeted treatments have emerged.

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

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

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

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

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

AUTHORS' CONCLUSIONS: Our review shows improvement in disability, muscle strength and skin symptoms following IVIg in people with refractory DM (for PM, these data are not reliable; other subtypes have not been investigated in RCTs). The improvements related to IVIg in DM may be clinically meaningful, but the absence of established minimal clinically important differences (MCIDs) for both disability and muscle strength in IIM does not facilitate interpretation. For the other agents, the small number of trials of immunosuppressive and immunomodulatory therapies is inadequate to decide whether these agents are beneficial in IIM (excluding IBM). Our review shows room for improvement in the conduct and reporting of clinical trials in IIM, as well as the need to further investigate MCIDs for important outcome measures in IIM.},
}

Humans
*Myositis/drug therapy
*Immunosuppressive Agents/therapeutic use/adverse effects
Randomized Controlled Trials as Topic
Dermatomyositis/drug therapy
*Immunomodulating Agents/therapeutic use/adverse effects
Bias
Child
Adult
Polymyositis/drug therapy

@article {pmid40794238,
year = {2026},
author = {Jellinger, KA},
title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {133},
number = {5},
pages = {831-841},
pmid = {40794238},
issn = {1435-1463},
support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; },
mesh = {Humans ; *Supranuclear Palsy, Progressive/epidemiology/pathology ; Comorbidity ; },
abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.},
}

Humans
*Supranuclear Palsy, Progressive/epidemiology/pathology
Comorbidity

@article {pmid40794569,
year = {2025},
author = {Benatar, M and Staffaroni, AM and Wuu, J and McDermott, MP and Quintana, M and Swidler, J and Andersen, G and Huey, ED and Turner, MR and Macklin, EA and Berry, JD and McMillan, CT and Gendron, T and Onyike, C and Rosen, H and Heuer, HW and Grignon, AL and Dave, KD and Balas, C and Gleixner, A and Satlin, A and Dunn, B and Dacks, P and Boxer, AL},
title = {Design considerations for C9orf72 disease prevention trials.},
journal = {Brain : a journal of neurology},
volume = {148},
number = {11},
pages = {3844-3855},
pmid = {40794569},
issn = {1460-2156},
support = {//Association for Frontotemporal Degeneration/ ; //ALS Association/ ; },
mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/prevention & control ; *Frontotemporal Dementia/genetics/prevention & control ; *Clinical Trials as Topic/methods ; DNA Repeat Expansion/genetics ; Research Design ; },
abstract = {The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.},
}

Humans
*C9orf72 Protein/genetics
*Amyotrophic Lateral Sclerosis/genetics/prevention & control
*Frontotemporal Dementia/genetics/prevention & control
*Clinical Trials as Topic/methods
DNA Repeat Expansion/genetics
Research Design

@article {pmid40795649,
year = {2025},
author = {Rabbani, MG and Alif, SM and Zhou, Z and Ryan, J and Karim, MN},
title = {Association between higher serum uric acid levels and cognitive function: a systematic review and meta-analysis.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {10},
pages = {},
pmid = {40795649},
issn = {1758-535X},
mesh = {Humans ; *Uric Acid/blood ; *Cognition/physiology ; Male ; Female ; Cross-Sectional Studies ; Biomarkers/blood ; },
abstract = {BACKGROUND: Serum uric acid (SUA) levels may be associated with cognitive function, but findings have been inconsistent, potentially varying by cognitive domain and sex. We aimed to determine the association of SUA and different domains of cognitive function.

METHODS: Five electronic databases were searched to identify relevant peer-reviewed articles. Studies investigating the association between SUA levels and cognitive function were included. Standardized mean difference (SMD) was calculated, and separate meta-analyses were conducted for each of the domains. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. Between-study heterogeneity was investigated through subgroup analysis and a meta-regression model using study-level covariates.

RESULTS: Ten prospective cohort and 16 cross-sectional studies were eligible for inclusion, but only a subset of these studies was included in each meta-analysis. Pooled estimates from cross-sectional studies showed that higher SUA levels were significantly associated with better global cognition (n = 6, SMD = 2.27, 95% CI, 1.18-3.35), and learning and memory (n = 4, SMD = 1.49, 95% CI, 1.12-1.87). Sensitivity analysis, excluding the study conducted on amyotrophic lateral sclerosis patients, resulted in better performance estimates for executive function (n = 4, SMD = 0.51, 95% CI, 0.47-0.55) and language (n = 2, SMD = 0.75, 95% CI, 0.71-0.79). The pooled result from 2 prospective cohort studies found a positive relationship between SUA levels and attention (SMD = 0.22, 95% CI, 0.07-0.36). Serum uric acid levels were associated with executive function and learning and memory in males, and with language in females.

CONCLUSIONS: Higher SUA levels were associated with better global cognitive performance executive function, learning and memory, attention and language. These findings highlight low SUA levels as a potentially useful biomarker for cognitive decline.},
}

Humans
*Uric Acid/blood
*Cognition/physiology
Male
Female
Cross-Sectional Studies
Biomarkers/blood

@article {pmid40799366,
year = {2025},
author = {Gao, B and Wang, L and Gong, J and Zhu, Z and Liu, Q and Yuan, H and Wang, H},
title = {The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1579208},
pmid = {40799366},
issn = {1663-4365},
abstract = {Brain health is increasingly recognized as a critical component of overall wellbeing, particularly concerning neurodegenerative diseases, which are characterized by the progressive degeneration of the nervous system. Conditions such as Alzheimer's disease (AD) and Parkinson's disease, together with less common disorders, resembling Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), significantly impact cognitive and physical health, affecting over 50 million individuals worldwide. This review explores the multifaceted relationship between brain health and neurodegeneration, emphasizing the roles of biological, environmental, and lifestyle factors. Notably, physical activity has been identified as a potent intervention that enhances neuroplasticity and metabolic resilience while mitigating the effects of neurodegeneration. Research indicates that exercise activates autophagy, which is crucial for clearing neurotoxic aggregates like amyloid-beta and α-synuclein, thereby promoting neuronal health. Additionally, exercise stimulates the production of neurotrophic factors such as BDNF and GDNF, which are essential for neuronal survival and function. Despite the promising findings regarding exercise as a preventive and therapeutic strategy for neurodegenerative diseases, further investigation into the underlying mechanisms is necessary to optimize these interventions. This review aims to elucidate the complex interactions between exercise, autophagy, and brain health to provide insights into effective strategies for combating neurodegeneration.},
}

@article {pmid40801430,
year = {2025},
author = {Foster-Powell, A and Rostami-Hodjegan, A and Meno-Tetang, G and Mager, DE and Ogungbenro, K},
title = {Mathematical Modeling of Neuroinflammation in Neurodegenerative Diseases.},
journal = {CPT: pharmacometrics & systems pharmacology},
volume = {14},
number = {12},
pages = {1908-1922},
pmid = {40801430},
issn = {2163-8306},
support = {BB/W509930/1//Biotechnology and Biosciences Research Council (BBSRC) Industrial CASE studentship in collaboration with AstraZeneca (AZ), UK/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; Animals ; *Models, Biological ; *Inflammation ; *Models, Theoretical ; *Neuroinflammatory Diseases ; },
abstract = {Age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD) are an increasing public health concern. Whereas the pathology of these diseases is complex, chronic central inflammation, or neuroinflammation, is commonly observed across many neurodegenerative diseases. Despite a huge wealth of resources and promising preclinical testing, effective disease-modifying therapies do not exist. This failure is owing to a combination of poor biological understanding of this response, unsuitable animal models, and poor scaling from pathway up to clinical levels. In order to address these challenges, systems-level mathematical models may be utilized. Here, we provide a background on neuroinflammation and summarize available mathematical models of this response. Models described by ordinary, partial, and delay differential equations, and Boolean logic are introduced and discussed. The results as discussed in this review suggest logic-based modeling as a formalism capable of managing the challenges associated with the modeling of CNS diseases.},
}

