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

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

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

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

@article {pmid40602832,
year = {2025},
author = {Abgueguen, E and Tortarolo, M and Rouviere, L and Marcuzzo, S and Camporeale, L and Henriques, A and Pasetto, L and Culley, GR and Bonetto, V and Marian, A and Lejeune, BL and Visbecq, A and Lauria, G and Kabashi, E and Callizot, N and Bendotti, C and Miniou, PY},
title = {Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.},
journal = {Life science alliance},
volume = {8},
number = {9},
pages = {},
doi = {10.26508/lsa.202403195},
pmid = {40602832},
issn = {2575-1077},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Motor Neurons/drug effects/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; Zebrafish ; Humans ; Unfolded Protein Response/drug effects ; Mice, Transgenic ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Cytoplasm/metabolism ; Mitochondria/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; Spinal Cord/metabolism ; },
abstract = {A pathological hallmark of ALS is the abnormal accumulation of misfolded proteins (e.g., TDP-43) and enlarged endoplasmic reticulum (ER), indicating ER stress. To resolve this stress, cells initiate the Unfolded Protein Response (UPR). However, unresolved stress leads to apoptosis. In ALS, UPR activation fails to resolve proteostasis impairment. UPR activation modulators, among them Sephin1, reduce protein aggregates and improve motor neuron survival in ALS models. We demonstrate that following glutamate intoxication, Sephin1 increases motor neuron survival by reducing mitochondria ROS production and extranuclear TDP-43. Sephin1 reduces abnormal splicing because of TDP-43 nuclear loss of function following oxidative stress. In SOD1[G93A] mice, Sephin1 treatment decreases TDP-43 in triton-insoluble fraction, improving motor neuron survival in spinal cord. Sephin1 improves motor neurons survival, motor function and survival of mutated TDP-43 transgenic zebrafish. Sephin1 improves motor neuron survival in ALS models by reducing TDP-43 cytoplasmic mislocalization and its toxicity. These findings open new therapeutic opportunities for Sephin1 in neurodegenerative pathologies with TDP-43 proteinopathy, including ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology
*Motor Neurons/drug effects/metabolism
*DNA-Binding Proteins/metabolism/genetics
Disease Models, Animal
Mice
Zebrafish
Humans
Unfolded Protein Response/drug effects
Mice, Transgenic
Cell Survival/drug effects
Endoplasmic Reticulum Stress/drug effects
Cytoplasm/metabolism
Mitochondria/metabolism/drug effects
Reactive Oxygen Species/metabolism
Apoptosis/drug effects
Oxidative Stress/drug effects
Spinal Cord/metabolism

@article {pmid40602644,
year = {2025},
author = {James, ML and Pink, AE and Woolf, RT and Batty, P and Mahil, S and Smith, CH and Whittaker, S and Langan, SM},
title = {Response to Lavin et al's paper: Cutaneous T-Cell Lymphoma after Dupilumab Use: A Real-World Pharmacovigilance Study of the FDA Adverse Event Reporting System.},
journal = {The Journal of investigative dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jid.2025.05.022},
pmid = {40602644},
issn = {1523-1747},
}

@article {pmid40602557,
year = {2025},
author = {Rodriguez-Romano, A and Gonzalez-Valdivieso, J and Moreno-Martinez, L and Costa, JFV and Osta, R and Rico, P},
title = {Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1[G93A] mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {145645},
doi = {10.1016/j.ijbiomac.2025.145645},
pmid = {40602557},
issn = {1879-0003},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.},
}

@article {pmid40601808,
year = {2025},
author = {Huang, J and Wang, B},
title = {Nanoscale Insights into the Formation Reaction Mechanism of Si-Al Oligomers in Alkali-Activated Materials.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.4c05076},
pmid = {40601808},
issn = {1520-5827},
abstract = {Alkali-activated materials (AAM) have garnered significant attention as environmentally friendly alternatives to cement due to their potential to mitigate greenhouse gas emissions and facilitate the effective utilization of industrial waste streams. Silicon-aluminum (Si-Al) monomers serve as the cornerstone units within the nanocomposite structure of AAMs, playing a pivotal role in the polycondensation reactions (PR) that govern their formation. Despite extensive research on the PR processes within AAM, the nanoscale reaction mechanisms remain elusive. In this study, MD simulations based on the ReaxFF were employed to delve into the structural evolution and reaction mechanisms of PR processes at the nanoscale. Analyses employing radial distribution functions, bond lengths, and bond angles demonstrated the robustness of the models developed in this investigation. The simulations revealed that when three Si-Al nanomolecular monomers, namely [SiO2(OH)2][2-], [SiO(OH)3][-], and [Al(OH)4][-], undergo pairwise PR, distinct reaction pathways emerge, leading to the formation of various Si-Al oligomers that collectively constitute the framework of the AAM gel. During the assembly of Si-Al oligomers, we aim to shed light on the crucial role played by Al monomers in driving the reaction forward and the subsequent polymerization of Si-Al oligomers. This disparity underscores Al's pivotal function in the PR mechanism, illuminating its indispensable role in governing the molecular architecture and kinetics of these complexes.},
}

@article {pmid40600544,
year = {2025},
author = {El Elhaj, A and Onger, ME},
title = {Exploring Neurodegenerative Diseases: Bridging the Gap between in vitro and in vivo Models.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128374254250605070049},
pmid = {40600544},
issn = {1873-4286},
abstract = {Neurological disorders are brain conditions characterized by the loss of nerve cells, leading to a decline in function. Standard examples include dementia, tremors, involuntary movements, muscle weakness, and autoimmune attacks. The most common form of dementia is Alzheimer's, affecting over 5 million elderly individuals, while tremors, stiffness, and slow movement are caused by Parkinson's. Involuntary movements and emotional problems are caused by Huntington's, while muscle weakness and eventual demise are caused by Amyotrophic lateral sclerosis. Vision problems, fatigue, and difficulty walking are caused by Multiple sclerosis (MS), an autoimmune disease that attacks the myelin sheath. In vitro models provide cost and complexity reduction, environmental control, and high-through". Researchers employ both cell-based (in vitro) and animal- based (in vivo) models to investigate neurodegenerative illnesses and endeavor to formulate novel treatments for diverse conditions. In vitro models provide cost and complexity reduction, environment control, and high-throughput screening of potential therapeutic agents compared to in vivo models. Nevertheless, they possess constraints, including the absence of intricate interactions that transpire in the entire organism and the inability to reproduce the disease progression completely.},
}

@article {pmid40600271,
year = {2025},
author = {Narayanan, A and Seaberg, BL and Buxton, A and Vernino, A and Williams, VE and Matarazzo, A and Kekre, J and Subramanian, B and Wang, W and Rutkowski, JM and Hook, M and McCreedy, DA and Muthuchamy, M and Rimer, M},
title = {Lymphatic dysfunction correlates with inflammation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.},
journal = {Disease models & mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1242/dmm.052148},
pmid = {40600271},
issn = {1754-8411},
support = {W81XWH2210678//Congressionally Directed Medical Research Programs/ ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, ultimately fatal neurodegenerative disease, without effective modifying treatments. It affects both lower and upper motor neurons, causing skeletal muscle denervation and paralysis. Regardless of the mechanisms that initiate and drive ALS, chronic neuroinflammation and systemic immune system activation play key roles in disease progression. The lymphatic system is a network of vessels and organs essential for immune surveillance, tissue fluid balance and lipid absorption, critical for the resolution and progression of inflammation in the periphery. Its recent rediscovery in the central nervous system raises the possibility of it playing similar roles in neurological and neurodegenerative diseases featuring prominent neuroinflammation, such as ALS. We hypothesized the structure and function of lymphatics are compromised in the most widely used murine model of ALS, the SOD1-G93A mouse. We found that these mice exhibit lymph transport dysfunction, diminished intrinsic lymphatic vessel tonic and phasic contractions, and an association between inflammation and lymphatic marker upregulation, despite absence of major structural changes in lymphatic network coverage in key affected tissues in the disease, skeletal muscle and spinal cord.},
}

@article {pmid40599765,
year = {2025},
author = {Wei, X and Qin, W},
title = {Exploring causal links between brain functional networks and neurodegenerative disease risk using Mendelian randomization.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251348844},
pmid = {40599765},
issn = {2542-4823},
abstract = {BACKGROUND: Resting-state functional magnetic resonance imaging (rsfMRI) is pivotal for mapping alterations in brain functional networks associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, the causal mechanisms linking such network dysfunction to disease pathogenesis remain unresolved.

OBJECTIVE: This study aimed to elucidate bidirectional causal relationships between 191 resting-state fMRI phenotypes (derived from 34,691 individuals) and six neurodegenerative diseases, specifically AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), using disease-specific GWAS data from European-ancestry cohorts.

METHODS: Bidirectional two-sample Mendelian randomization (MR) was performed using rsfMRI phenotypes from Zhao et al. (2022) and GWAS summary statistics (AD: ieu-b-5067/ebi-a-GCST90027158, ALS: ebi-a-GCST90027164, FTD: ieu-b-43, MS: ieu-b-18, DLB: ebi-a-GCST90001390, PD: ieu-b-7). Instrumental variables were filtered for significance (p < 5 × 10^-8), with sensitivity analyses (MR-PRESSO, Cochran's Q, MR-Egger) to ensure robustness.

RESULTS: Forward MR identified 26 rsfMRI phenotypes causally linked to neurodegenerative diseases. AD risk was associated with reduced cerebellum-subcortical connectivity (OR = 0.957, p = 0.004), while heightened cerebellar activity increased DLB risk (OR = 2.58, p = 0.0063). Reverse MR revealed 64 disease-to-network effects: AD altered default mode network connectivity (OR = 0.965, p = 0.034), and PD disrupted salience-central executive network interactions (OR = 0.950, p = 0.00011).

CONCLUSIONS: This study establishes robust bidirectional causal pathways between brain functional networks and neurodegenerative diseases, with AD showing unique vulnerability in cerebellar-subcortical and default mode circuits. These findings highlight network-specific therapeutic targets for AD and related disorders.},
}

@article {pmid40597943,
year = {2025},
author = {Duan, Q and Li, C and Wei, C and Wang, Q and Wang, B and Sun, L and He, Y and Qin, J and Huang, X},
title = {Botulinum toxin type A for amyotrophic lateral sclerosis lower limb spasm: two case reports.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {263},
pmid = {40597943},
issn = {1471-2377},
support = {No.2024AFD137//the Natural Science Foundation of Hubei Province (Joint Fund Program)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Male ; *Botulinum Toxins, Type A/therapeutic use/administration & dosage ; Middle Aged ; *Neuromuscular Agents/therapeutic use/administration & dosage ; *Lower Extremity/physiopathology ; *Muscle Spasticity/drug therapy/etiology ; *Spasm/drug therapy/etiology ; },
abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) often experience spasticity, which can severely affect their ability to perform basic activities like standing and walking, potentially diminishing their already compromised quality of life. Botulinum toxin type A (BTX-A) is a first-line drug for spastic management. However, there are limited reports on its effectiveness in reducing muscle tone among ALS patients, with scarcely any related research conducted in China. We conducted the clinical observation and follow-up study through the relevant ethical post (ChiCTR2200061794). Clinical registration was on July 2, 2022. All participants provided written informed consent.

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

CONCLUSION: Appropriate BTX-A injected into the target muscles could effectively depress the spasticity of ALS patients without apparent side effects.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/drug therapy
Male
*Botulinum Toxins, Type A/therapeutic use/administration & dosage
Middle Aged
*Neuromuscular Agents/therapeutic use/administration & dosage
*Lower Extremity/physiopathology
*Muscle Spasticity/drug therapy/etiology
*Spasm/drug therapy/etiology

@article {pmid40596818,
year = {2025},
author = {Moreno-García, L and Moreno-Martínez, L and de la Torre, M and Macías-Redondo, S and García-Redondo, A and Osta, R and Toivonen, JM and Calvo, AC},
title = {Circular RNA expression in ALS is progressively deregulated and tissue-dependent.},
journal = {BMC genomics},
volume = {26},
number = {1},
pages = {576},
pmid = {40596818},
issn = {1471-2164},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA, Circular/genetics/metabolism ; Animals ; Humans ; Mice ; Male ; Female ; Spinal Cord/metabolism ; Disease Models, Animal ; Muscle, Skeletal/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics ; Organ Specificity ; *Gene Expression Regulation ; },
abstract = {BACKGROUND: There is increasing evidence on the role of circular RNAs (circRNAs) in neuronal and muscular processes. Accordingly, their dysregulation is associated with neurodegenerative diseases and myopathies. We investigated circRNA expression in the central nervous system (CNS) and skeletal muscle, the two main tissues affected in amyotrophic lateral sclerosis (ALS).

RESULTS: Based on circRNA sequencing analysis in spinal cord from ALS mice (SOD1G93A) followed by a literature search, 30 circRNAs potentially involved in ALS were tested. All selected circRNAs were downregulated in the SOD1G93A spinal cord, whereas only half of these were quantifiable and were generally upregulated in quadriceps muscle of SOD1G93A mice. Such tissue-dependent expression pattern was observed in both sexes and circRNA abundance in the spinal cord was higher than in the muscle, both in wild type and in SOD1G93A mice. Finally, we assessed the 18 circRNAs with the largest expression differences and the highest degree of interspecies conservation in brain samples from sporadic ALS (sALS) patients and healthy controls. Similar to the mouse model, circRNA levels tended to decrease in the CNS of sALS patients.