Humans
*Neurodegenerative Diseases/pathology/physiopathology
Animals
*Models, Biological
*Inflammation
*Models, Theoretical
*Neuroinflammatory Diseases

@article {pmid40801981,
year = {2025},
author = {Goleij, P and Amini, A and Sanaye, PM and Heidari, MM and Tabari, MAK and Aschner, M and Larsen, DS and Khan, H and Daglia, M},
title = {The IL-12 family cytokines in neurodegenerative diseases: dual roles in neurotoxicity and neuroprotection.},
journal = {Inflammopharmacology},
volume = {33},
number = {9},
pages = {5235-5256},
pmid = {40801981},
issn = {1568-5608},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/immunology ; Animals ; *Interleukin-12/metabolism ; *Neuroprotection/physiology/drug effects ; Neuroprotective Agents/pharmacology ; *Cytokines/metabolism ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and chronic neuroinflammation. Increasing evidence highlights the interleukin-12 (IL-12) cytokine family-including IL-12, IL-23, IL-27, and IL-35-as central regulators of immune responses in the central nervous system (CNS). IL-12 and IL-23 predominantly promote pro-inflammatory pathways by driving Th1/Th17 activity, microglial activation, and neurotoxicity, whereas IL-27 and IL-35 exert anti-inflammatory and neuroprotective effects through IL-10 induction and expansion of regulatory immune subsets. This review synthesizes disease-specific expression patterns and experimental findings, underscoring the dual pathogenic and protective roles of these cytokines. Therapeutic strategies targeting IL-12 family signaling have shown promise in preclinical and clinical contexts. In AD, blockade of IL-12/IL-23 reduced amyloid burden and improved cognition, while agents such as tadalafil and bergapten enhanced IL-27-mediated neuroprotection via PI3K/Akt, Wnt/β-catenin, and cGMP/PKG pathways. In MS, approaches including p40 blockade (ustekinumab, ABT-874), interferon-β therapy, hematopoietic stem cell transplantation, and B-cell depletion (ocrelizumab) variably suppressed IL-12/IL-23 and augmented IL-27/IL-35, influencing relapse rates and progression. Natural compounds such as curcumin, berberine, and vitamin D further highlight metabolic and dietary opportunities for cytokine modulation. In PD, combinatorial regimens combining herbal formulations with anti-inflammatory agents dampened IL-12-driven macrophage activation and supported dopaminergic neuron survival. Taken together, IL-12 family cytokines emerge as both biomarkers and therapeutic targets in NDs. However, context-dependent activity, blood-brain barrier constraints, and incomplete understanding-particularly of IL-35-pose translational challenges warranting further investigation.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy/immunology
Animals
*Interleukin-12/metabolism
*Neuroprotection/physiology/drug effects
Neuroprotective Agents/pharmacology
*Cytokines/metabolism

@article {pmid40802439,
year = {2025},
author = {Sousa, ES and Silva, LACD and Paiva, RM and Soares, KD and Azevedo, IC and Santos, VEP},
title = {Transitional Care for Patients with Amyotrophic Lateral Sclerosis to the Home: A Scoping Review.},
journal = {Revista brasileira de enfermagem},
volume = {78},
number = {3},
pages = {e20240297},
pmid = {40802439},
issn = {1984-0446},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Transitional Care/standards/trends ; *Home Care Services/trends/standards ; },
abstract = {OBJECTIVES: to map the care required for the transition of patients with Amyotrophic Lateral Sclerosis to the home environment.

METHODS: a scoping review was conducted following the JBI guidelines. The search for publications on the topic was carried out in databases such as PubMed and Web of Science between February and May 2023. Full-text studies that addressed the research objective were included. Letters to the editor, editorials, and opinion articles were excluded.

RESULTS: the final sample consisted of seven articles. Regarding care, the studies highlighted assistance with basic life needs, care planning, protocol development, the use of telehealth, and communication between healthcare services.

CONCLUSIONS: the care required for the transition of individuals with Amyotrophic Lateral Sclerosis to the home environment ranges from assistance with basic human needs to the coordination with other healthcare services. Altogether, these actions contribute to a safe and effective transitional process.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/complications
*Transitional Care/standards/trends
*Home Care Services/trends/standards

@article {pmid40806339,
year = {2025},
author = {Sonkodi, B},
title = {The Microbiota-Gut-Brain Axis in Light of the Brain Axes and Dysbiosis Where Piezo2 Is the Critical Initiating Player.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
pmid = {40806339},
issn = {1422-0067},
mesh = {Animals ; Humans ; Alzheimer Disease/metabolism ; *Brain/metabolism ; Circadian Rhythm ; *Dysbiosis/metabolism/microbiology ; *Gastrointestinal Microbiome/physiology ; Hippocampus/metabolism ; *Ion Channels/metabolism ; },
abstract = {The current opinion paper puts into perspective how altered microbiota transplanted from Alzheimer's patients initiates the impairment of the microbiota-gut-brain axis of a healthy recipient, leading to impaired cognition primarily arising from the hippocampus, dysfunctional adult hippocampal neurogenesis, dysregulated systemic inflammation, long-term spatial memory impairment, or chronic pain with hippocampal involvement. This altered microbiota may induce acquired Piezo2 channelopathy on enterochromaffin cells, which, in turn, impairs the ultrafast long-range proton-based oscillatory synchronization to the hippocampus. Therefore, an intact microbiota-gut-brain axis could be responsible for the synchronization of ultradian and circadian rhythms, with the assistance of rhythmic bacteria within microbiota, to circadian regulation, and hippocampal learning and memory formation. Hippocampal ultradian clock encoding is proposed to be through a Piezo2-initiated proton-signaled manner via VGLUT3 allosteric transmission at a distance. Furthermore, this paper posits that these unaccounted-for ultrafast proton-based long-range oscillatory synchronizing ultradian axes may exist not only within the brain but also between the periphery and the brain in an analogous way, like in the case of this depicted microbiota-gut-brain axis. Accordingly, the irreversible Piezo2 channelopathy-induced loss of the Piezo2-initiated ultradian prefrontal-hippocampal axis leads to Alzheimer's disease pathophysiology onset. Moreover, the same irreversible microdamage-induced loss of the Piezo2-initiated ultradian muscle spindle-hippocampal and cerebellum-hippocampal axes may lead to amyotrophic lateral sclerosis and Parkinson's disease initiation, respectively.},
}

Animals
Humans
Alzheimer Disease/metabolism
*Brain/metabolism
Circadian Rhythm
*Dysbiosis/metabolism/microbiology
*Gastrointestinal Microbiome/physiology
Hippocampus/metabolism
*Ion Channels/metabolism