CONCLUSIONS: Expression of circRNAs may be systematically altered in the two tissues most affected by ALS in a progressive and opposed manner. Although more detailed studies are warranted, circRNAs are potentially related to ALS etiopathogenesis and could possibly serve as future biomarkers, therapeutic targets, or customized therapeutic tools to modulate the pathology.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*RNA, Circular/genetics/metabolism
Animals
Humans
Mice
Male
Female
Spinal Cord/metabolism
Disease Models, Animal
Muscle, Skeletal/metabolism
Mice, Transgenic
Superoxide Dismutase-1/genetics
Organ Specificity
*Gene Expression Regulation

@article {pmid40595276,
year = {2025},
author = {Sancho-Cantus, D and Sanchis, ES and Casani-Cubel, J and Privado, J and Escriba, J and Carriquí-Suárez, AB and Benlloch, M and Cerón, JJ and Rubio, CP and Cubero-Plazas, L and de la Rubia Ortí, JE},
title = {Prediction of antioxidant capacity, age, and sex on sleep impairment in patients with amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {21145},
pmid = {40595276},
issn = {2045-2322},
support = {2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; 2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/metabolism ; Male ; Female ; Middle Aged ; *Antioxidants/metabolism ; Aged ; Cross-Sectional Studies ; *Sleep Wake Disorders/etiology ; Sex Factors ; Oxidative Stress ; Age Factors ; Adult ; Quality of Life ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by high levels of inflammation and oxidative stress, predominantly affecting males, particularly those between the ages of 50 and 65 years. It is characterised by progressive loss of motor neurones, leading to both motor and non-motor symptoms, such as sleep impairment, diagnosed in most patients, which adversely affects their quality of life. Therefore, this study aimed to determine the predictive role of antioxidant capacity, psychological distress, age, and sex on sleep impairment in an adult population of patients with ALS. A descriptive, quantitative, cross-sectional study was conducted using a sample of 74 patients diagnosed with bulbar or spinal ALS. To assess sleep disturbances in these patients, the Pittsburgh sleep quality index (PSQI), epworth sleepiness scale (ESS), and Insomnia severity index were used. Additionally, plasma antioxidant capacity was analysed using the total antioxidant capacity (TEAC), Cupric Ion reducing antioxidant capacity (CUPRAC), and ferric reducing power (FRAP). Anxiety and depression measures were used to measure psychological distress. Men exhibited a higher antioxidant status (lower oxidative stress) than women, and higher antioxidant capacity was associated with fewer sleep impairments (β = -0.43). Psychological distress may increase sleep impairment (β = -0.26). Furthermore, older individuals experienced less sleep impairment (β = -0.27), while sex had minimal influence on sleep deterioration, although it appears that men had fewer disturbances (β = -0.12). Having a higher antioxidant status, lower psychological distress, being male, and being older seem to act as predictors of reduced sleep impairment in ALS. Specifically, these four predictors account for 32% of sleep deterioration.Clínical trial registration: The present descriptive, quantitative, cross-sectional study was part of a clinical trial involving ALS patients, registered under the number NCT04654689 (https://clinicaltrials.gov/study/NCT04654689#wrapper).},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/metabolism
Male
Female
Middle Aged
*Antioxidants/metabolism
Aged
Cross-Sectional Studies
*Sleep Wake Disorders/etiology
Sex Factors
Oxidative Stress
Age Factors
Adult
Quality of Life

@article {pmid40594383,
year = {2025},
author = {Bernardi, S and Vitolo, S and Gabellini, C and Marchese, M and Ferraro, E},
title = {Trimetazidine stimulates intracellular Ca[2+] transients and zebrafish locomotor activity in spinal neurons.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {22854},
pmid = {40594383},
issn = {2045-2322},
support = {GSA23C003//Telethon Foundation/ ; AFM 23771//AFM-TELETHON/ ; P2022LSW98//PRIN 2022 PNRR/ ; },
mesh = {Animals ; Zebrafish/physiology ; *Calcium/metabolism ; Animals, Genetically Modified ; *Motor Neurons/drug effects/metabolism ; *Locomotion/drug effects ; *Trimetazidine/pharmacology ; *Spinal Cord/drug effects/cytology/metabolism ; *Calcium Signaling/drug effects ; },
abstract = {The metabolic modulator trimetazidine (TMZ) is an antianginal recently found to improve skeletal muscle performance in mice models of sarcopenia and of amyotrophic lateral sclerosis (ALS). The mechanism underlying the effect of TMZ on locomotor activity has been proposed to rely on its ability to enhance metabolic efficiency with a consequent improvement of myogenesis and of neuromuscular junction (NMJ) and muscle function. However, although promising and therefore under clinical trials, the mechanism of action of TMZ has not been clearly disclosed; here we hypothesized that it might involve the modulation of neuronal Ca[2+] flows. We studied the effect of TMZ on Ca[2+] dynamics in vivo, by using the transgenic zebrafish line Tg(neurod1:GCaMP6f) in which the neuronal expression of the Ca[2+] indicator GCaMP allows to visualize Ca[2+] dynamics in neurons of zebrafish larvae. By this elegant tool, we demonstrated, for the first time, that TMZ promotes an increase of intracellular Ca[2+] transients in zebrafish spinal neurons likely enhancing motor neuron firing, which correlates with enhanced motor performance induced by this drug. Even though elevated intracellular Ca[2+] levels have often been associated to neurotoxicity, it is unclear if the neuronal excitability features in some neuro-muscular disorders are compensatory or pathological. Therefore, this newly reported effect of TMZ which transiently and selectively enhances spinal neuron firing deserves to be further detailed and taken into account when the possible repurposing of this drug is proposed for the treatment of neuro-muscular disorders.},
}

Animals
Zebrafish/physiology
*Calcium/metabolism
Animals, Genetically Modified
*Motor Neurons/drug effects/metabolism
*Locomotion/drug effects
*Trimetazidine/pharmacology
*Spinal Cord/drug effects/cytology/metabolism
*Calcium Signaling/drug effects

@article {pmid40593943,
year = {2025},
author = {Gbadamosi, I and Binias, S and Gielniewski, B and Magno, R and Duarte, I and Jawaid, A},
title = {Coding and non-coding RNA expression in NSC34 cells following TDP-43 depletion and mutant TDP-43 M337V expression.},
journal = {Scientific data},
volume = {12},
number = {1},
pages = {1110},
pmid = {40593943},
issn = {2052-4463},
support = {TREMENDOS; UMO-2022/04/Y/NZ5/00122//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; },
mesh = {*DNA-Binding Proteins/genetics ; Mutation ; *Amyotrophic Lateral Sclerosis/genetics ; Mice ; *Motor Neurons/metabolism ; Animals ; Humans ; Cell Line ; *RNA, Untranslated/genetics ; Transcriptome ; RNA Interference ; },
abstract = {Several neurodegenerative disorders (NDDs), notably amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by pathological cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) in neurons and glia. Primarily localized in the nucleus under physiological conditions, TDP-43 is a critical regulator of RNA processing and metabolism. Therefore, RNA changes induced by TDP-43 depletion or mutation could play an important role in the pathogenesis of ALS and other TDP-43 related NDDs.To investigate these effects in NSC34 motor neuron-like cells, a commonly used cellular model of ALS, we used RNA interference to knock down TDP-43 and overexpressed the ALS-associated TDP-43 M337V mutation. RNA from both these experiments was enriched for small and large transcripts and subsequently analyzed via next-generation sequencing.The resulting transcriptomics datasets offer a valuable resource for studying the impact of TDP-43 depletion and mutant over-expression in motor neurons. These data enable comprehensive differential expression analyses and functional enrichment studies, identifying cellular pathways affected by TDP-43 depletion or mutation. Additionally, the inclusion of non-coding RNAs facilitates the construction of gene regulatory networks, providing insights into the interplay between coding and non-coding RNAs in gene expression regulation under TDP-43 loss-of-function or pathogenic mutation conditions.},
}

*DNA-Binding Proteins/genetics
Mutation
*Amyotrophic Lateral Sclerosis/genetics
Mice
*Motor Neurons/metabolism
Animals
Humans
Cell Line
*RNA, Untranslated/genetics
Transcriptome
RNA Interference

@article {pmid40590340,
year = {2025},
author = {Takahashi, F and Genge, A and Hirai, M and Selness, D and Todorovic, V and Wamil, A and Sasson, N and Apple, S and Ushirogawa, Y},
title = {Analysis of Long-Term Function and Survival of Edaravone Oral Suspension-Treated Patients With Amyotrophic Lateral Sclerosis Using PRO-ACT Data as Historical Placebo Controls.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28462},
pmid = {40590340},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
abstract = {INTRODUCTION/AIMS: On/Off dosing of intravenous (IV) edaravone and edaravone oral suspension was US Food and Drug Administration (FDA)-approved for Amyotrophic Lateral Sclerosis (ALS) treatment. Placebo-controlled trials showed that IV edaravone slows the rate of physical functional decline in patients with ALS. Here, the impact of edaravone oral suspension on function and survival was assessed.

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

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

DISCUSSION: This suggests edaravone oral suspension significantly increases survival time and decreases physical functional decline versus PRO-ACT placebo patients.},
}

@article {pmid40589992,
year = {2025},
author = {Yue, Y and Chang, N and Shi, Z},
title = {Nonlinear characteristics of gait signals in neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1607273},
pmid = {40589992},
issn = {1664-2295},
abstract = {Based on the asymmetric characteristics of left and right movements in patients with neurodegenerative diseases and their inherent coupling relationships, as well as the inevitable internal connection between them according to the principles of mechanical kinematics, and a processing method for the ratio of gait signals to left and right limb data is proposed. Using gait time series data collected from left and right limbs via pressure-sensitive insoles, a comparison was conducted among patients with Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), and a healthy control group (Ctrl) in terms of the average, standard deviation, and coefficient of variation of the left and right sequences, as well as the ratios between them. It was discovered that there exists a close correlation between the ratios of left to right sequences and the actual standard deviation and coefficient of variation of these sequences. These ratios can be utilized for identifying the categories of PD, ALS, and HD patients. After using a median filter (n = 3) to filter four sets of stride ratio data (Ctr1, A1s, PD, and HD), it was found that the data before filtering generally showed significant fluctuations, with many peaks and valleys, indicating that the original data may contain a lot of noise or outliers. In contrast, the filtered data showed relatively smaller fluctuations and a smoother curve, indicating that the filtering process effectively reduced noise in the data and enhanced its stability. The raw data distribution for the left and right limbs of patients with PD, ALS, HD, and the Ctrl was relatively large, posing certain difficulties in analyzing the patients' diseases. The use of the ratio of left to right data effectively improves the discreteness of the data. The ranking of CO complexity features from highest to lowest is ALS, HD, PD, and Ctrl. The ranking of sample entropy features from largest to smallest is ALS, HD, PD, and Ctrl. The ranking of wavelet coefficient features from largest to smallest is ALS, PD, HD, and Ctrl.},
}

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

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

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

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

@article {pmid40589421,
year = {2025},
author = {Ravera, F and Efeoglu, E and Byrne, HJ},
title = {Monitoring the kinetic evolution of mesenchymal stem cell differentiation using Raman microspectroscopy.},
journal = {The Analyst},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4an01509f},
pmid = {40589421},
issn = {1364-5528},
abstract = {Raman microspectroscopy (RMS) offers a powerful, non-destructive approach for in situ monitoring of dynamic biochemical processes within cells. However, the ability to reliably data-mine the spectroscopic signatures and their evolution and extract meaningful information can be challenging. Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) regression analysis is a powerful chemometric technique that can potentially address this challenge by deconvoluting the spectra into individual component spectra, each representing a specific biochemical species, and regressing the solutions against kinetic constraints. In this study, MCR-ALS analysis was performed on spectral data of differentiation process of mesenchymal stem cells into chondrocytes, carried out on two different substrates, collagen 3-dimensional hydrogel and the conventional 2-dimensional culture model at time intervals of 1-7, 14, 21 days. The kinetic evolution of the chondrogenesis was modelled according to a phenomenological rate equation model, in an attempt to describe the biochemical evolution of the cell composition within the process. Moreover, the ability of the algorithm to faithfully extract the correct reaction rates and spectral profiles has been explored. The results indicated that the differentiation process originates in the nucleolar regions, subsequently extending to the nuclear and cytoplasmic compartments and corroborated a more rapid differentiation rate in cell cultures grown on 3D collagen hydrogels compared to 2D substrates. The combination of Raman microspectroscopy and MCR-ALS offers a powerful approach for elucidating the complex mechanisms underlying chondrogenesis and developing innovative strategies for regenerative medicine.},
}

@article {pmid40589142,
year = {2025},
author = {Tiwari, R and Paswan, A and Tiwari, G and Reddy, VJS and Posa, MK},
title = {Perspectives on Fecal Microbiota Transplantation: Uses and Modes of Administration.},
journal = {Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology},
volume = {41},
number = {},
pages = {e20250014},
doi = {10.62958/j.cjap.2025.014},
pmid = {40589142},
issn = {1000-6834},
mesh = {*Fecal Microbiota Transplantation/methods ; Humans ; *Gastrointestinal Microbiome ; Feces/microbiology ; *Nervous System Diseases/therapy ; },
abstract = {Fecal microbiota Transplantation (FMT), often referred to as stool transplantation, fecal transfusion, and fecal bacteria therapy, is considered one of the most medical innovations of the 20th century. Fecal microbiota Transplantation entails filtering and dilution of a healthy donor's feces before injecting it into the recipient's digestive system. In China, it was first administered orally in the fourth century for diarrhea and food poisoning under the name "Yellow Soup." It has recently been widely employed in a variety of clinical settings, including cases of Clostridium difficile infection that are recurring and resistant. By replacing the unhealthy intestinal microbiota with a healthy bacterial community, the FMT treatment aims to enhance the intestinal flora. It also looks at neurological conditions where alterations in gut microbiota are prevalent. We have discussed FMT in the context of its use in conditions affecting the nerve system, such as neurological and other conditions (multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, epilepsy, Amyotrophic lateral sclerosis, Tourette syndrome, neuropathic pain, Huntington's diseases, etc.), as well as the role of gut microbiota in many neurological disorders.},
}

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

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

@article {pmid40586230,
year = {2025},
author = {Knudsen, LF and Nikolajevic-Pujic, S},
title = {Prevalence and predictors of prolonged grief disorder, anxiety and depression in bereaved ALS family caregivers: a national survey of distress and support needs after bereavement.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/21678421.2025.2523948},
pmid = {40586230},
issn = {2167-9223},
abstract = {OBJECTIVE: The distress of amyotrophic lateral sclerosis (ALS) family caregivers may not end after bereavement. Yet, the prevalence of psychological distress and support needs after bereavement are unclear. This study examined the prevalence and predictors of prolonged grief disorder (PGD), anxiety and depression, and level of needed and received support after bereavement.