@article {pmid40806377,
year = {2025},
author = {Ghosh, M and Bayat, AH and Pearse, DD},
title = {Small Extracellular Vesicles in Neurodegenerative Disease: Emerging Roles in Pathogenesis, Biomarker Discovery, and Therapy.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
pmid = {40806377},
issn = {1422-0067},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis/pathology/etiology ; Animals ; },
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, ALS, and Huntington's pose a growing global challenge due to their complex pathobiology and aging demographics. Once considered as cellular debris, small extracellular vesicles (sEVs) are now recognized as active mediators of intercellular signaling in NDD progression. These nanovesicles (~30-150 nm), capable of crossing the blood-brain barrier, carry pathological proteins, RNAs, and lipids, facilitating the spread of toxic species like Aβ, tau, TDP-43, and α-synuclein. sEVs are increasingly recognized as valuable diagnostic tools, outperforming traditional CSF biomarkers in early detection and disease monitoring. On the therapeutic front, engineered sEVs offer a promising platform for CNS-targeted delivery of siRNAs, CRISPR tools, and neuroprotective agents, demonstrating efficacy in preclinical models. However, translational hurdles persist, including standardization, scalability, and regulatory alignment. Promising solutions are emerging, such as CRISPR-based barcoding, which enables high-resolution tracking of vesicle biodistribution; AI-guided analytics to enhance quality control; and coordinated regulatory efforts by the FDA, EMA, and ISEV aimed at unifying identity and purity criteria under forthcoming Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. This review critically examines the mechanistic roles, diagnostic potential, and therapeutic applications of sEVs in NDDs, and outlines key strategies for clinical translation.},
}

Humans
*Extracellular Vesicles/metabolism
*Biomarkers/metabolism
*Neurodegenerative Diseases/therapy/metabolism/diagnosis/pathology/etiology
Animals

@article {pmid40806469,
year = {2025},
author = {Wang, J and Shen, Y and Liao, P and Yang, B and Jiang, R},
title = {Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
pmid = {40806469},
issn = {1422-0067},
support = {82401445//National Natural Science Foundation of China/ ; 82271249//National Natural Science Foundation of China/ ; 2024M752251//China Postdoctoral Science Foundation/ ; 2024NSFSC1636//Sichuan Science and Technology Program/ ; 2024HXBH013//Post doctor Research Fund of West China Hospital of Sichuan University/ ; ZYYC23002//1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University/ ; GZC20241141//Postdoctoral Fellowship Program of CPSF/ ; },
mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Oligodendrocyte Precursor Cells/metabolism/pathology ; Oligodendroglia/metabolism ; Cell Differentiation ; },
abstract = {Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.},
}

Humans
*Ion Channels/metabolism
Animals
*Oligodendrocyte Precursor Cells/metabolism/pathology
Oligodendroglia/metabolism
Cell Differentiation

@article {pmid40806624,
year = {2025},
author = {Șerban, M and Toader, C and Covache-Busuioc, RA},
title = {The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
pmid = {40806624},
issn = {1422-0067},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/therapy/drug therapy ; *Artificial Intelligence ; Oxidation-Reduction ; Antioxidants/therapeutic use/pharmacology ; Biomarkers/metabolism ; *Precision Medicine/methods ; Animals ; Reactive Oxygen Species/metabolism ; Brain/metabolism ; Multiomics ; },
abstract = {Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.},
}

Humans
*Oxidative Stress/drug effects
*Mitochondria/metabolism/drug effects
*Neurodegenerative Diseases/metabolism/therapy/drug therapy
*Artificial Intelligence
Oxidation-Reduction
Antioxidants/therapeutic use/pharmacology
Biomarkers/metabolism
*Precision Medicine/methods
Animals
Reactive Oxygen Species/metabolism
Brain/metabolism
Multiomics

@article {pmid40806770,
year = {2025},
author = {Sharbafshaaer, M and Pepe, R and Notariale, R and Canale, F and Tessitore, A and Tedeschi, G and Trojsi, F},
title = {Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
pmid = {40806770},
issn = {1422-0067},
support = {PERMEALS PNRR-MAD-2022-12375731//Italian Ministry of Health/ ; },
mesh = {Humans ; *Motor Neuron Disease/genetics/metabolism/pathology/therapy ; Animals ; *RNA/genetics/metabolism ; *Axons/pathology/metabolism ; *Nerve Degeneration/genetics/pathology ; Molecular Targeted Therapy ; },
abstract = {Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.},
}

Humans
*Motor Neuron Disease/genetics/metabolism/pathology/therapy
Animals
*RNA/genetics/metabolism
*Axons/pathology/metabolism
*Nerve Degeneration/genetics/pathology
Molecular Targeted Therapy

@article {pmid40807333,
year = {2025},
author = {Godela, A and Rogacz, D and Pawłowska, B and Biczak, R},
title = {Natural Neuroinflammatory Modulators: Therapeutic Potential of Fungi-Derived Compounds in Selected Neurodegenerative Diseases.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {15},
pages = {},
pmid = {40807333},
issn = {1420-3049},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Fungi/chemistry ; *Biological Products/therapeutic use/pharmacology/chemistry ; Animals ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients' quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds-such as phenolic compounds, carbohydrates, peptides and proteins, and lipids-that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms.},
}

Humans
*Neurodegenerative Diseases/drug therapy
*Fungi/chemistry
*Biological Products/therapeutic use/pharmacology/chemistry
Animals

@article {pmid40810164,
year = {2025},
author = {Alo, B and Lamers, C},
title = {Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {8},
pages = {2353-2383},
pmid = {40810164},
issn = {2575-9108},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood-brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood-brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood-brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood-brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such in vitro and in vivo testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.},
}

@article {pmid40813983,
year = {2025},
author = {Wang, YT and Li, Q and Liu, JC and Chen, C and Ding, HX and Zha, X and Zhang, K},
title = {Cystatin F-a key player in central nervous system disease.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {203},
pmid = {40813983},
issn = {1742-2094},
support = {81901005//National Natural Science Foundation of China/ ; 81571046//National Natural Science Foundation of China/ ; 2022-MS-203//Natural Science Foundation of Liaoning Province/ ; JYTMS20230122//Basic Scientific Research Project of the Education Department of Liaoning Province/ ; LJKZ0755//Educational Department of Liaoning province/ ; 2023JH2/20200116//Department of Science & Technology of Liaoning province/ ; },
mesh = {Humans ; *Central Nervous System Diseases/metabolism ; Animals ; *Cystatins/metabolism ; Biomarkers, Tumor ; },
abstract = {Cystatin F is an endogenous cysteine protease inhibitor that belongs to the type II cystatin family. It has several unique characteristic structures that determine some of its specific functions. Cystatin F is expressed predominantly in peripheral immune cells and in the microglia of the central nervous system (CNS). Under physiological conditions, the expression of cystatin F in the CNS is minimal. However, emerging evidence suggests that it is significantly upregulated in several CNS diseases. Intriguingly, the role of cystatin F differs across disease contexts-serving a neuroprotective function while promoting pathological progression. Moreover, its function may shift across different pathological stages within the same disorder, reflecting a multifaceted pathophysiology. Cystatin F primarily acts by modulating neuroinflammation, clearing debris, and orchestrating immune responses via its selective expression in disease-associated microglia. As a vital player in CNS diseases, various intervention strategies targeting cystatin F have been proposed, including receptor-interacting protein kinase 1 pathway inhibition, miRNA targeting, mRNA stabilization, necroptosis inhibition, transcriptional regulation and upstream pathway modulation. Several approaches have yielded encouraging results in preclinical models, underscoring the therapeutic potential of modulating cystatin F activity. This review provides a comprehensive overview of the structural features, biological functions, and diverse roles of cystatin F in CNS diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, stroke, Aicardi-Goutières syndrome, prion disease, and glioblastoma. Recent advances in therapeutic interventions focusing on cystatin F have been critically assessed, and key challenges related to clinical translation are outlined, offering new perspectives on therapeutic directions.},
}

Humans
*Central Nervous System Diseases/metabolism
Animals
*Cystatins/metabolism
Biomarkers, Tumor

@article {pmid40817956,
year = {2025},
author = {Mannan, A and Sharma, A and Singh, TG},
title = {Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?.},
journal = {Molecular neurobiology},
volume = {62},
number = {12},
pages = {16512-16556},
pmid = {40817956},
issn = {1559-1182},
mesh = {Humans ; *Neuroprotection/genetics ; Animals ; *Brain/metabolism/pathology ; *Ubiquitin/metabolism/genetics ; *Proteasome Endopeptidase Complex/genetics/metabolism ; Neurodegenerative Diseases/genetics/metabolism ; *Gene Targeting/methods ; },
abstract = {The ubiquitin-proteasome system (UPS) plays a critical role in protein homeostasis within eukaryotic cells. This review article examines the UPS's role in neuronal morphology and neurodegeneration through systematic analysis of current research. In neurodegenerative disorders (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), UPS dysfunction contributes significantly to pathogenesis through accumulation of ubiquitinated misfolded proteins, disruption of cellular proteostasis, impaired substrate ubiquitination, and proteasomal deterioration. The UPS maintains normal central nervous system (CNS) function by regulating protein degradation. When this system fails, cellular proteostasis becomes compromised, accelerating neurodegeneration. Recent research has identified potential interventions for UPS activation through genetic modification and synthetic compounds. This review assesses how specific UPS components could serve as pharmacological targets for treating NDDs. By modulating UPS-mediated genes and pathways, novel therapeutic strategies may emerge for conditions including AD, PD, HD), and ALS. Current evidence suggests the UPS represents a promising therapeutic target for addressing the fundamental protein homeostasis disruptions underlying these devastating neurological conditions. Targeting this system could potentially slow disease progression by restoring proper protein degradation mechanisms and preventing toxic protein accumulation characteristic of NDDs.},
}

Humans
*Neuroprotection/genetics
Animals
*Brain/metabolism/pathology
*Ubiquitin/metabolism/genetics
*Proteasome Endopeptidase Complex/genetics/metabolism
Neurodegenerative Diseases/genetics/metabolism
*Gene Targeting/methods

@article {pmid40821656,
year = {2025},
author = {Sanghai, N and Tranmer, GK},
title = {Use of Proteomics to Explore Biomarkers of Amyotrophic Lateral Sclerosis (ALS): Proof of Principle from Humanized SOD1 Mouse to Human ALS.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {8},
pages = {2415-2430},
pmid = {40821656},
issn = {2575-9108},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disease affecting multiple cellular proteins during the progression of the disease. ALS was first discovered by Charcot in 1869, and since then, scientists have been unable to identify a singular cause of the disease. Further, there are no effective treatments available to cure ALS. The benchmark discovery of humanized preclinical SOD1 mouse models, which recapitulates the clinical and pathological phenotypes of human ALS, gives hope to medicinal chemists and neuroscientists around the globe that a suitable drug-like molecule can be discovered and translated into human beings as a means to slow down the progression of the disease. However, little success has been achieved until now in terms of finding an effective treatment for heterogenic and incurable ALS. One area marked for improvement is the use of semiquantitative, antibody-based targeted Western blotting (WB) experiments, which lack the power to analyze multiple cellular events within the entire dysregulated proteomic system. With the inconsistency of WB experiments, unexpected cellular pathways go undiscovered, and hence, loss of translation with no target engagement is seen from preclinical to human clinical ALS. Recent advancements in discovery-based quantitative proteomics have many advantages over WB. These innovative techniques could help solve the inherent problem in WB and their inability to discover multiple altered proteins with the added capability of longitudinal analysis in preclinical SOD1 models, further validating the findings in human ALS. Herein, we applied a holistic approach to summarize various reports on the use of proteomics in ALS from the published literature, and importantly, we found that using a discovery-based proteomics approach in SOD1 preclinical ALS models has revealed a more diverse and global picture of pathological proteins that affect multiple pathways during different stages of disease progression. Furthermore, we found that the proteomic profiling of the humanized SOD1 mouse model provided a proof of principle for translating the diverse pathological biomarker proteins identified in clinical human ALS cases. Moreover, we believe that advancements in the proteomics approach toward ALS biomarkers could bridge the gap between preclinical and clinical studies, enabling scientists worldwide to discover novel biomarkers and treatments that modify the progression of ALS.},
}

@article {pmid40821767,
year = {2025},
author = {Zhao, S and Fu, D and Lin, Y and Sun, X and Wang, X and Wu, X and Zhang, X},
title = {The role of the microbiome on immune homeostasis of the host nervous system.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1609960},
pmid = {40821767},
issn = {1664-3224},
mesh = {Humans ; *Gastrointestinal Microbiome/immunology ; *Homeostasis/immunology ; Animals ; *Central Nervous System/immunology ; Nervous System Diseases/immunology/microbiology ; },
abstract = {The gut microbiota is often termed the "second genome" of the human body. It has been shown to be one of the most significant environmental factors (non-genetic) influencing the onset, progression, and prognosis of various neurological and psychiatric disorders through its interactions with the host immune, nervous, and endocrine systems. Changes in the function and composition of the gut microbiota are strongly associated with amyotrophic lateral sclerosis, autism spectrum disorder, depression, Parkinson's disease, and Alzheimer's disease. This review summarizes the research regarding the associations and regulatory mechanisms between the gut microbiota and the central nervous system in order to explore the role of the gut microbiota in maintaining neural homeostasis.},
}

Humans
*Gastrointestinal Microbiome/immunology
*Homeostasis/immunology
Animals
*Central Nervous System/immunology
Nervous System Diseases/immunology/microbiology

@article {pmid40822241,
year = {2025},
author = {Tan, X and Gao, N},
title = {The emerging role of cellular senescence in amyotrophic lateral sclerosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1599492},
pmid = {40822241},
issn = {1662-4548},
abstract = {Cellular senescence is a state of permanent cell cycle arrest and is considered a key contributor to aging and age-related diseases, including amyotrophic lateral sclerosis (ALS). The physiological processes of aging lead to a variety of molecular and cellular phenotypes, and evidence of overlap between ALS and aging-related biomarkers suggests that cell type-specific senescence may be a critical factor in ALS. Senescent microglial cells, astrocytes, and neurons have been detected in ALS patients and animal models. However, while accumulating evidence suggests a potential link between cellular senescence and ALS, this connection remains not yet conclusively established. Importantly, how senescent cells may contribute to the neuropathophysiology of ALS remains largely unknown. Additionally, the growing popularity of anti-aging therapies has highlighted the potential of senescent cell clearance as a promising strategy for treating age-related diseases, including ALS. This review provides an overview of cellular senescence, discusses recent advances in understanding how senescence in different cell types influences ALS pathogenesis, and explores the potential role of anti-senescence therapies in ALS treatment.},
}

@article {pmid40829685,
year = {2025},
author = {Wang, Y and Zhou, Y and Tian, H and Li, Q and Chen, Y and Wang, L and Yin, Z and Zhou, J and Liang, F},
title = {NF-κB signalling pathway in neurodegenerative diseases: Acupuncture as a potential therapeutic approach.},
journal = {Brain research},
volume = {1865},
number = {},
pages = {149893},
doi = {10.1016/j.brainres.2025.149893},
pmid = {40829685},
issn = {1872-6240},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism ; *Acupuncture Therapy/methods ; *Signal Transduction/physiology ; Animals ; *NF-kappa B/metabolism ; },
abstract = {The NF-κB signaling pathway plays a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, particularly through its role in the regulation neuroinflammation, oxidative stress, protein misfolding, and apoptosis. Emerging evidence suggests that acupuncture modulates the NF-κB pathway, thus offering therapeutic potential by mitigating neuroinflammation, reducing oxidative stress, and protecting mitochondrial function. Specifically, acupuncture inhibits NF-κB activation, downregulates pro-inflammatory mediators like TNF-α and IL-6, and mitigates neurotoxicity and apoptosis. These effects are substantiated in animal models of Alzheimer's and Parkinson's diseases, with preliminary evidence in amyotrophic lateral sclerosis models. However, current studies largely rely on preclinical models with limited acupoint selection, short observation periods, and a lack of standardized protocols, posing challenges for translation to clinical settings. Future research should prioritize well-designed clinical trials, expand acupoint combinations, and explore synergistic effects with conventional therapies, aiming to maximize acupuncture's therapeutic efficacy in neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/therapy/metabolism
*Acupuncture Therapy/methods
*Signal Transduction/physiology
Animals
*NF-kappa B/metabolism