METHODS: We conducted a cross-sectional online survey of a national cohort of bereaved ALS family caregivers recruited through the National Rehabilitation Center for Neuromuscular Diseases in Denmark. Questions included disease-related factors, care involvement, burden (Zarit Burden Inventory), loneliness (Three-Item Loneliness Scale), coping style (CSQ-37), PGD (PG-13), anxiety/depression (HADS), time since bereavement, needed and received support during and after ALS.

RESULTS: A total of 162 caregivers (46.4%) with a median of 24 months since bereavement responded. PGD prevalence was 5.6%, anxiety 22.2%, depression 16.0%. PGD was predicted by more caregiving hours. Anxiety and depression by high emotional coping and not receiving the needed information post bereavement and, anxiety, also by a more recent bereavement. Half of the participants had needed information about ALS after bereavement with 17.4% receiving it to a small degree and 32.3% not at all. Nearly 80% had needed emotional support with 31.0% receiving it to a small degree/not at all.

CONCLUSIONS: Caregivers may be distressed for a long time. Healthcare professionals should offer information about ALS to bereaved caregivers and screen caregivers for PGD, anxiety, depression, and coping style to offer targeted interventions post bereavement. Future longitudinal studies should investigate predictors for post-loss psychological distress including pre-loss anxiety/depression and formal care.},
}

@article {pmid40586110,
year = {2025},
author = {Appukuttan, S and Grapperon, AM and El Mendili, MM and Dary, H and Guye, M and Verschueren, A and Ranjeva, JP and Attarian, S and Zaaraoui, W and Gilson, M},
title = {Evaluating machine learning pipelines for multimodal neuroimaging in small cohorts: an ALS case study.},
journal = {Frontiers in neuroinformatics},
volume = {19},
number = {},
pages = {1568116},
doi = {10.3389/fninf.2025.1568116},
pmid = {40586110},
issn = {1662-5196},
abstract = {Advancements in machine learning hold great promise for the analysis of multimodal neuroimaging data. They can help identify biomarkers and improve diagnosis for various neurological disorders. However, the application of such techniques for rare and heterogeneous diseases remains challenging due to small-cohorts available for acquiring data. Efforts are therefore commonly directed toward improving the classification models, in an effort to optimize outcomes given the limited data. In this study, we systematically evaluated the impact of various machine learning pipeline configurations, including scaling methods, feature selection, dimensionality reduction, and hyperparameter optimization. The efficacy of such components in the pipeline was evaluated on classification performance using multimodal MRI data from a cohort of 16 ALS patients and 14 healthy controls. Our findings reveal that, while certain pipeline components, such as subject-wise feature normalization, help improve classification outcomes, the overall influence of pipeline refinements on performance is modest. Feature selection and dimensionality reduction steps were found to have limited utility, and the choice of hyperparameter optimization strategies produced only marginal gains. Our results suggest that, for small-cohort studies, the emphasis should shift from extensive tuning of these pipelines to addressing data-related limitations, such as progressively expanding cohort size, integrating additional modalities, and maximizing the information extracted from existing datasets. This study provides a methodological framework to guide future research and emphasizes the need for dataset enrichment to improve clinical utility.},
}

@article {pmid40585924,
year = {2025},
author = {Almuhanna, Z and Bohulaigah, Z and Alkhawaja, H and Aljafar, H},
title = {Posterior trachea wall erosion: a case report and literature review of a catastrophic complication of cuff overinflation.},
journal = {Journal of surgical case reports},
volume = {2025},
number = {6},
pages = {rjaf361},
doi = {10.1093/jscr/rjaf361},
pmid = {40585924},
issn = {2042-8812},
abstract = {Tracheostomy complications range from early to late complications. One of the late complications can be seen with cuff over-inflation that exceeds tracheal capillary perfusion pressure, which leads to segmental tracheomalacia and rarely, tracheal wall erosion. A 40-year-old male with amyotrophic lateral sclerosis and mechanical ventilation dependence was found to have a persistent ventilatory leak. Endoscopic examination revealed a large posterior tracheal wall erosion that was confirmed by computed tomography. Conservative management by the placement of a long endotracheal tube through the tracheostoma was chosen. Cuff pressure over 20-25 cm H2O, which exceeds tracheal capillary perfusion pressure, increases the risk of tracheal mucosal ischemia. Preventive strategies such as the use of pressure-limiting devices and careful tube selection, should be implemented. Regular implementation of preventive measures along with early identification are essential for avoiding tracheostomy tube complications. This case demonstrates the importance of strict cuff pressure maintenance to avoid tracheal wall injuries.},
}

@article {pmid40585812,
year = {2025},
author = {Barbier, M and Gareau, T and Camuzat, A and Guillaud-Bataille, M and Boluda, S and Clot, F and Araktingi, L and Borroni, B and van der Zee, J and Ghidoni, R and Bellini, S and Galimberti, D and Rossi, G and Nacmias, B and De la Casa-Fages, B and Pastor, P and , and Latouche, M and le Guern, E and Durr, A and Laquerrière, A and Moccia, R and Seilhean, D and Alvarez, V and Le Ber, I},
title = {Analysis of short tandem repeats linked to polyglutamine diseases from whole-genome sequencing reveals intermediate alleles of HTT associated with an early disease onset in C9orf72 carriers.},
journal = {Brain communications},
volume = {7},
number = {3},
pages = {fcaf220},
doi = {10.1093/braincomms/fcaf220},
pmid = {40585812},
issn = {2632-1297},
abstract = {Carriers of the GGGGCC pathogenic expansion in C9orf72 can develop symptoms of frontotemporal dementia and/or amyotrophic lateral sclerosis, with variable and unpredictable ages at onset. Previous studies aiming to decipher the genetic bases of the clinical variability in this rare disease included bi-allelic polymorphisms, excluding short tandem repeats. Whole-genome sequencing data of 195 C9orf72 patients were used to consider all short tandem repeats linked to polyglutamine disorders as potential genetic modifiers given the existing links between C9orf72 and polyglutamine diseases. Intermediate alleles of HTT encoding huntingtin were associated with an earlier age at onset among C9orf72 carriers in the discovery cohort (n = 195, P = 0.0003) and in a European replication cohort (n = 145, P = 0.006). In the merged cohort (n = 340), the average difference of age at disease onset was 9.42 ± 2.14 years (P = 1.3 × 10[e-5]) between carriers and non-carriers of HTT-intermediate alleles. Neuropathology of one C9orf72 case heterozygous for HTT-intermediate allele showed typical TDP-43 inclusions related to the C9orf72 pathogenic expansion and was negative for polyglutamine inclusion. No somatic expansion of HTT was detected in blood of all C9orf72exp/HTT-intermediate carriers. If this study reinforces potential biological links between huntingtin and C9orf72 that remain to be explored, the results also illustrate the interest of considering short tandem repeats from whole-genome data in association studies which paves the way to more exhaustive approaches to explore the trait heritability due to short-tandem-repeats still hidden in the genome.},
}

@article {pmid40585720,
year = {2025},
author = {Kato, T and Yorimoto, K and Ariake, Y and Shimizu-Motohashi, Y and Hara, T},
title = {Acute Respiratory Distress Syndrome Exacerbated by Inappropriate Use of Mechanical Insufflation-Exsufflation Following Infection in a Patient With Amyotrophic Lateral Sclerosis: A Case Report.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e84991},
doi = {10.7759/cureus.84991},
pmid = {40585720},
issn = {2168-8184},
abstract = {Mechanical insufflation-exsufflation (MI-E) is widely used to assist airway secretion clearance in patients with neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). While MI-E is generally considered safe when used intermittently for cough augmentation, its prolonged and unsupervised use as a substitute for invasive ventilation is discouraged by current clinical guidelines, including those issued by the American College of Chest Physicians and the American Academy of Neurology. We report the case of a 53-year-old man with advanced ALS, diagnosed approximately 10 years earlier, who developed acute respiratory distress syndrome (ARDS) exacerbated by inappropriate use of MI-E following a recent respiratory infection. The patient had previously relied on tracheostomy invasive ventilation (TIV) but chose to suspend its use, instead employing MI-E continuously for 62 hours (28,234 cycles), based on prior positive experiences and personal preference. Upon hospital admission, the patient was diagnosed with mild ARDS, bacterial pneumonia, and influenza B infection. Although the respiratory infection was likely the primary cause of deterioration, MI-E-related pressure changes may have exacerbated pulmonary injury, particularly in the context of acute infection. Rapid improvement in gas exchange and imaging findings within 48 hours of MI-E discontinuation further supports this hypothesis. We discuss possible mechanisms linking excessive MI-E usage to lung injury, including barotrauma and negative pressure pulmonary edema. We also emphasize the importance of clearly defined device indications, structured caregiver education, and regular clinical supervision in home respiratory care. To our knowledge, this may be the first reported case of ARDS potentially resulting from the combined effects of infection and inappropriate MI-E application, highlighting the need for multidisciplinary coordination and proper device supervision in managing advanced neuromuscular respiratory failure at home.},
}

@article {pmid40585388,
year = {2025},
author = {Wang, X and Sun, Y and Han, C and Meng, X and Wen, K and Wu, J and Min, P and Li, K and Zhang, Y},
title = {Research trends of piezoelectric materials in neurodegenerative disease applications.},
journal = {Bioactive materials},
volume = {52},
number = {},
pages = {366-392},
doi = {10.1016/j.bioactmat.2025.06.022},
pmid = {40585388},
issn = {2452-199X},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and huntington's disease, pose significant threats to human health, with current treatment options remaining limited. Piezoelectric materials, known for their ability to convert mechanical energy into electrical signals at the nanoscale, hold great promise in the diagnosis and treatment of neurodegenerative diseases due to their excellent electromechanical properties, environmental stability, and sensitivity. This review systematically outlines the working principles and classifications of piezoelectric materials. Subsequently, the recent advances in piezoelectric materials and their applications in the diagnosis and treatment of neurodegenerative diseases are highlighted. Finally, the challenges and perspectives regarding the development of future piezoelectric materials are discussed. This review aims to provide a comprehensive reference for the further application of piezoelectric materials in neurodegenerative diseases.},
}

@article {pmid40585370,
year = {2025},
author = {Maurel, C and Scherer, NM and Luu, L and Radford, RA and Hogan, A and Merjane, J and Vidal-Itriago, A and Don, EK and Chapman, T and Cull, S and Vourc'h, P and Lisowski, L and Lee, A and Chung, RS and Morsch, M},
title = {Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates.},
journal = {iScience},
volume = {28},
number = {7},
pages = {112761},
doi = {10.1016/j.isci.2025.112761},
pmid = {40585370},
issn = {2589-0042},
abstract = {TDP-43 is a nuclear RNA-binding protein that undergoes liquid-liquid phase separation (LLPS) and forms insoluble aggregates in neurodegenerative diseases. By studying TDP-43 in living vertebrates, we confirmed that TDP-43 undergoes LLPS and forms dynamic biomolecular condensates in spinal motor neurons. We validated in vivo that interfering with the lysine residue at position 136 altered the phase separation behavior of TDP-43 by reducing cytoplasmic mislocalization and aggregation. These alterations were post-translational modification (PTM) independent, highlighting that residue 136 is a key structural regulator of TDP-43 function. We further established an adeno-associated virus (AAV)-mediated expression approach in mice that confirmed altered nuclear condensation characteristics of lysine-modified TDP-43. These assessments exposed the formation of dynamic nuclear TDP-43 condensates and emphasize the important role of lysine 136 in maintaining TDP-43 function. Altogether, we establish lysine 136 as a molecular regulator for phase separation and TDP-43 aggregation in amyotrophic lateral sclerosis (ALS) in two in vivo platforms.},
}

@article {pmid40585363,
year = {2025},
author = {Wang, C and Xu, J and Pan, K and Xu, Y and Yu, J},
title = {Relationship between endocrine disruptors and neurodegenerative diseases: Systematic review and meta-analysis.},
journal = {iScience},
volume = {28},
number = {7},
pages = {112779},
doi = {10.1016/j.isci.2025.112779},
pmid = {40585363},
issn = {2589-0042},
abstract = {We conducted a meta-analysis to evaluate relevant literature published between January 2003 and December 2023 in order to provide updated epidemiological evidence on the relationship between endocrine-disrupting chemicals (EDCs) and neurodegenerative diseases (NDs). A systematic search of related studies was conducted in PubMed, Web of Science, and Embase. A total of 21 studies were included, with 286,610 subjects for meta-analysis. Analysis revealed that exposure to polychlorinated biphenyls (odds ratio [OR] = 1.08, 95% confidence interval [CI]: 1.03-1.14) posed a risk for NDs, while organochlorine pesticide (OR = 1.11, 95% CI: 1.05-1.17) exposure exhibited a positive correlation with ND risk. Subgroup analysis by disease indicated a positive association between EDC exposure and Alzheimer's disease (OR = 1.03, 95% CI: 1.00-1.07) and amyotrophic lateral sclerosis (OR = 1.02, 95% CI: 1.01-1.03) risk. Our meta-analysis indicates that human exposure to EDCs has adverse effects on NDs.},
}

@article {pmid40585304,
year = {2025},
author = {Cesaro, G and Baruzzo, G and Tussardi, G and Di Camillo, B},
title = {Differential cellular communication inference framework for large-scale single-cell RNA-sequencing data.},
journal = {NAR genomics and bioinformatics},
volume = {7},
number = {2},
pages = {lqaf084},
doi = {10.1093/nargab/lqaf084},
pmid = {40585304},
issn = {2631-9268},
mesh = {*Single-Cell Analysis/methods ; *Cell Communication/genetics ; Humans ; *Sequence Analysis, RNA/methods ; *Transcriptome ; *Software ; Gene Expression Profiling/methods ; Computational Biology/methods ; },
abstract = {Single-cell transcriptomics data have been widely used to characterize biological systems, particularly in studying cell-cell communication, which plays a significant role in many biological processes. Despite the availability of various computational tools for inferring cellular communication, quantifying variations across different experimental conditions at both intercellular and intracellular levels remains challenging. Moreover, available methods are in general limited in terms of flexibility in analyzing different experimental designs and the ability to visualize results in an easily interpretable way. Here, we present a generalizable computational framework designed to infer and support differential cellular communication analysis across two experimental conditions from large-scale single-cell transcriptomics data. The scSeqCommDiff tool employs a statistical and network-based computational approach for characterizing altered cellular cross-talk in a fast and memory-efficient way. The framework is complemented with CClens, a user-friendly Shiny app to facilitate interactive analysis of inferred cell-cell communication. Validation through spatial transcriptomics data, comparison with other tools, and application to large-scale datasets (including a cell atlas) confirms the reliability, scalability, and efficiency of the framework. Moreover, the application to a single-nucleus transcriptomics dataset shows the validity and ability of the proposed workflow to support and unravel alterations in cell-cell interactions among patients with amyotrophic lateral sclerosis and healthy subjects.},
}

*Single-Cell Analysis/methods
*Cell Communication/genetics
Humans
*Sequence Analysis, RNA/methods
*Transcriptome
*Software
Gene Expression Profiling/methods
Computational Biology/methods

@article {pmid40585174,
year = {2025},
author = {Cassel, R and Lorenc, F and Bombardier, A and De Tapia, C and Dieterle, S and Gouveia Roque, C and Jackson, CA and Stuart-Lopez, G and Rouaux, C and Guillot, SJ and Birling, MC and Kessler, P and Grassano, M and Traynor, B and Chio, A and Roy, R and Shorter, J and Waldron, FM and Gregory, JM and Phatnani, H and Dupuis, L and Megat, S},
title = {FUS Mislocalization Rewires a Cortical Gene Network to Drive Cognitive and Behavioral Impairment in ALS.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.16.25329673},
pmid = {40585174},
abstract = {UNLABELLED: Cognitive and behavioral impairment affects up to half of individuals with amyotrophic lateral sclerosis (ALS), but their molecular origin remains unresolved. Here, we identify mislocalization of the RNA-binding protein FUS in cortical neurons as a defining feature in ALS patients with cognitive impairment (ALS-ci). Selective mislocalization of FUS in adult cortical projection neurons in mice is sufficient to trigger ALS-ci- and ALS with behavioral impairment (ALS-bi)-like phenotypes, including deficits in sociability, and neurodegeneration. Single-nucleus transcriptomics reveal a conserved FUS-dependent gene network downregulated in these mice and ALS-ci patients. This regulon is enriched for ALS genetic risk factors and newly implicates FBXO16 in ALS-bi. Carriers of protein-truncating FBXO16 variants display behavioral abnormalities, frontotemporal atrophy, and increased levels of dementia-linked biomarkers. These findings define a neuron-intrinsic mechanism for cognitive and behavioral dysfunction in ALS and nominate FUS mislocalization and its downstream gene network as therapeutic targets.

HIGHLIGHTS: Transcriptional fingerprint of FUS mislocalization is observed in cortical projection neurons of ALS patientsFUS mislocalization leads to downregulation in cortical projection neurons of a cross-species conserved regulon shared with TDP43FUS mislocalization in adult cortical projection neurons is sufficient to trigger ALS related cognitive and behavioral impairment in mouse modelsFUS is mislocalized and the FUS regulon is downregulated in ALS patients with cognitive impairmentThe FUS regulon is enriched in genetic risk factors for cognitive and behavioral impairment in ALS Carriers of protein truncating variants of FBXO16 , one of the FUS regulon genes, display behavioral, imaging and biochemical markers of ALS with behavioral impairment.},
}

@article {pmid40585089,
year = {2025},
author = {Shen, T and Spencer, BE and Kuksa, PP and Van Deerlin, VM and Phatnani, H and , and Lee, EB and McMillan, CT},
title = {Unraveling temporal dynamics of the post-mortem transcriptome in amyotrophic lateral sclerosis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.10.25329061},
pmid = {40585089},
abstract = {Human tissue transcriptomics are crucial for understanding neurodegeneration but limited by cross-sectional post-mortem sampling, which represents end-stage disease. Subtype and Stage Inference (SuStaIn) modeling addresses these limitations by inferring temporal gene expression dynamics while also identifying potential transcriptomic subtypes. Applied to bulk RNA-seq data from post-mortem lumbar spinal cord in amyotrophic lateral sclerosis (ALS), SuStaIn unraveled that more advanced transcriptomic stages were associated with higher microglia and reduced neuron proportions, which mapped onto two ALS subtypes: Immune/Apoptosis/Proteostasis subtype with early immune/apoptotic/proteostatic dysregulation, worse prognosis and higher microglia proportions; Synapse/RNA-Metabolism subtype with early synaptic/RNA-processing deficits, lower male prevalence and neuron loss. Lumbar patterns demonstrated high concordance with cervical patterns and a strong correlation in staging across regional tissues. These findings revealed subtype-specific mechanisms underlying ALS heterogeneities, prioritized key genes driving subtyping/staging as potential therapeutic targets. More broadly, we established a framework to decode temporal dynamics from traditionally constrained post-mortem transcriptomic studies.},
}

@article {pmid40584972,
year = {2025},
author = {Khandelwal, N and Sanchirico, M and Ajibade, A and Munshi, K and Vu, M and Engel-Nitz, N and Steiger, C and Anderson, AJ and Karam, C},
title = {Characteristics, Treatment Patterns, Healthcare Resource Utilization, and Costs Among Patients with Multifocal Motor Neuropathy: A US Claims Database Cohort Study.},
journal = {Journal of health economics and outcomes research},
volume = {12},
number = {1},
pages = {261-268},
doi = {10.36469/001c.140817},
pmid = {40584972},
issn = {2327-2236},
abstract = {Background: Multifocal motor neuropathy (MMN) is a rare, slowly progressive nerve disorder characterized by asymmetric limb weakness without sensory abnormalities. MMN is often misdiagnosed due to similarities in clinical symptoms with conditions including amyotrophic lateral sclerosis (ALS), making diagnosis and treatment challenging. Objectives: This study assessed patient characteristics, treatment patterns, and the economic burden of MMN in the United States. Methods: Using the Optum Research Database, this retrospective analysis included patients with ≥1 diagnostic or nondiagnostic medical claim with an MMN diagnosis code between 2016 and 2020 (date of first diagnosis-related claim =index date), and continuous enrollment for 12 months preindex and postindex. Patients with MMN within this group were identified using more specific criteria; ≥2 MMN nondiagnostic claims separated by ≥30 days, with no subsequent ALS diagnosis during follow-up. All patients who did not meet these criteria were included in the MMN-mimic cohort. Outcomes included treatment patterns, differential diagnoses, healthcare utilization, and costs. Results: Of 904 patients identified, 37% had MMN and 63% had an MMN-mimic condition. Patients with MMN were significantly younger than patients in the MMN-mimic cohort (mean, 64.9 vs 66.8 years; P = .047). At preindex, significantly more patients with MMN received MMN-related medications than patients in the MMN-mimic cohort (20.5% vs 9.0%, respectively; P < .001). Intravenous immunoglobulin (IVIG) was the most common MMN-related medication. At postindex, more patients with MMN used IVIG (28.0%) compared with preindex (16.4%). In the 12 months preindex and postindex, >70% of patients had ≥1 differential diagnosis. The MMN cohort had higher all-cause total costs than the MMN-mimic cohort (mean preindex, 58 974 v s 48 132, respectively [P = .100]; mean postindex, 74 187 v s 50 652 [P = .002]); they also had significantly higher MMN-related healthcare costs (mean preindex, 23 625 v s 12 890 [P = .011]; mean postindex, 39 521 v s 11 938 [P < .001]). Discussion: This study showed that most patients with initial MMN diagnoses had an alternative disorder after subsequent evaluation/follow-up, and patients with MMN incurred higher costs. Many patients with MMN did not receive IVIG, suggesting that undertreatment or misattribution of diagnosis codes are common. Conclusions: Further education is needed regarding accurate diagnosis of MMN to ensure patient access to guideline-recommended treatment.},
}

@article {pmid40584588,
year = {2025},
author = {Odenbring, Y and Lindén, L},
title = {Reaching everyone: school nurses' experiences of including refugee and migrant students in the extended school-based HPV vaccination programme in Sweden.},
journal = {Journal of research in nursing : JRN},
volume = {},
number = {},
pages = {17449871251329001},
doi = {10.1177/17449871251329001},
pmid = {40584588},
issn = {1744-988X},
abstract = {BACKGROUND: In Sweden, providing a free-of-charge national child vaccination programme is part of national public health work to promote health and prevent illness. Yet Sweden is no exception when it comes to systematic societal inequality. Research worldwide has shown that childhood vaccination coverage is lower among refugee and migrant children than among non-migrant children.

AIM: The aim of this study is to explore how school nurses working in one of Sweden's largest regions reflect on their strategies and experiences of including children with refugee or migrant backgrounds in the school-based extended HPV vaccination programme.

METHODS: The study draws from semi-structured individual interviews with 21 school nurses. Analysis drew on Braun et al's (2011) four contextual dimensions: 1) the situated context; 2) the professional context; 3) material contexts; 4) external contexts. Thematic analysis was undertaken (Braun and Clarke, 2006; Clarke and Braun, 2013).

RESULTS: Three themes were identified: 1) social and economic deprivation; 2) ways of communicating; 3) gratitude. According to the school nurses, mapping the families' social situation and building trusting relationships are essential. Providing written information about the vaccination in diverse languages and/or involving an interpreter are also important strategies to reach refugee and migrant parents. Despite the families' often marginalised position, the children and their parents favour the HPV vaccination, which could be interpreted as vaccine confidence.

CONCLUSIONS: Meeting the needs of children and families with refugee or migrant backgrounds requires that school nursing practice take a holistic perspective. The study contributes new insights regarding these issues.},
}

@article {pmid40584177,
year = {2025},
author = {Wu, Q and Yang, J and Duan, Y and Ma, Y and Zhang, Y and Tan, S and Wang, J and Wang, Y and Liu, B and Zhang, J and Liu, X},
title = {Environmental risk factors, protective factors, and biomarkers for amyotrophic lateral sclerosis: an umbrella review.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1541779},
doi = {10.3389/fnagi.2025.1541779},
pmid = {40584177},
issn = {1663-4365},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the rapid loss of motor neurons. Given the significant global economic impact of ALS, effective preventive measures are urgently needed to reduce the incidence of this devastating disease. Recent meta-analyses have explored potential links between environmental factors, biomarkers, and ALS occurrence. However, the findings of these studies have been inconsistent and controversial. Therefore, we present a comprehensive umbrella review of recent meta-analyses to systematically summarize the available epidemiological evidence and evaluate its credibility.