@article {pmid40831763,
year = {2025},
author = {B S, P and Talwar, P},
title = {Influence of palmitoylation in axonal transport mechanisms in neurodegenerative diseases.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1613379},
pmid = {40831763},
issn = {1662-5102},
abstract = {Progressive functional loss and death of neurons are characteristics of neurodegenerative diseases such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). These diseases are often linked with disruptions in axonal transport and synaptic functions. Accumulation of misfolded proteins is observed as a commonly shared pathology for these diseases, where aberrant accumulation of amyloid beta (Aβ), tau, α-synuclein (α-syn) and TAR DNA-binding protein 43 (TDP-43), are found in AD, PD and ALS, respectively. These accumulations are observed to be involved in disrupting axonal transport and compromising neuronal survival. Axonal transport is an essential process where proper functioning of the transport mechanism is important for maintaining neuronal hemostasis by transporting of proteins, organelles and neurotransmitter complexes. This review explores the role of palmitoylation in regulating neuronal axonal transport and their impact on other neuronal functions along with neurodegeneration mechanisms. Palmitoylation is a reversible lipid modification, which is widely studied second to phosphorylation. Enzymes like palmitoyl acyltransferases and acyl-protein thioesterases are responsible for attachment and detachment of palmitic acid causing palmitoylation and depalmitoylation of neuronal proteins. In axonal transport, palmitoylation influences the localization and functioning of the proteins, which connectively plays a role in synaptic stability by interacting with synaptic scaffolding proteins and neurotransmission receptors.},
}

@article {pmid40832740,
year = {2025},
author = {Lang, C},
title = {Sleep alterations in amyotrophic lateral sclerosis.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {606-613},
pmid = {40832740},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Sleep Wake Disorders/etiology/physiopathology ; },
abstract = {PURPOSE OF REVIEW: This review summarizes recent evidence on sleep disturbances in amyotrophic lateral sclerosis (ALS), emphasizing their role as intrinsic features of the disease process rather than consequence of motor decline.

RECENT FINDINGS: Emerging data suggest that sleep disturbances such as sleep fragmentation, rapid eye movement sleep (REM) and non rapid eye movement sleep (NREM) alterations and circadian changes often precede classic motor symptoms. Structural and functional hypothalamic changes have been observed in early ALS, suggesting a direct role in sleep-wake dysregulation. In addition, impaired glymphatic clearance during sleep may contribute to neurodegeneration by impairing the removal of protein waste. Polysomnographic studies and cohort data support the presence of prodromal sleep abnormalities in both symptomatic patients and gene mutation carriers. Noninvasive ventilation has shown benefits not only in respiratory management but also in improving sleep quality and overall prognosis.

SUMMARY: Sleep alterations in ALS are increasingly recognized as early indicators and potential modulators of disease progression. The hypothalamus and the glymphatic system emerge as key contributors to these disturbances, highlighting sleep as a therapeutic target. Understanding the role of sleep in ALS pathophysiology may aid in earlier diagnosis and novel intervention strategies aimed at modifying disease course.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology
*Sleep Wake Disorders/etiology/physiopathology

@article {pmid40832743,
year = {2025},
author = {Verde, F},
title = {Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {614-619},
doi = {10.1097/WCO.0000000000001411},
pmid = {40832743},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid/metabolism ; *Neurofilament Proteins/cerebrospinal fluid/blood/metabolism ; DNA-Binding Proteins/blood ; tau Proteins/blood ; },
abstract = {REVIEW PURPOSE: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS).

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

SUMMARY: NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid/blood
*Biomarkers/blood/cerebrospinal fluid/metabolism
*Neurofilament Proteins/cerebrospinal fluid/blood/metabolism
DNA-Binding Proteins/blood
tau Proteins/blood

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

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

SUMMARY: ASO therapies have made some promising steps towards treating familial ALS, particularly SOD1 . Ongoing early clinical/preclinical phase research is underway to utilise this technology in other genetic mutations linked with ALS, as well as in sporadic cases.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy
Humans
*Oligonucleotides, Antisense/therapeutic use
Animals
C9orf72 Protein
Superoxide Dismutase-1
*Genetic Therapy/methods
Superoxide Dismutase/genetics
DNA-Binding Proteins/genetics

@article {pmid40835551,
year = {2025},
author = {Rajsic, S and Treml, B and Breitkopf, R and Lederer, W},
title = {Ethical Considerations for Patients Requiring Extracorporeal Cardiopulmonary Resuscitation.},
journal = {Journal of cardiothoracic and vascular anesthesia},
volume = {39},
number = {12},
pages = {3541-3550},
doi = {10.1053/j.jvca.2025.07.032},
pmid = {40835551},
issn = {1532-8422},
mesh = {Humans ; *Extracorporeal Membrane Oxygenation/ethics/methods ; *Cardiopulmonary Resuscitation/ethics/methods ; *Heart Arrest/therapy ; },
abstract = {Immediate recognition of cardiac arrest and the initiation of cardiopulmonary resuscitation (CPR) can significantly improve survival chances. The use of extracorporeal membrane oxygenation during CPR (eCPR) could further enhance survival rates. Current evidence supports the implementation of eCPR as a part of the Advanced Life Support protocol, which may positively affect survival and long-term neurological outcomes and provide additional time for diagnosing and treating the underlying cause of cardiac arrest. Based on the patient's potential for recovery and neurological outcome, multidisciplinary teams can pursue weaning of the patient from mechanical support or withdrawal of care in the case of an unfavorable outcome. These decisions should align with the patient's values, prognosis, and ethical guidelines. A healthcare system that actively promotes eCPR as a standardized part of every Advanced Life Support protocol may face challenges, such as an increased number of patients requiring constant care in long-term care facilities. This could potentially lead to a reduced quality of life and create burdens on patients, families, the healthcare system, and society. Furthermore, in cases of potential organ donation, the principles of beneficence and autonomy may place healthcare providers in significant ethical dilemmas. Given the potential for eCPR to become a standard of care for eligible patients, this work focuses on the ethical and social implications, as well as the impact on the healthcare system.},
}

Humans
*Extracorporeal Membrane Oxygenation/ethics/methods
*Cardiopulmonary Resuscitation/ethics/methods
*Heart Arrest/therapy

@article {pmid40837865,
year = {2025},
author = {Khan, H and Riaz, H and Ahmed, A and Kiyani, MM and Jawad, SM and Ud Din Shah, SS and Abualait, T and Al-Hussain, F and Li, HT and Bashir, S},
title = {CRISPR/Cas9 a genomic engineering technology for treatment in ALS mouse models.},
journal = {Regenerative therapy},
volume = {30},
number = {},
pages = {575-583},
pmid = {40837865},
issn = {2352-3204},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by the death of motor neurons in the spinal cord and brain regions, leading to a reduced survival rate in patients. Nearly 20 gene mutations are associated with ALS, with SOD1, FUS, TARDBP, and C9orf72 mutations being more common. Ninety percent of ALS cases are related to sporadic ALS, while the remaining 10 % are associated with familial ALS. CRISPR/Cas9, a genome engineering technology known as clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9, has the potential for gene editing and for studying the underlying mechanisms of ALS in mouse models. This technique enables neuroscientists to reverse mutations found in ALS mouse models, providing new hope for understanding the complexities of ALS. Additionally, this tool can create mutations to probe the functional changes of genetic diseases. Using CRISPR/Cas9 with an in vivo delivery method involving adeno-associated vectors, it is possible to silence mutations in the SOD1-linked ALS mouse model. Some limitations related to CRISPR/Cas9 have been discussed in previous studies and need to be addressed before clinical trials can proceed. In this review-based study, we summarise the latest research on CRISPR/Cas9 genome editing for ALS in mouse models and discuss its limitations and future prospects as well.},
}

@article {pmid40838713,
year = {2026},
author = {Noor, SM and Reddy, DH and Srikanth, Y and Viswanadh, MK and Dumala, N and Chakravarthy, G and Nalluri, BN and Naryanarao, A and Duguluri, S and Yadagiri, G and Prasanna, VS and Sundaram, S and Gujjari, L and Ramakrishna, K},
title = {Morin hydrate: a comprehensive review on therapeutic potential in treating neurological diseases.},
journal = {Nutritional neuroscience},
volume = {29},
number = {1},
pages = {55-79},
doi = {10.1080/1028415X.2025.2544605},
pmid = {40838713},
issn = {1476-8305},
mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Flavones ; },
abstract = {Background: Morin hydrate is a polyphenolic flavonoid present in various vegetables, fruits, nuts, and sea products. It has been reported to offer multiple protective effects against a range of diseases, including cancer, cardiovascular, liver, neurological, metabolic, and renal disorders.Objective: This review highlights the molecular mechanisms and therapeutic potential of Morin in neurological diseases, including Parkinson's disease, Alzheimer's disease, traumatic brain injury, neuropathic pain, stroke, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, depression, anxiety, sleep, encephalopathy, schizophrenia, and psychosis, etc.Methods: The research and review articles were collected from the Pubmed, Scopus, Web of Science, and Google Scholar databases using 'Morin' and the above-mentioned neurological diseases as keywords.Results: The neuroprotective effects of Morin are primarily attributed to its ability to mitigate oxidative stress, inflammation, excitotoxicity, calcium dysregulation, mitochondrial dysfunction, neurotransmitter alterations, protein modifications, and enzymatic inhibition.Conclusion: Despite its promising pharmacological profile, the clinical adaptation of Morin for combating neurological diseases requires further validation through comprehensive preclinical and clinical investigations.},
}

*Flavonoids/therapeutic use/pharmacology
Humans
*Nervous System Diseases/drug therapy
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects
Flavones

@article {pmid40839108,
year = {2025},
author = {Mukherjea, N and Khandelwal, A and Saluja, R and Kalra, N},
title = {The Role of the human microbiome in neurodegenerative diseases: A Perspective.},
journal = {Current genetics},
volume = {71},
number = {1},
pages = {17},
pmid = {40839108},
issn = {1432-0983},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology ; *Microbiota ; Parkinson Disease/microbiology ; *Gastrointestinal Microbiome ; Alzheimer Disease/microbiology ; Inflammasomes ; Inflammation/microbiology ; },
abstract = {Advances in diagnostics, therapeutics, and large-scale clinical studies have significantly expanded our understanding how human health is shaped by the microorganisms that colonize the body since birth. This article explores the rapidly evolving field of human microbiome research, focusing upon how microbial communities influence neurological health and contribute to the development of neurodegenerative diseases (NDs). Multiple factors, including age, lifestyle, and immunological memory, are recognized as major determinants of an individual's microbiome composition, which in turn can influence the onset and the progression of disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions have been linked to mechanisms including the aggregation of pathogenic proteins (e.g., amyloid-β and α-synuclein), inflammation driven by activation of the Toll-like receptor (TLR) signaling pathway, the NLRP3 inflammasome, as well as the modulatory effect of microbial metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS). The article also highlights ongoing research and emerging strategies aimed at leveraging the human microbiome for better diagnosis, and management of NDs.},
}

Humans
*Neurodegenerative Diseases/microbiology
*Microbiota
Parkinson Disease/microbiology
*Gastrointestinal Microbiome
Alzheimer Disease/microbiology
Inflammasomes
Inflammation/microbiology

@article {pmid40840854,
year = {2025},
author = {Fernàndez-Bernal, A and Mota, N and Pamplona, R and Area-Gómez, E and Portero-Otin, M},
title = {Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1871},
number = {8},
pages = {168021},
doi = {10.1016/j.bbadis.2025.168021},
pmid = {40840854},
issn = {1879-260X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Cholesterol/metabolism ; Animals ; Neurons/metabolism/pathology ; Endoplasmic Reticulum/metabolism/pathology ; Mitochondria/metabolism/pathology ; Astrocytes/metabolism/pathology ; },
abstract = {Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Cholesterol/metabolism
Animals
Neurons/metabolism/pathology
Endoplasmic Reticulum/metabolism/pathology
Mitochondria/metabolism/pathology
Astrocytes/metabolism/pathology

@article {pmid40848858,
year = {2025},
author = {Chen, X and Ma, Y and Liu, H and Wang, Y},
title = {Multifunctional regulation and treatment of ubiquitin specific protease 10.},
journal = {Biochemical pharmacology},
volume = {242},
number = {Pt 1},
pages = {117251},
doi = {10.1016/j.bcp.2025.117251},
pmid = {40848858},
issn = {1873-2968},
mesh = {Humans ; *Ubiquitin Thiolesterase/metabolism/antagonists & inhibitors/chemistry/genetics ; Animals ; Neoplasms/drug therapy/metabolism/enzymology ; Neurodegenerative Diseases/drug therapy/enzymology/metabolism ; },
abstract = {USP10 is a critical deubiquitinating enzyme within the ubiquitin-specific protease family, playing multifaceted roles in cellular physiology and disease pathogenesis. Structurally composed of a G3BP1-interacting motif, a N-terminal domain (mediating most protein interactions), and a catalytic USP domain (residues 415-795, catalytic triad C424-H736-D751), USP10 regulates diverse cellular pathways by stabilizing key proteins through deubiquitination. It exhibits context-dependent functional duality, particularly in cancer: USP10 promotes tumorigenesis in various cancers (e.g., glioblastoma, esophageal, pancreatic, breast cancers) by stabilizing oncoproteins like CCND1, YAP1, HDAC7, and RUNX1, enhancing proliferation, metastasis, and immune evasion. Conversely, it suppresses tumors (e.g., NSCLC, CRC, thyroid cancer) by stabilizing tumor suppressors like p53, PTEN, and Axin1, inhibiting pathways such as Wnt/β-catenin. Beyond oncology, USP10 contributes to neurodegenerative diseases (neuroprotective in PD/ALS, neurotoxic in AD via Tau stabilization), viral immunity (inhibits SARS-CoV-2 infection), inflammatory responses, male reproduction, and metabolic/cardiovascular disorders. Its regulatory mechanisms include phosphorylation (e.g., by AMPK, AKT, ATM) controlling subcellular localization and activity, and ubiquitination via USP13. USP10's therapeutic significance drives inhibitor development (Spautin-1, D1, Wu-5, P22077, Parthenolide), though cross-reactivity within the USP family due to conserved catalytic domains remains a challenge. Novel strategies like PROTACs and engineered ubiquitin variants (UbVs) offer promise for future selective targeting of USP10 dysregulation in diverse diseases. A comprehensive understanding of its structure and context-specific functions is essential for exploiting its full therapeutic potential.},
}