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

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

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

@article {pmid40583986,
year = {2025},
author = {Shobe, SM and Melka, D and Mulugeta, M and Adane, L},
title = {Bright tongue sign as a radiological clue of bulbar onset amyotrophic lateral sclerosis: A case report.},
journal = {Radiology case reports},
volume = {20},
number = {9},
pages = {4338-4341},
doi = {10.1016/j.radcr.2025.05.044},
pmid = {40583986},
issn = {1930-0433},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by degeneration of motor neurons, with the tongue often involved in clinical presentation. In this case, a 60-year-old female presented with progressive choking episodes and speech slurring over 9 months, exhibiting dysarthria, prominent tongue atrophy, fasciculations, and hyperreflexia. Needle electromyography (EMG) showed diffuse chronic neurogenic changes with signs of active denervation changes prominent on the tongue and right arm with normal sensory nerve studies. Magnetic resonance imaging (MRI) brain imaging revealed a Diffuse T1 Weighted image (T1WI) hyperintense of tongue known as "bright tongue sign" indicating fatty infiltration of tongue muscles, consistent with neurogenic atrophy. This case underscores the importance of recognizing this characteristic tongue hyperintensity as a valuable radiological clue in diagnosing bulbar-onset ALS and highlights the potential for early diagnosis to improve patient management and outcomes.},
}

@article {pmid40583561,
year = {2025},
author = {Magarotto, M and Gawne, RT and Vilkaite, G and Beltrami, M and Mason, AS and Chen, HJ},
title = {Familial ALS/FTD-associated RNA-binding deficient TDP-43 mutants cause neuronal and synaptic transcript dysregulation in vitro.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf111},
pmid = {40583561},
issn = {1460-2083},
support = {SBF006\1088//British Heart Foundation and Diabetes UK/ ; //ASM's York Against Cancer (York, UK)/ ; },
abstract = {TDP-43 is an RNA-binding protein constituting the pathological inclusions observed in ~ 95% of ALS and ~ 50% of FTD patients. In ALS and FTD, TDP-43 mislocalises to the cytoplasm and forms insoluble, hyperphosphorylated and ubiquitinated aggregates that enhance cytotoxicity and contribute to neurodegeneration. Despite its primary role as an RNA/DNA-binding protein, how RNA-binding deficiencies contribute to disease onset and progression are little understood. Among many identified familial mutations in TDP-43 causing ALS/FTD, only two mutations cause an RNA-binding deficiency, K181E and K263E. In this study, we used CRISPR/Cas9 to knock-in the two disease-linked RNA-binding deficient mutations in SH-SY5Y cells, generating both homozygous and heterozygous versions of the mutant TDP-43 to investigate TDP-43-mediated neuronal disruption. Significant changes were identified in the transcriptomic profiles of these cells, in particular, between K181E homozygous and heterozygous cells, with the most affected genes involved in neuronal differentiation and synaptic pathways. This result was validated in cell studies where the neuronal differentiation efficiency and neurite morphology were compromised in TDP-43 cells compared to unmodified control. Interestingly, divergent neuronal regulation was observed in K181E-TDP-43 homozygous and heterozygous cells, suggesting a more complex signalling network associated with TDP-43 genotypes and expression level which warrants further study. Overall, our data using cell models expressing the ALS/FTD disease-causing RNA-binding deficient TDP-43 mutations at endogenous levels show a robust impact on transcriptomic profiles at the whole gene and transcript isoform level that compromise neuronal differentiation and processing, providing further insights on TDP-43-mediated neurodegeneration.},
}

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

@article {pmid40583130,
year = {2025},
author = {Yang, M and Wang, Q and Kang, D and Wang, S and Jiang, Y and Wang, JZ and Ming, C and Liu, R and Gu, J and Wang, X},
title = {Cryptic Splicing of GAP43 mRNA is a Novel Hallmark of TDP-43-Associated ALS and AD.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e12054},
doi = {10.1002/advs.202412054},
pmid = {40583130},
issn = {2198-3844},
support = {82330041//National Natural Science Foundation of China/ ; 92049107//National Natural Science Foundation of China/ ; 32171258//National Natural Science Foundation of China/ ; 2022-72-18//Science and Technology Innovation Team project from Department of Science and Technology of Hubei Province/ ; //Co-lnnovation Center of Neuroregeneration, Nantong University/ ; },
abstract = {Cytoplasmic aggregation of transactive response DNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS) and occurs in 57% of Alzheimer's disease (AD) cases. TDP-43 regulates RNA processing, including cryptic exon splicing. Here, we demonstrate that TDP-43 directly controls growth-associated protein (GAP43) expression by binding to its pre-mRNA. Loss or hyperphosphorylation of TDP-43 disrupts this binding, leading to the inclusion of cryptic exon 4a1, which introduces premature stop codons and reduces GAP43 protein levels. RNA sequencing analysis of ALS and AD brains revealed GAP43 downregulation, while 4a1 is upregulated in AD cases with phosphorylated TDP-43. TDP-43 knockdown impaired axonal regeneration in induced pluripotent stem cell (iPSC)-derived motor neurons, whereas GAP43 restoration rescued this defect. These findings suggest that the loss of GAP43 contributes to neurodegeneration in ALS and AD. The inclusion of GAP43 cryptic exon 4a1 may serve as a hallmark of TDP-43 proteinopathies, highlighting a mechanistic link between TDP-43 dysfunction and neuronal vulnerability.},
}

@article {pmid40582651,
year = {2025},
author = {Abdullah, M and Sedeek, A and Keebler, M and Hickey, G and Hartwick, M and Kaczorowski, DJ},
title = {First Successful Cardiac Allograft Donation and Transplantation after Medical Assistance in Dying (MAiD).},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.healun.2025.06.026},
pmid = {40582651},
issn = {1557-3117},
abstract = {Medical assistance in dying (MAiD) provides capable patients with intolerable suffering the option to retain control over the timing and circumstances of their deaths. This case reports the first successful cardiac transplantation after MAiD. A 59-year-old male with end-stage heart failure received a donor heart from a 38-year-old male with ALS who underwent MAiD. The donor heart was retrieved using the TransMedics Organ Care System and successfully transplanted with excellent postoperative function. The recipient's recovery included transient mild rejection and acute kidney injury, both of which resolved with treatment. This case demonstrates the feasibility of cardiac transplantation following MAiD and highlights its potential to expand the donor pool.},
}

@article {pmid40587259,
year = {2025},
author = {Hattori, Y and Kumashiro, M and Kumeta, H and Kyo, T and Kawagoe, S and Matsusaki, M and Saio, T},
title = {A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00260},
pmid = {40587259},
issn = {1520-4995},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. Peptidylprolyl cis-trans isomerase A (PPIA) is a molecular chaperone involved in protein folding, and its dysfunction has been linked to ALS pathogenesis, as proline is recognized as a key residue for maintaining proper folding of ALS-related proteins. A recent study identified a K76E mutation in PPIA in sporadic ALS patients, but its effect on protein function and structure remain unclear. In this study, we used biochemical and biophysical techniques to investigate the structural and functional consequences of the K76E mutation. Our results show that K76E significantly reduces enzyme activity without affecting structure, monodispersity, or substrate recognition. Significant effects of K76E mutation were identified by relaxation dispersion NMR experiments, showing that K76E disrupts key protein dynamics and alters an allosteric network essential for isomerase activity. Corroborated by theoretical kinetic analysis, these dynamics data, revealing the exchange process for K76E to be approximately 1 order of magnitude slower than that of the wild type, explain the reduced cis-trans isomerase activity of the K76E mutant. These findings suggest that the pathogenic effect of K76E arises primarily from impaired protein dynamics rather than direct structural disruption. Our study provides new insights into the molecular mechanisms underlying ALS-associated mutations and their impact on protein function.},
}

@article {pmid40587112,
year = {2025},
author = {Regev, S and Talmy, T and Gelikas, S and Mitchnik, IY},
title = {Impact of ongoing clinical experience on advanced life support provider performance in multicasualty simulations.},
journal = {The journal of trauma and acute care surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/TA.0000000000004697},
pmid = {40587112},
issn = {2163-0763},
abstract = {BACKGROUND: Effective response to multicasualty events may depend on the performance of advanced life support (ALS) providers. This study examines the relationship between ALS training, clinical skill maintenance through a Competency Maintenance Program, and provider performance in multicasualty event simulations.

METHODS: Military medical teams, led by Israel Defense Forces (IDF) Military Trauma Life Support (MTLS)-trained providers (physicians or paramedics), participated in a multicasualty scenario simulation. Performance was assessed using a task checklist and the Trauma Non-Technical Skills scale. Data were collected on MTLS training and participation in the Competency Maintenance Program, which mandates ALS providers to complete hospital and ambulance shifts for continuous skill maintenance. Regression analyses were conducted to evaluate the impact of these variables on simulation performance.

RESULTS: The study included 25 teams, the majority of which were led by paramedics (78%). Clinical experience in hospitals and ambulance services showed moderate correlations with simulation performance (R = 0.562, p = 0.009, and R = 0.664, p = 0.003, respectively). However, ALS provider type (physician vs. paramedic) and MTLS course performance did not correlate with simulation performance (R = 0.009, p = 0.952, and R = 0.390, p = 0.054, respectively). Simulation performance was also correlated with the teams' nontechnical skills (R = 0.550, p < 0.001, β = 0.393, p = 0.014), which functioned as both an independent factor and a partial mediator in the relationship between ALS providers' attributes and simulation performance (R2 = 0.725, R2 change = 0.475). Specifically, clinical experience in hospitals was directly linked to performance, whereas ambulance experience was indirectly associated with performance through its impact on nontechnical skills.

CONCLUSION: Clinical skill maintenance through hospital and ambulance experience may enhance ALS providers' performance in multicasualty event simulations. These findings suggest that structured skill maintenance programs could better prepare teams for managing complex scenarios.

LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.},
}

@article {pmid40581791,
year = {2025},
author = {Al Ojaimi, Y and Osman, S and Alarcan, H and Emond, P and Veyrat-Durebex, C and Lanznaster, D and Meme, S and Clemencon, R and Galineau, L and Corcia, P and Andres, C and Vourc'h, P and Masse, F and Trovero, F and Blasco, H},
title = {Identification of disease-associated molecular signatures in the Prp-TDP-43A315T mouse model of ALS: Toward preclinical biomarker development.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlaf071},
pmid = {40581791},
issn = {1554-6578},
support = {//Région Centre Val de Loire/ ; //French National Research Agency/ ; //ARSLA/ ; },
abstract = {Identifying disease-related molecular signatures that can be used as biomarkers is critical for the development of preclinical therapies for amyotrophic lateral sclerosis (ALS). In this study, we focused on the Prp-TDP-43A315T transgenic mouse model of ALS to explore peripheral and central molecular alterations associated with disease progression. Prp-TDP-43A315T transgenic (Tg) and C57BL/6J wild-type mice were monitored from 50 to 400 postnatal days. One cohort assessed phenotypic parameters and MRI activity at 3 timepoints, ie, before (T0), at disease onset (T1), and at end-stage (T2). A second cohort validated findings from the first using omics analyses of tissues to examine ALS-related markers. Tg mice showed reduced body weight, decreased grip strength and tail position, and increased gait impairment at T1. Changes in (p)TDP-43, NRF2, GFAP, and pAMPK expression were noted in brain samples from the second cohort at T1. Metabolomic and lipidomic analyses revealed shifts in specific molecules in the brain and muscle of Tg mice. These data highlight individual differences in ALS pathology and adaptive responses to TDP-43-induced damage. This model provides valuable insights into TDP-43 proteinopathies and presents an innovative method for analyzing pathophysiological pathways through dried blood spot analysis, thereby expanding its applicability across various research fields.},
}

@article {pmid40581671,
year = {2025},
author = {Ono, S and Nakamura, M and Ikegami, T and Kajiyama, Y and Kume, K and Takahashi, Y and Takahashi, M and Mochizuki, H and Mizusawa, H and Kawakami, H and Yakushiji, Y},
title = {Spinocerebellar ataxia type 2 followed by amyotrophic lateral sclerosis due to a pure CAG repeat expansion in ATXN2: a case report and literature review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40581671},
issn = {1590-3478},
abstract = {BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia caused by abnormal CAG expansions (≥ 34 repeats) in the ATXN2 gene (ATXN2), whereas intermediate CAG expansions (27-33 repeats) have been linked to amyotrophic lateral sclerosis (ALS).

CASE DESCRIPTION: A 53-year-old woman with longstanding cerebellar ataxia developed progressive upper limb weakness and muscle atrophy at the age of 51 years. On neurological examination, she was found to have ataxic dysarthria, slow saccadic eye movements, tongue atrophy with fasciculations, muscle atrophy and weakness in both upper limbs, hyperreflexia with Babinski's sign, and limb and gait ataxia. Brain magnetic resonance imaging (MRI) showed brainstem and cerebellar atrophy. Genetic analysis identified an expanded CAG-repeat of 39/22 in ATXN2, and screening for other known ALS-related gene mutations was negative, leading to a diagnosis of both SCA2 and ALS associated with ATXN2.