Humans
*Ubiquitin Thiolesterase/metabolism/antagonists & inhibitors/chemistry/genetics
Animals
Neoplasms/drug therapy/metabolism/enzymology
Neurodegenerative Diseases/drug therapy/enzymology/metabolism

@article {pmid40849485,
year = {2025},
author = {Helal, MM and AbouShawareb, H and Abbas, OH and Haddad, R and Zain, Y and Osman, ASA and Hassan, AK},
title = {GLP-1 receptor agonists in Parkinson's disease: an updated comprehensive systematic review with meta-analysis.},
journal = {Diabetology & metabolic syndrome},
volume = {17},
number = {1},
pages = {352},
pmid = {40849485},
issn = {1758-5996},
abstract = {Previous studies have demonstrated an increased risk of developing Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM), as well as more severe and rapid motor and non-motor deterioration in diabetic PD patients compared to their non-diabetic counterparts. Additional research has suggested that diabetic subjects treated with glucagon-like peptide-1 (GLP-1) receptor agonists exhibit a reduced incidence of PD compared to those receiving other anti-diabetic medications. GLP-1 receptor agonists are FDA-approved therapies for T2DM, and recent studies have explored their potential as repurposed treatments for neurodegenerative diseases, including PD, AD, and ALS, as well as cerebrovascular disorders. This systematic review aims to assess the available literature on the efficacy and safety profiles of GLP-1 receptor agonists in PD management. A comprehensive search of PubMed, Scopus, CENTRAL, Web of Science, Embase, and ClinicalTrials.gov was conducted to identify relevant studies. The primary outcomes of this review include motor impairment in PD, as assessed by MDS-UPDRS Part III, as well as motor complications (Part IV) and motor experiences of daily living (Part II), and the incidence of gastrointestinal and systemic side effects. Meta-analysis showed that GLP-1 receptor agonists significantly improved motor function, as reflected by MDS-UPDRS Part III scores in the ON state (mean difference = - 2.88; p = 0.01; I[2] = 30%), although they were associated with a higher incidence of adverse events across all safety outcomes. Findings and conclusions of this review will contribute to a clearer understanding of the therapeutic potential of GLP-1 receptor agonists in PD, guiding future clinical research and treatment strategies.},
}

@article {pmid40849781,
year = {2025},
author = {Kurochkina, N and Rudrabhatla, P},
title = {Role of Calmodulin in Neurodegeneration and Neuroprotection.},
journal = {Mini reviews in medicinal chemistry},
volume = {25},
number = {13},
pages = {965-974},
pmid = {40849781},
issn = {1875-5607},
support = {1142025//School of Theoretical Modeling, Washington, DC, USA/ ; },
mesh = {*Calmodulin/metabolism/chemistry/antagonists & inhibitors ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Neuroprotection ; *Neuroprotective Agents/pharmacology/chemistry ; Calcium/metabolism ; },
abstract = {Intracellular calcium (Ca[2+]) levels are critical in maintaining cellular activities and are tightly regulated. Neuronal degeneration and regeneration rely on calcium-binding proteins. Calmodulin (CaM) is a calcium sensor and the primary regulator of receptors and ion channels that maintain calcium homeostasis. The calmodulin binding domains are present in proteins that serve as risk factors and biomarkers associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases, suggesting calmodulin ligands as emerging therapeutic targets for treatment. Inhibiting CaM to develop new therapies has drawbacks, as CaM is a ubiquitous molecule involved in many regulatory pathways. Recently, new strategies for disrupting CaM interactions with its targets have shown promising approaches to treatment. The structures of human CaM, its binding proteins, and inhibitors are well studied, with particular emphasis on the conservation of CaM amino acid sequences and the ability to bind protein fragments of high sequence variability, which exhibit common characteristics of amphipathic helices carrying basic amino acids. In this review, we discuss structural characteristics of CaM and its ligands in the context of transcriptional regulation. Specific binding of CaM to (1) basic region/helix-loop-helix/leucine zipper and (2) helix-turn-helix high mobility group box containing Sox families of transcription factors highlights common features of CaM binding sequences, which suggest their regulatory functions. We describe key proteins involved in neurodegeneration and transcription factors subject to calmodulin regulation that are candidates for the development of new approaches to treating neuronal diseases.},
}

*Calmodulin/metabolism/chemistry/antagonists & inhibitors
Humans
*Neurodegenerative Diseases/metabolism/drug therapy/pathology
Animals
*Neuroprotection
*Neuroprotective Agents/pharmacology/chemistry
Calcium/metabolism

@article {pmid40855953,
year = {2025},
author = {Logroscino, G and Giannoni-Luza, S and Urso, D and Hamdi, N},
title = {Heterogeneity of frequencies of motor neuron disease across ethnicities and geographical areas: focus on Arabic countries in the Mediterranean area.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {588-595},
pmid = {40855953},
issn = {1473-6551},
mesh = {Humans ; Mediterranean Region/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/ethnology/genetics ; Prevalence ; Incidence ; *Motor Neuron Disease/epidemiology/ethnology ; Registries ; Egypt/epidemiology ; Ethnicity ; },
abstract = {PURPOSE OF REVIEW: Although amyotrophic lateral sclerosis (ALS) epidemiology has been increasingly characterized in many regions, data from Arabic countries remain limited. This review aims to summarize the current knowledge on the burden of ALS in Arabic Mediterranean countries, with a particular focus on Egypt.

RECENT FINDINGS: ALS exhibits significant geographic and ethnic variability in terms of incidence, phenotype, and genetic background. Data from the Global Burden of Disease Study 2021 show that Egypt has one of the lowest age-standardized rates of ALS incidence, prevalence, and mortality in the Mediterranean basin. During the past three decades, Egypt has seen a notable decline in ALS-related Disability-Adjusted Life Years and deaths, in contrast to neighboring countries. A national registry has recently been initiated to enhance epidemiological surveillance in the country.

SUMMARY: ALS in Arabic Mediterranean countries presents a distinct epidemiological profile. These differences likely reflect a combination of genetic, demographic, and healthcare-related factors. Strengthening national registries and promoting regional collaborations will be crucial for gaining a deeper understanding of the determinants of ALS in these underrepresented populations.},
}

Humans
Mediterranean Region/epidemiology
*Amyotrophic Lateral Sclerosis/epidemiology/ethnology/genetics
Prevalence
Incidence
*Motor Neuron Disease/epidemiology/ethnology
Registries
Egypt/epidemiology
Ethnicity

@article {pmid40856865,
year = {2025},
author = {Shandilya, C and Mani, S},
title = {Rho kinase isoforms in neurodegeneration: from cellular functions to therapeutic targets.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {846},
pmid = {40856865},
issn = {1573-4978},
mesh = {Humans ; *rho-Associated Kinases/metabolism/antagonists & inhibitors/genetics ; *Neurodegenerative Diseases/metabolism/drug therapy ; Mitochondria/metabolism ; Animals ; Mitophagy ; Neurons/metabolism ; Protein Isoforms/metabolism ; Signal Transduction ; Reactive Oxygen Species/metabolism ; Mitochondrial Dynamics ; Isoenzymes/metabolism ; Oxidative Stress ; },
abstract = {Mitochondria serve as an important cellular organelle for maintaining neurotransmission and synaptic plasticity in neuronal cells by playing a key role in ATP generation, maintaining calcium homeostasis, and regulating the levels of reactive oxygen species (ROS), etc. The regulation of the dynamic nature of mitochondria, including their fission, fusion, and removal of damaged mitochondria by mitophagy, is also very important for neuronal health. Abnormalities in mitochondrial processes, including but not limited to fission, fusion, and mitophagy, are known to be associated with numerous neurodegenerative diseases (NDDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). In the recent past, the Rho kinase (ROCK) isoforms, particularly ROCK1 and ROCK2, have gained a lot of attention in NDDs, mainly for their role in regulating the dynamics of the mitochondria, mitophagy, and other cell signalling pathways. By adding phosphate groups to Drp1, ROCK1 is crucial in supporting excessive mitochondrial fission, causing the death of neuronal cells. On the other hand, ROCK2 inhibits Parkin-dependent mitophagy by inhibiting the PTEN protein, the activator of Parkin-dependent mitophagy. This impaired mitochondrial quality control via reduced mitophagic flux leads to oxidative stress and neuronal degeneration, the central pathological feature of NDDs. The inhibition of ROCK isoforms has shown great promise in neuroprotective effects, controlling the dynamics of mitochondria in neuronal cells, lowering inflammation, and improving motor and cognitive functions in preclinical models of different NDDs, indicating ROCK isoforms as an attractive therapeutic target in different NDDs. This review aims to highlight the therapeutic significance of targeting ROCK isoforms in different NDDs.},
}

Humans
*rho-Associated Kinases/metabolism/antagonists & inhibitors/genetics
*Neurodegenerative Diseases/metabolism/drug therapy
Mitochondria/metabolism
Animals
Mitophagy
Neurons/metabolism
Protein Isoforms/metabolism
Signal Transduction
Reactive Oxygen Species/metabolism
Mitochondrial Dynamics
Isoenzymes/metabolism
Oxidative Stress

@article {pmid40858858,
year = {2025},
author = {Loo, YS and Yusoh, NA and Yap, K and Ng, CS},
title = {Programmable self-replicating JEV nanotherapeutics redefine RNA delivery in ALS.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1282},
pmid = {40858858},
issn = {2399-3642},
support = {PM010CNI000148//International Brain Research Organization (IBRO)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Encephalitis Virus, Japanese/genetics/physiology ; *Oligonucleotides, Antisense/administration & dosage/genetics ; *Genetic Therapy/methods ; MicroRNAs/genetics ; Virus Replication ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, leading to paralysis and respiratory failure. Current therapies offer limited benefits, highlighting the need for novel therapeutic strategies. Antisense oligonucleotides (ASO) and CRISPR/Cas9 gene editing hold promise, but their effective delivery to the central nervous system (CNS) remains a significant challenge. Here, a potential approach involves utilizing engineered Japanese encephalitis virus (JEV) as a self-replicating nanocarrier for targeted ASO delivery to motor neurons. By leveraging JEV's natural neurotropism and "Trojan horse" mechanism of immune cell-mediated CNS entry, this strategy overcomes the blood-brain and blood-spinal cord barriers (BBB/BSCB). Incorporation of ASO sequences within the JEV genome facilitates co-packaging and sustained therapeutic delivery, while microRNA (miRNA)-mediated attenuation may enhance safety and CNS specificity. This theoretical framework offers a potential paradigm shift in CNS gene therapy for ALS and other neurodegenerative diseases by enabling efficient, targeted, and sustained ASO delivery. However, experimental validation remains critical to assess its safety and therapeutic efficacy.},
}

*Amyotrophic Lateral Sclerosis/therapy/genetics
Humans
Animals
*Encephalitis Virus, Japanese/genetics/physiology
*Oligonucleotides, Antisense/administration & dosage/genetics
*Genetic Therapy/methods
MicroRNAs/genetics
Virus Replication

@article {pmid40859959,
year = {2025},
author = {Mao, S and Qiao, R and Wang, Q and Shen, L and Li, D and Huo, X and Wang, J and Liu, K and Chen, W and Zhu, T and Zhang, B and Leng, S and Bai, Y},
title = {Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.},
journal = {MedComm},
volume = {6},
number = {9},
pages = {e70329},
pmid = {40859959},
issn = {2688-2663},
abstract = {Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.},
}

@article {pmid40863128,
year = {2025},
author = {Pawłowska, M and Kruszka, J and Porzych, M and Garbarek, J and Nuszkiewicz, J},
title = {Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.},
journal = {Metabolites},
volume = {15},
number = {8},
pages = {},
pmid = {40863128},
issn = {2218-1989},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders.},
}

@article {pmid40866928,
year = {2025},
author = {Tsang, VSK and Malaspina, A and Henson, SM},
title = {The metabolic intersection between immunosenescence and neuroinflammation in amyotrophic lateral sclerosis.},
journal = {Journal of inflammation (London, England)},
volume = {22},
number = {1},
pages = {36},
pmid = {40866928},
issn = {1476-9255},
support = {BBX009610/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Although it is traditionally viewed as a neuron-centric disease, neurodegeneration is increasingly linked to immunosenescence and age-related immune dysfunction, but the mechanisms connecting immune ageing to neurodegeneration remain poorly understood. In this review, we explore how metabolic reprogramming, especially the loss of metabolic plasticity in senescent immune cells, drives neuroinflammation in ALS. Senescent immune cells, including microglia and T cells, exhibit mitochondrial dysfunction, redox imbalance, impaired autophagy, and altered nutrient-sensing pathways that impair their homeostatic and reparative capacities. These cells adopt a metabolically demanding pro-inflammatory phenotype, sustaining an inflammatory secretome while promoting glial activation and neuronal damage. Finally, we discuss how targeting immunometabolic pathways may offer new therapeutic opportunities to restore immune balance, mitigate neuroinflammation, and potentially slow ALS progression. Understanding the metabolic basis of immune ageing is essential for developing effective, age-tailored interventions for ALS.},
}

@article {pmid40868211,
year = {2025},
author = {Flor, J and Silveira, AT and Martins, IA and Otero, LB and Silva, FM and Vizuete, AFK and Wink, MR and Rigatto, K},
title = {Biological Actions of Alamandine: A Scoping Review.},
journal = {Biomedicines},
volume = {13},
number = {8},
pages = {},
pmid = {40868211},
issn = {2227-9059},
abstract = {Objective: This scoping review aims to comprehensively map the existing literature on the mechanisms of action of Alamandine (ALA), a peptide within the renin-angiotensin system, and its effects across various physiological systems. Materials and Methods: Utilizing the Joanna Briggs Institute methodology, a thorough search of databases including PubMed, Embase, Scopus, and Web of Science was conducted up to 30 January 2025. The review focused on identifying studies that explore the biological and therapeutic roles of ALA in different contexts, incorporating in vivo, in vitro, and in silico research. Results: A total of 590 records were initially identified, with 25 meeting the eligibility criteria for inclusion in this review. China emerged as the leading contributor to the research in this area, with a significant focus on the cardiovascular system. The studies revealed that ALA exhibits a range of beneficial effects, including anti-inflammatory, vasodilatory, antifibrotic, and antiapoptotic actions. These effects are primarily mediated through the inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway and modulation of the nitric oxide pathway. The review also highlighted AL's potential in mitigating oxidative stress and its implications in treating cardiovascular diseases, fibrosis, and cancer. Conclusions: The findings suggest that ALA holds significant therapeutic potential, offering antihypertensive, anti-inflammatory, antifibrotic, and anticancer benefits without notable adverse effects, warranting further research to explore its full potential and mechanism of action.},
}

@article {pmid40868276,
year = {2025},
author = {Voicu, V and Toader, C and Șerban, M and Covache-Busuioc, RA and Ciurea, AV},
title = {Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.},
journal = {Biomedicines},
volume = {13},
number = {8},
pages = {},
pmid = {40868276},
issn = {2227-9059},
abstract = {Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization-spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways-including PI3K-AKT-mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades-undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome-lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3-CR3 axis), and excitatory-inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network "meaning-making"-a collapse of coordinated signal interpretation, triage prioritization, and adaptive response-the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning-a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration.},
}