CONCLUSIONS: SCA2 is typically associated with uninterrupted CAG-repeat expansions, whereas ALS-related ATXN2 expansions usually contain at least one CAA triplet. However, despite carrying an uninterrupted CAG-repeat expansion, this patient developed ALS. This case shows that ALS can emerge several decades after SCA2 onset, even in patients with pure CAG-repeats, underscoring the need for long-term monitoring in SCA2 patients. Further research is needed to clarify the roles of repeat length, CAA interruptions, and other factors in ATXN2-related ALS.},
}

@article {pmid40581653,
year = {2025},
author = {Lin, LT and Shenouda, M and McGoldrick, P and Lau, A and Robertson, J},
title = {C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {136},
pmid = {40581653},
issn = {2051-5960},
support = {#189242, #507996, #20012625//ALS Society of Canada/ ; 2023-001//Association for Frontotemporal Degeneration/ ; MOP-137005/CAPMC/CIHR/Canada ; AL161011//Weston Brain Institute/ ; },
mesh = {Animals ; *C9orf72 Protein/deficiency/genetics ; *Autophagy/physiology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Mice, Transgenic ; Frontotemporal Dementia/pathology/genetics/metabolism ; Disease Models, Animal ; Male ; Neurons/pathology/metabolism ; Brain/pathology/metabolism ; *Nerve Degeneration/pathology/metabolism ; },
abstract = {Cytoplasmic aggregates of the predominantly nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases caused by G4C2 hexanucleotide repeat expansions in C9orf72 (C9-ALS/FTD). While these repeat expansions are associated with both gain- and loss-of-function mechanisms, the contribution of C9orf72 loss of function to disease pathogenesis remains unclear. C9orf72 has been shown to regulate autophagy, and its deficiency has been shown to exacerbate phenotypes in gain-of-function G4C2 models, implicating impaired autophagic clearance in disease pathogenesis. Here, we directly test whether C9orf72 deficiency exacerbates TDP-43 pathology and neurodegeneration in vivo. Using AAV9-vectors to drive neuron-specific expression of pathologically relevant C-terminal species of TDP-43, TDP-35 and TDP-25, we established models of TDP-43 pathology that recapitulate key disease features, including cytoplasmic aggregates, motor and cognitive decline, and neuronal loss. TDP-25 expression in particular produced robust, abnormally phosphorylated, ubiquitinated and p62-labelled cytoplasmic aggregates, modelling TDP-43 pathology in disease. Loss of C9orf72 in TDP-25-expressing mice accelerated the onset of motor deficits, increased neurodegeneration, and impaired the autophagic response to TDP-25 expression. These findings reveal that C9orf72 deficiency disrupts autophagy and exacerbates TDP-25-mediated toxicity in vivo, supporting a contributory role for C9orf72 loss-of-function in driving neurodegeneration in C9-ALS/FTD.},
}

Animals
*C9orf72 Protein/deficiency/genetics
*Autophagy/physiology/genetics
*DNA-Binding Proteins/metabolism/genetics
Mice
Humans
Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
Mice, Transgenic
Frontotemporal Dementia/pathology/genetics/metabolism
Disease Models, Animal
Male
Neurons/pathology/metabolism
Brain/pathology/metabolism
*Nerve Degeneration/pathology/metabolism

@article {pmid40581642,
year = {2025},
author = {Sanadgol, N and Samadi, M and Voelz, C and Khalseh, R and Amini, J and Beyer, C and Kipp, M and Clarner, T},
title = {Genomic ncRNAs regulating mitochondrial function in neurodegeneration: a neglected clue in the complex etiopathogenesis of multiple sclerosis.},
journal = {Cell & bioscience},
volume = {15},
number = {1},
pages = {93},
pmid = {40581642},
issn = {2045-3701},
abstract = {Multiple sclerosis (MS), the most prevalent myelinopathy with unclear etiology, involves mitochondrial dysfunction that critically contributes to oligodendrocyte damage and neurodegeneration. Recent interest has surged around the role of inflammatory non-coding RNAs (ncRNAs) in mitochondrial function, particularly in the context of neurodegenerative diseases (NDs), where neuroinflammation is a hallmark feature. This review highlights the collection and characterization of mitochondrial-related ncRNAs (MRncRNAs) that have been extensively studied in the context of NDs. Through a literature review, we identified 35 MRncRNAs (23 miRNAs, 8 LncRNAs, and 4 circRNAs) across Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Notably, the inflammatory miRNAs miR-34a and miR-146a were commonly dysregulated in both PD and AD, while in HD, only a single miRNA, miR-196a, was identified. As expected, due to the mitochondrial nature of PD, the majority of MRncRNAs (9 miRNAs, 8 lncRNAs, and 3 circRNAs) were associated with this disorder. Further bioinformatic analysis of MRmiRNAs revealed that miR-124-5p, -146a-3p, and -15b-3p target mitochondrial genes more than others, and mRNA of pro-apoptotic protein BCL2L11 is the most targeted. Notably, the link between these MRncRNAs and mitochondrial function in MS remains unidentified. By evaluating upregulated MS-related ncRNAs in patients and comparing them with identified MRncRNAs, we found nine overlapping miRNAs (miR-15b, miR-21, miR-27b, miR-34a, miR-124, miR-137, miR-146a, miR-155, and miR-92a) as well as two shared lncRNAs, MALAT1 and HOTAIR (called MS/MRncRNAs). Further bioinformatic analysis of MS/MRmiRNAs revealed that the autophagy pathway is the most involved. Six of these miRNAs are significantly involved in MR diseases. Notably, miR-34a-5p showed a connection to oligodendrocyte mitochondria, while miR-15b targeted two MR hub genes, SDHC and BCL2. Moreover, several hub proteins (HIF1A, STAT3, MAPK1, GSK3B) targeted by these miRNAs are well-known regulators of inflammatory pathways and mitochondrial homeostasis: These findings highlight the critical roles of ncRNAs in mitochondrial dysfunction and neurodegeneration, emphasizing the urgent need for experimental studies on MRmiRNAs, particularly in the context of MS and other myelinopathies.},
}

@article {pmid40581291,
year = {2025},
author = {Ha, T and Ganesh, S and Narendran, K and Uduman, MS and Rajan, R and Sankaridurg, P and Nguyen, N and Tran, H},
title = {Comparison of axial length measurements of myopic eyes from ocular biometers versus axial length estimator.},
journal = {Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus},
volume = {},
number = {},
pages = {104254},
doi = {10.1016/j.jaapos.2025.104254},
pmid = {40581291},
issn = {1528-3933},
abstract = {PURPOSE: To compare axial length (AL) estimates of myopic eyes obtained using an axial length estimator (ALE) and AL measurements made with the IOLMaster 700 in India and the Lenstar 900 in Vietnam.

METHODS: This multicenter retrospective cross-sectional study analyzed masked data of both eyes from myopic children (<18 years of age). Estimated AL was derived from mean keratometry and refraction values using ALE. Differences between actual and estimated ALs and their correlation were assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs).

RESULTS: A total of 237 myopic children (474 eyes) aged 5-16 years were included: 90 Indian and 147 Vietnamese children. ALE estimates exceeded actual AL measurements, with mean differences of -0.26 mm (95% limits of agreement, -1.25 to 0.73 mm) for ALE formula, and -0.21 mm (95% limits of agreement, -1.14 to 0.71 mm) for ALE data input. ICCs showed strong agreement: 0.90 (95% CI, 0.83-0.93) for actual AL versus ALE data input and 0.89 (95% CI, 0.78-0.93) for actual AL versus ALE formula. Indian children had shorter actual AL than Vietnamese children (24.56 ± 0.90 vs 24.91 ± 0.86 mm [P < 0.001]) and exhibited slightly smaller differences between actual and estimated AL (-0.13 vs -0.27 mm for ALE data input; -0.17 vs -0.31 mm for ALE formula).

CONCLUSIONS: In our cohorts, ALE demonstrated strong agreement with IOLMaster 700 and Lenstar 900 AL measurements in myopic children. ALE may be a useful clinical tool for this population when direct measurements of AL are unavailable.},
}

@article {pmid40580876,
year = {2025},
author = {García-Toscano, L and Rodríguez-Cueto, C and Furiano, A and Hind, W and de Lago, E and Fernández-Ruiz, J},
title = {Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {189},
number = {},
pages = {118288},
doi = {10.1016/j.biopha.2025.118288},
pmid = {40580876},
issn = {1950-6007},
abstract = {Plant-derived cannabinoids, including Δ[9]-THC, cannabinol, and Sativex-like combinations, have shown neuroprotection in preclinical ALS models. However, minor phytocannabinoids like cannabidiolic acid (CBDA) remain unexplored. This study evaluated the neuroprotective effects of CBDA, cannabidivarin, CBD, Δ[9]-THC, and Δ[9]-tetrahydrocannabidivarin in Prp-hTDP-43(A315T) transgenic male mice from early symptomatic (day 65) to advanced stages (day 90). CBDA proved the most effective, improving motor coordination (rotarod test) and reducing neuronal cell death, gliosis, microglial reactivity, and pro-inflammatory mediators in the spinal cord. A dose-response study confirmed that 10 mg/kg CBDA improved motor performance and preserved motor neurons, while lower doses were less effective and higher doses caused toxicity. Flow cytometry revealed a shift from an M1 proinflammatory to an M2 anti-inflammatory phenotype in microglial cells after CBDA treatment, mirroring effects in BV2 cells exposed to LPS. Comparing CBDA with riluzole (standard ALS therapy), CBDA showed superior neuroprotection, except for rotarod performance, where no improvement was observed. A combination of CBD and riluzole failed to enhance efficacy and even weakened microglial response benefits. In conclusion, CBDA was the most effective of the five phytocannabinoids studied and outperformed riluzole in ALS models. These findings support further clinical evaluation of CBDA for ALS treatment.},
}

@article {pmid40580685,
year = {2025},
author = {Deng, Z and Chen, H and Chen, J and Du, Z and Zhou, W and Yuan, Z},
title = {Multifaceted roles of extracellular vesicles in the interplay of neuroinflammation and neurodegenerative diseases.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1871},
number = {7},
pages = {167960},
doi = {10.1016/j.bbadis.2025.167960},
pmid = {40580685},
issn = {1879-260X},
abstract = {Despite advances in understanding neurodegenerative disease mechanisms, effective treatments remain elusive. Extracellular vesicles (EVs), key mediators of intercellular communication within the central nervous system (CNS), are increasingly recognized for their involvement in the pathogenesis of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). In vivo studies demonstrate EVs' crucial role in maintaining CNS homeostasis, modulating neuroinflammatory responses, and influencing tissue repair and regeneration following injury, thereby impacting disease progression and recovery. Their unique properties, including small size and ability to cross the blood-brain barrier (BBB), position them as promising candidates for both biomarkers and therapeutics in CNS diseases. This review delves into the significant impact of neuroinflammation on neurodegenerative conditions, specifically focusing on the multifaceted contributions of EVs and their intricate interplay with the inflammatory landscape. We explore EV biogenesis, cargo composition, diverse roles in neuroinflammation (including intercellular communication and neuroprotection), their potential as biomarkers and drug delivery vehicles across the BBB for diagnosis or treatment of neuroinflammation implemented neurodegenerative diseases.},
}

@article {pmid40580336,
year = {2025},
author = {Wang, T and Wang, Y and Yang, Y and Wang, S and Wang, X and Feng, H},
title = {Fisetin Attenuates Mutant SOD1 Aggregation in Amyotrophic Lateral Sclerosis via Nrf2-Mediated Autophagy Activation.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {3},
pages = {84},
pmid = {40580336},
issn = {1559-1166},
support = {2020B11//the First Affiliated Hospital of Harbin Medical University Research Innovation Fund/ ; 2020B11//the First Affiliated Hospital of Harbin Medical University Research Innovation Fund/ ; 2020-127//the Health Commission Scientific Research Foundation of Heilongjiang Province of China/ ; 21042240013//2024 Heilongjiang Province Postdoctoral Research Start-up Fund/ ; },
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Autophagy ; Flavonols ; *Flavonoids/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Animals ; Motor Neurons/metabolism/drug effects ; Humans ; Cell Line ; Sequestosome-1 Protein/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Protein Aggregates ; Protein Aggregation, Pathological ; },
abstract = {Dysregulated autophagy and copper/zinc superoxide dismutase (SOD1) protein aggregation play a crucial role in amyotrophic lateral sclerosis (ALS). Here, we used stably transfected NSC34 motor neuron-like cells: (1) SOD1[G93A] mutants (G93A), (2) wild-type SOD1 (WT) controls, and (3) empty vector (EV) controls to observe the effects of fisetin. Pharmacological autophagy inhibition (Bafilomycin A1, 40 nM) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene silencing (siRNA transfection) were employed to dissect molecular pathways. Protein aggregation dynamics and autophagy markers (LC3, p62/SQSTM1) were quantified through immunofluorescence and immunoblotting. SOD1[G93A] models exhibited impaired autophagic flux evidenced by elevated LC3-II and p62 levels, correlating with increased detergent-insoluble SOD1 aggregates. Fisetin treatment (1-10 μ M) dose-dependently reduced both soluble and aggregated SOD1[G93A] protein, concomitantly with restored autophagic flux. Mechanistically, fisetin promoted nuclear translocation while decreasing cytoplasmic Nrf2. After administration of an autophagy inhibitor and interference with Nrf2, the regulation of fisetin on p62 and mutant hSOD1 protein was inhibited. Our findings demonstrate that fisetin ameliorates mutant SOD1 proteotoxicity through coordinated activation of Nrf2-mediated autophagy pathways, suggesting therapeutic potential for SOD1-associated ALS pathologies.},
}

*NF-E2-Related Factor 2/metabolism/genetics
*Autophagy
Flavonols
*Flavonoids/pharmacology
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics
*Superoxide Dismutase-1/genetics/metabolism
Mice
Animals
Motor Neurons/metabolism/drug effects
Humans
Cell Line
Sequestosome-1 Protein/metabolism/genetics
*Neuroprotective Agents/pharmacology
Protein Aggregates
Protein Aggregation, Pathological

@article {pmid40580315,
year = {2025},
author = {Jellinger, KA},
title = {Co-occurrence of amyotrophic lateral sclerosis and multiple sclerosis: a rare but interesting association.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40580315},
issn = {1435-1463},
support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; },
abstract = {Multiple sclerosis (MS) is an inflammatory demyelinating disease with highly variable clinical course and usual onset in younger age, caused by genetic and environmental factors. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord, resulting in gradual loss of voluntary muscle and respiratory control. Both ALS and MS exhibit distinct underlying causes and disease mechanisms, despite some shared clinical effects. About 10% of ALS are linked to genetic factors, such as C9orf72, the remaining sporadic ones being potentially influenced by environmental, toxic and oxidative stress, while MS is an autoimmune disorder where the immune system leads to inflammation and attacks the myelin sheath, genetic predisposition and viral infections playing a role in its susceptibility. The co-occurrence of ALS and MS is extremely rare, with 46 cases being reported in the available literature from 1986 to 2024, while in the earlier literature, cases with coincidental muscular atrophy simulating ALS were described. In the overwhelming majority, ALS manifested between one and 41 years after the onset of MS; only in four cases was ALS present before detection of MS. The concurrence of MS and ALS can be explained by similarities in their pathogenesis related to neurodegeneration, inflammation, and/or genetic susceptibility. The role of rare genetic ALS forms in this comorbidity deserves further studies. The shared inflammatory component with a cascade of oxidative stress and other noxious mechanisms leads to progressive motor and bulbar or other symptoms that underscore the potential for cross-disease research to yield insights applicable to both conditions and their relations to immune-mediated disorders.},
}

@article {pmid40580203,
year = {2025},
author = {Pirozzi, MA and Canale, F and Di Nardo, F and Sharbafshaaer, M and Passaniti, C and Siciliano, M and Cirillo, M and Tessitore, A and Tedeschi, G and Esposito, F and Trojsi, F},
title = {Quantitative susceptibility mapping for investigating brain iron deposits in amyotrophic lateral sclerosis: correlations with clinical phenotype and disease progression.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2522406},
pmid = {40580203},
issn = {2167-9223},
abstract = {Objective: Perturbation of iron homeostasis is a potential key mechanism involved in neurodegeneration across many neurological disorders, including amyotrophic lateral sclerosis (ALS). We hypothesized that changes in quantitative susceptibility mapping (QSM) could capture perturbations in brain iron concentration in subgroups of ALS patients stratified by clinical phenotype and disease progression. Method: We enrolled 38 ALS patients (23 males - mean age: 58.7 ± 9.8), screened by clinical (ALS functional rating scale-revised, ALSFRS-R) and neuropsychological scales. Patients were a posteriori classified as fast (n = 16) or slow (n = 22) progressors. Two subgroups were also considered: pyramidal (or upper motor neuron+, UMN+) patients (n = 18), and patients with other phenotypes (n = 20). Results: Comparing fast vs. slow progressors, significant differences in iron deposits were observed in the left (p = 0.028) and right amygdala (p = 0.022), and in susceptibility distribution on the right hippocampus (p = 0.0011). Comparing UMN+ vs. other phenotypes, significant susceptibility differences emerged in the left thalamus (p = 0.0014) and right amygdala (p = 0.001). QSM changes were associated with baseline ALSFRS-R (rho = 0.36, p = 0.026) in the left paracentral cortex, and iron concentration with UMN score (rho = 0.35, p = 0.034). Moreover, the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) was associated with iron deposits in the left thalamus (rho=-0.46, p = 0.0041). Conclusions: We confirmed that QSM alterations in extra-motor areas and subcortical regions may be distinctive hallmarks of neurodegeneration in pure/dominant UMN phenotypes of ALS. Moreover, we showed that QSM could be a valuable tool to differentiate patients with different progression rates and phenotypes, suggesting that QSM may support a prognostically useful early stratification of ALS patients.},
}

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

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

@article {pmid40577240,
year = {2025},
author = {O'Brien, D and Alhathli, E and Harwood, C and Bhattacharya, D and Gupta, K and Julian, T and Weinreich, M and West, RJH and Wang, D and Byrne, RP and McLaughlin, RL and Wuu, J and Benatar, M and Cooper-Knock, J and Shaw, PJ},
title = {Extreme exercise in males is linked to mTOR signalling and onset of amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf235},
pmid = {40577240},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is thought to be caused by interaction between genetic and environmental factors leading to motor neuron (MN) degeneration. Physical exercise has been linked to ALS but controversy remains. A key question is to determine which individuals might be at risk of exercise-associated ALS, because unnecessary avoidance of exercise could be harmful. We implemented complementary strategies including Mendelian randomization and multiple questionnaire-based measures of physical exercise in different cohorts. We include a prospective study in UK Biobank participants where we could test for a relationship between exercise and the timing of future ALS symptom onset. To interrogate the molecular basis of our observations we performed a genetic association study of 'extreme' exercise, equivalent to >6 hours of strenuous exercise or >12 hours of any leisure-time exercise per week. Our data suggest that the link between increased physical exercise and ALS is particularly important for males who perform the most activity; with no evidence of a link in females. We determined that extreme exercise in males is associated with loss-of-function genetic variants within a number of mammalian target of rapamycin (mTOR) signalling genes that are also differentially expressed in ALS spinal cord. Activity-induced mTOR signalling has been shown to selectively benefit MN. Therefore, our findings could imply that moderate exercise is neuroprotective via enhanced mTOR signalling, but extreme exercise in men is associated with neurotoxicity and ALS via a failure of this mechanism. There was no significant overlap between genes associated with extreme exercise and those associated with ALS risk, consistent with a true gene-environment interaction rather than a shared genetic basis. We are not yet able to make individual-level recommendations regarding exercise and risk of ALS, but our conclusions should focus future investigation.},
}

@article {pmid40576748,
year = {2025},
author = {Gupta, MK and Chauhan, K and Bhardwaj, S and Srivastava, R},
title = {Innovative Interventions: Postbiotics and Psychobiotics in Neurodegenerative Disease Treatment.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {40576748},
issn = {1867-1314},
abstract = {Neurodegenerative disorders, including Huntington's disease, Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, create more challenges as the population gets older and there are no curative therapies available. Recent advances in gut microbiome research have spotlighted postbiotics and psychobiotics as innovative therapeutic strategies targeting the gut-brain axis to alleviate neurodegenerative symptoms and slow disease progression. Postbiotics, which are metabolites and cellular components released by probiotic bacteria, and psychobiotics, a class of probiotics with potential mental health benefits, offer novel approaches to neuroprotection. This chapter examines the ways in which postbiotics and psychobiotics modulate inflammation, oxidative stress, neurotrophic factors, and gut barrier integrity to provide neuroprotective effects. We review scientific research that highlights the efficacy of specific microbial strains and their metabolites in enhancing cognitive function and reducing neurodegeneration. In addition, we explore the consequences of diet and specific nutrition on strengthening the therapeutic results of these medications. The purpose of this chapter is to provide a detailed analysis of the existing data supporting the use of postbiotics and psychobiotics in both the prevention and management of neurological diseases. By integrating perspectives from microbiology, neurology, and clinical nutrition, we highlight the potential of these interventions to enhance patient outcomes and quality of life. In addition, we discuss the translational limitations and future research approaches required to successfully transition these microbiome-based treatments from the laboratory to clinical practice, emphasizing the importance of a holistic and personalized approach in combating neurodegenerative diseases.},
}

@article {pmid40576049,
year = {2025},
author = {Rudnicki, SA and Gebrehiwet, P and Kupfer, S and Malik, FI and Meng, L and Simkins, T and Wei, J and Wolff, AA and Shefner, JM},
title = {Participant, site personnel and sponsor perspectives on decentralized trial features in COURAGE-ALS: a randomized clinical trial.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2523941},
pmid = {40576049},
issn = {2167-9223},
abstract = {OBJECTIVES: To describe participant, site personnel (SP) and sponsor perspectives regarding their experiences with a decentralized clinical trial (DCT).

METHODS: COURAGE-ALS was a 48-week, double-blind, randomized, phase III, hybrid DCT of reldesemtiv versus placebo for ALS. Fifty participants completed semi-structured interviews at Week ∼22; the majority provided feedback on DCT features. Subsequently, a planned interim analysis led to termination of COURAGE-ALS for futility; 486 participants were randomized and dosed. SP completed an online survey focusing on operational aspects of the hybrid design.

RESULTS: RVs influenced the decision to pursue the trial in 13/31 participants. Remotely performing forced vital capacity (FVC) was a concern for 17/43 (40%). Survey response rate for SP was 41% (141/344). The trial was viewed as less time/labour for the site versus a traditional design by 52/136 (38%) of SP. Twenty percent (25/125) agreed their participants liked doing remote FVC assessments; 6% (7/109) of SP reported no challenges in obtaining FVC remotely. Technological problems were commonly reported by SP (71/109, 65%). Biospecimen collection and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale done at in-clinic visits (ICVs) and return visits (RVs) had similar completion rates, FVCs were missed more often at RVs than ICVs (completion rates 82% vs. 96%, p < 0.001).

CONCLUSIONS AND RELEVANCE: Participants and SP viewed RVs favorably, despite common technical challenges. RV FVC assessments were more likely to be missed. COURAGE-ALS demonstrated that an interventional hybrid DCT is feasible in ALS but limitations remain that will need to be considered when designing future DCTs.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT04944784).},
}

@article {pmid40575896,
year = {2025},
author = {Thorarinsson, BL and Halldorsdottir, KE and Hilmarsson, A and Sveinsson, OA},
title = {[Treatment of familial ALS with the drug tofersen].},
journal = {Laeknabladid},
volume = {111},
number = {7-08},
pages = {314-317},
doi = {10.17992/lbl.2025.0708.848},
pmid = {40575896},
issn = {1670-4959},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis/cerebrospinal fluid ; Treatment Outcome ; Mutation ; Male ; Middle Aged ; Female ; Superoxide Dismutase-1/genetics ; Neurofilament Proteins/cerebrospinal fluid ; Injections, Spinal ; Iceland ; Genetic Predisposition to Disease ; *Oligonucleotides/administration & dosage/therapeutic use ; Adult ; Biomarkers/cerebrospinal fluid ; *Oligonucleotides, Antisense/administration & dosage ; Phenotype ; Hospitals, University ; Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a severe and progressive neurodegenerative disorder. We describe four cases of familial ALS based on SOD1 mutations who received intrathecal treatment with the antisense oligonucleotide tofersen at Landspítali University Hospital Iceland. Since initiation of treatment, there has not been any significant deterioration, and three patients have shown signs of cinical improvement. The cerebrospinal fluid concentration of neurofilament light chain (Nf-L), a biomarker of neuronal axonal damage, has decreased to the reference range of healthy individuals. No serious side effects have been observed.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis/cerebrospinal fluid
Treatment Outcome
Mutation
Male
Middle Aged
Female
Superoxide Dismutase-1/genetics
Neurofilament Proteins/cerebrospinal fluid
Injections, Spinal
Iceland
Genetic Predisposition to Disease
*Oligonucleotides/administration & dosage/therapeutic use
Adult
Biomarkers/cerebrospinal fluid
*Oligonucleotides, Antisense/administration & dosage
Phenotype
Hospitals, University
Aged

@article {pmid40575894,
year = {2025},
author = {Eliasdottir, OJ},
title = {[Antisense oliconucleotides-potential treatment for familial Amyotrophic lateral sclerosis (ALS).].},
journal = {Laeknabladid},
volume = {111},
number = {7-08},
pages = {311},
doi = {10.17992/lbl.2025.0708.846},
pmid = {40575894},
issn = {1670-4959},
}

@article {pmid40575640,
year = {2025},
author = {Ahmed, S and Nashwan, AJ},
title = {Rising adult hepatitis A in Pakistan: Shifting trends and public health solutions.},
journal = {World journal of virology},
volume = {14},
number = {2},
pages = {102519},
pmid = {40575640},
issn = {2220-3249},
abstract = {This letter evaluates Shahid et al's study in 2025 on the rising hepatitis A virus (HAV) among adults in Pakistan, highlighting a shift in the virus's epidemiology. Once primarily a childhood disease in low-income regions, HAV is now increasingly affecting adults, also seen globally due to improved sanitation. The study highlights public health challenges from adult HAV infections, which can lead to complications like coagulopathy and acute liver failure. It also has limitations, including being a single-center study and lacking seroprevalence and socioeconomic data, indicating the need for further research. This letter calls for urgent public health measures to extend adult vaccination programs and improve sanitation to address the increasing HAV infection in adult populations.},
}

@article {pmid40575450,
year = {2025},
author = {Barker, MS and Shneider, NA and Manoochehri, M and Huey, ED and Lindenberger, EC},
title = {Excessive emotional reactivity in a case of behavioral variant frontotemporal dementia with amyotrophic lateral sclerosis.},
journal = {Psychiatry research case reports},
volume = {4},
number = {1},
pages = {},
pmid = {40575450},
issn = {2773-0212},
support = {R00 NS060766/NS/NINDS NIH HHS/United States ; R01 NS076837/NS/NINDS NIH HHS/United States ; },
abstract = {Although amyotrophic lateral sclerosis (ALS) is defined as a neuromuscular disease, cognitive and/or behavioral symptoms are relatively common, and a portion of ALS patients will meet criteria for behavioral variant frontotemporal dementia (bvFTD). In this report, we describe the case of a man with ALS with bvFTD (ALS-FTD) presenting with excessive emotional reactivity, including severe anger, aggression, and obsessive thoughts. We contrast this case with the decreased emotional reactivity that is usually observed in patients with bvFTD without ALS. We discuss possible explanations including that: 1) the behavioral symptoms of bvFTD and ALS-FTD are the same, but the motor dysfunction influences the clinical manifestations of the behavioral symptoms in ALS-FTD; 2) the emotional and behavioral symptoms of bvFTD and ALS-FTD are the same, but ALS-FTD patients come to clinical attention earlier in the course of their FTD than bvFTD patients without ALS; and 3) the emotional and behavioral symptoms of bvFTD and ALS-FTD could differ.},
}

@article {pmid40574975,
year = {2025},
author = {Lehto, A and Schumacher, J and Teipel, S and Machts, J and Vielhaber, S and Hermann, A and Prudlo, J and Kasper, E},
title = {Cerebellar grey matter volume is associated with semantic fluency performance in amyotrophic lateral sclerosis patients.},
journal = {Brain communications},
volume = {7},
number = {3},
pages = {fcaf230},
pmid = {40574975},
issn = {2632-1297},
abstract = {The cerebellum has been shown to contribute to different cognitive functions such as verbal fluency and different aspects of executive functioning, which are also commonly impaired in amyotrophic lateral sclerosis (ALS) patients. Whereas cerebellar involvement has been indicated in ALS patients in general, its relative contribution to the patients' specific cognitive deficits remains unclear. In the current analyses, the demographic, clinical, neuropsychological and imaging data of 120 ALS patients and 88 healthy controls were analysed. Grey matter volume (GMV) and white matter (WM) fractional anisotropy were extracted for a comprehensive list of cerebral and cerebellar regions and bootstrapped elastic net regularized regression analyses were employed to identify regional structural metrics that were related to various cognitive scores. We further examined the stability of predictor variables selection and the regression coefficient distributions across the bootstrap samples. Both regional GMV and WM integrity are featured as informative predictors for patients' cognitive scores. The GMV of cerebellar lobules V and VIIIa were related to semantic fluency, but cerebellar regions did not reliably contribute to other cognitive outcomes. The GMV of pallidum was positively correlated with fluency outcomes and working memory, whereas hippocampus volume was positively related to fluency and episodic memory outcomes. Unsurprisingly, educational achievement emerged as the most general and reliable predictor of cognitive performance. Based on the current findings, cerebellar GMV seems to be specifically associated with semantic fluency performance in ALS patients but not any of the other cognitive measures. Further cognitive functions were associated with both cerebral grey matter (GM) and WM metrics. Future investigations could examine the possible involvement of the cerebellum in the affective and social-emotional dysfunction present in a subset of ALS patients.},
}

@article {pmid40574889,
year = {2025},
author = {Kulshreshtha, NN and Barthélémy, P},
title = {Lock and key: locked G quadruplexes could be the key to new modalities in nucleic acid therapeutics.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {40574889},
issn = {2632-8682},
abstract = {G quadruplexes are secondary structures formed by G-rich sequences in DNA/RNA. They are critical regulatory centres for gene activation and chromosome stability. Malfunctions in their number or topology often results in ailments such as frontotemporal dementia, amyotrophic lateral sclerosis, coronary heart disease, anaemia, and various cancers. Proteins and ligands can bind to them only if the quadruplex topology matches their requirements. Hence, stabilizing or destabilizing this topology can have profound implications in therapeutics. Novel nucleic acid modalities involving intra-conjugated G4s are an interesting prospect as they have a fixed topology without the use of additional ligand stabilizers. They could also efficiently bind to G4-associated proteins and have important consequences in clinical research and development. In this opinion, a justification for the development of these modalities is presented by highlighting their advantages and the potential applications that can be unlocked by locking G4 sequences.},
}

@article {pmid40574761,
year = {2025},
author = {Yıldız, GN and Çiftçi, B},
title = {Interplay between insomnia, anxiety, and depression.},
journal = {World journal of psychiatry},
volume = {15},
number = {6},
pages = {104796},
pmid = {40574761},
issn = {2220-3206},
abstract = {Insomnia, anxiety, and depression have become critical mental health issues exacerbated by the coronavirus disease 2019 pandemic, highlighting the importance of understanding their interrelationships. This article evaluates the study by Li et al, which investigates the links between insomnia, anxiety, and depression while examining the mediating role of cognitive failures and the moderating effect of neuroticism. The study employed a cross-sectional design with 1011 participants, using validated scales to measure insomnia severity, neuroticism, cognitive failures, and mental health indicators. Li et al found that approximately 40% of participants exhibited symptoms of anxiety, depression, and insomnia, with most cases being mild. The results demonstrated that cognitive failures play a mediating role in the relationship between insomnia and both anxiety and depression. Furthermore, neuroticism moderated the relationship between insomnia and cognitive failures, with a stronger effect observed in individuals with lower levels of neuroticism. These findings underscore the importance of considering personality traits and cognitive processes in understanding mental health outcomes. This study emphasizes the critical need for interventions aimed at reducing cognitive failures and enhancing emotional stability to mitigate the impact of insomnia on mental health. Strategies to improve sleep quality, boost cognitive resilience, and regulate emotional responses could significantly enhance individuals' mental well-being. Moreover, integrating personality assessments into mental health services could facilitate more effective and personalized interventions. This article provides an original perspective on the effects of the coronavirus disease 2019 pandemic on global mental health. The content of the article addresses the complex relationships between sleep disorders, cognitive function losses, and neuroticism in light of data compiled from existing literature and current research. In addition, how these relationships have deepened during the pandemic and the effectiveness of proposed treatment methods for these phenomena are discussed in comparison with previous studies. The arguments in the article offer new perspectives and suggestions aimed at filling gaps in the literature, and make an important contribution to both clinical practice and public health policies. Li et al's study provides a comprehensive framework for understanding the connections between insomnia, cognitive failures, and neuroticism, as well as their influence on anxiety and depression. The findings offer valuable implications for public health strategies, emphasizing the necessity of holistic approaches to address post-pandemic mental health challenges.},
}

@article {pmid40574759,
year = {2025},
author = {Kalawatia, M and Lucke-Wold, B and Mehrunkar, A},
title = {Closer look at the cardiovascular and metabolic predictors of postpartum depression.},
journal = {World journal of psychiatry},
volume = {15},
number = {6},
pages = {106283},
pmid = {40574759},
issn = {2220-3206},
abstract = {Postpartum depression (PPD) is a severe mental health disorder affecting 10% to 15% of postpartum women worldwide. Pre-eclampsia is a hypertensive disorder of pregnancy that has been identified as a significant factor for PPD due to its vascular dysfunction, systemic inflammation and neurobiological alterations. The neuroinflammatory mechanisms common to both pre-eclampsia and PPD, that contribute to depressive symptoms include elevated proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha), activation of the kynurenine pathway, and oxidative stress. To critically evaluate Wu et al's study, which investigates blood pressure variability (BPV) and gestational body mass index (BMI) as independent predictors of PPD. To integrate recent findings on the metabolic and cardiovascular links between depression, pre-eclampsia, and postpartum mental health outcomes. Pre-pregnancy BMI is found to be a stronger predictor of PPD than gestational weight gain. A vascular-neuropsychiatric connection has been indicated in pre-eclamptic women, indicating a significant correlation between BPV and depressive postpartum symptoms. There is increased susceptibility to depression due to neuroinflammation contributed by blood pressure fluctuations and metabolic dysregulation. The incidence of PPD could be reduced by early identification and intervention for BP fluctuations. Early detection and intervention in high-risk pregnancies should be conducted through public health strategies that prioritize awareness, education, and accessibility to mental health care.},
}

@article {pmid40571936,
year = {2025},
author = {Evans, DM and Smith, GD and Moen, GH},
title = {Woolf et al's "GWAS by subtraction" is not useful for cross-generational Mendelian randomization studies.},
journal = {BMC research notes},
volume = {18},
number = {1},
pages = {247},
pmid = {40571936},
issn = {1756-0500},
support = {2017942//National Health and Medical Research Council/ ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; DE220101226//Australian Research Council/ ; 325640//Norges Forskningsråd/ ; },
abstract = {Mendelian randomization (MR) is an epidemiological method that can be used to strengthen causal inference regarding the relationship between a modifiable environmental exposure and a medically relevant trait and to estimate the magnitude of this relationship [1]. Recently, there has been considerable interest in using MR to examine potential causal relationships between parental phenotypes and outcomes amongst their offspring [–4] (interestingly one of the earliest exemplars of MR was confirmation that antenatal maternal folate was protective against offspring neural tube defects [1]). In a recent issue of BMC Research Notes, Woolf, Sallis, Munafo and Gill (2023) [5] (abbreviated as WSMG from now on) present a method they call “GWAS by subtraction” (not to be confused with GWAS by subtraction via genomic SEM [6, 7]), to derive genome-wide summary statistics for paternal smoking and other “paternal phenotypes” with the goal that these estimates can then be used in downstream (including two sample) MR studies [8]. Whilst a potentially useful goal, WSMG (2023) focus on the wrong parameter of interest for useful genome-wide association studies (GWAS) and downstream cross-generational MR studies, and the estimator that they derive is neither efficient nor appropriate for such use.},
}

@article {pmid40571723,
year = {2025},
author = {Li, TY and Gao, AW and Yang, R and Sun, Y and Lei, Y and Li, X and Chen, L and Liu, YJ and Arey, RN and Morales, K and Liu, RB and Wang, W and Zhou, A and Zhao, TJ and Li, W and Lalou, A and Wang, Q and Lima, T and Houtkooper, RH and Auwerx, J},
title = {A lysosomal surveillance response to stress extends healthspan.},
journal = {Nature cell biology},
volume = {},
number = {},
pages = {},
pmid = {40571723},
issn = {1476-4679},
support = {ERC-AdG-787702//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; SNSF 31003A_179435; Sinergia CRSII5_202302//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; NRF 2017K1A1A2013124//National Research Foundation of Korea (NRF)/ ; LT000731/2018-L//Human Frontier Science Program (HFSP)/ ; PF-19-0232//United Mitochondrial Disease Foundation (UMDF)/ ; 82300708//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H[+]-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.},
}

@article {pmid40571717,
year = {2025},
author = {Khan, R and Rahman, N and Prasannan, A and Ganiyeva, K and Chakrabortty, S and Sangaraju, S},
title = {Phase transition and bandgap modulation in TiO2 nanostructures for enhanced visible-light activity and environmental applications.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {20309},
pmid = {40571717},
issn = {2045-2322},
abstract = {Due to its wide-ranging applications in the climate and energy fields, enhancing the visible-light photoactivity of TiO2 nanoparticles remains a crucial challenge in photocatalysis. Interestingly, this work examined the phase transition, structural, optical, and photocatalytic characteristics of TiO2 nanoparticles doped with Al[3][+]/Al[2][+] and S[6+] ions. It was observed that the anatase phase (AP) dominates in pure TiO2 (100%) nanoparticles, whereas the rutile phase (RP) content increases in doped samples, reaching 20 ± 2.1% for X1 (Al = 2%, S = 2%) and falling to 12 ± 1.2% in X4 (Al = 2%, S = 8%). The introduction of Al[3][+]/Al[2][+] and S[6+] induces oxygen vacancies (Ovs) and alters the phase stability, as evidenced by the reduction of transformation energy to - 0.033 eV, facilitating the AP to RP transition. The effective integration of dopants indicates that a redshift and intensity in the Photoluminescence spectrum reduced by X-series nanoparticles is due to band gap reductions (from 3.23 eV for pure TiO2 to 1.98 eV for X4) and distortions in the lattice generated by Al/S doping. Raman spectroscopy results show peak broadening and shifts due to lattice strain from dopants, which validates dopant incorporation via peak shifts in Fourier-transform infrared spectroscopy. ESR study reveals paramagnetic centers in Ti[3][+]-Ovs complexes, indicating defect-induced magnetic characteristics. When methylene blue (MB) dye is photocatalyzed under visible light exhibits increased activity and degradation efficiencies that are higher than pure TiO2. The pseudo-first-order kinetic results show that co-doping effectively improves photocatalytic activity. Rate constants of 0.017 min[-][1] for X4 are found to be much higher than 7.28 × 10[-][4] min[-][1] for pure TiO2 nanoparticles. Finally, anatase X-series samples degraded MB at a maximum rate of 96.4% in 150 min, outperforming undoped TiO2 (15%) and rutile-TiO2 nanoparticles (65% degradation). The fundamental mechanism explains that the photocatalytic characteristics of TiO2 are modulated by co-doping, which is why these compounds are potential candidates for environmental remediation applications.},
}

@article {pmid40571609,
year = {2025},
author = {Watanabe, Y and Uemoto, M and Otsuki, M and Fukuhara, H and Tajiri, Y and Murakami, T and Hanajima, R},
title = {Can language characteristics contribute to the classification of neurodegenerative disorders? -An exploratory study.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.5202-24},
pmid = {40571609},
issn = {1349-7235},
abstract = {Objective Evaluating language symptoms is challenging owing to their varied presentations. We developed a Japanese Language Screen (JLS) to assess 11 language aspects, including agrammatism, impairment of articulation and prosody (IAP), word recall, syntactic comprehension, meaning of proverbs, and writing, considering the unique features of the Japanese language. Methods Using the JLS, we assessed the language functions in patients with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and HC to identify language symptoms specific to each condition and determine whether the JLS can differentiate between diseases and HC. Results The study included 168 participants. The total JLS score categorized the participants' language status as normal or impaired. According to the total score, PSP patients had more severe language deficits than AD patients, despite comparable cognitive scores. Substantial differences were found in the 11 assessed items for each disease. Patients with AD and PSP showed decreased performance in more than half of the items compared to HC, with the PSP group being more impaired. ALS patients showed decreases in IAP and writing, notably in the meaning of proverbs, whereas PD was closely comparable to HC. Conclusion This study suggests that while the JLS is useful for understanding the language symptoms associated with neurodegenerative disorders, its ability to classify them remains limited.},
}

@article {pmid40571082,
year = {2025},
author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C},
title = {Associations between long-term air pollution exposure and the development of amyotrophic lateral sclerosis: A matched case-control study.},
journal = {Environmental research},
volume = {},
number = {},
pages = {122232},
doi = {10.1016/j.envres.2025.122232},
pmid = {40571082},
issn = {1096-0953},
abstract = {There is increasing evidence of an association between air pollution, particularly nitrogen dioxide (NO2), and the development of amyotrophic lateral sclerosis (ALS). However, investigation into sulfur dioxide (SO2) remains understudied. Also, empirical identification of confounding variables to adjust for in ALS environmental studies is largely absent. Thus, we created a multifactorial database, mapped hypothesized direct effects of air pollutants, and conducted a matched case-control study in New Brunswick, Canada to investigate the association between long-term exposure to various air pollutants and the development of ALS. Odds of ALS onset was significantly associated with increased SO2 exposure (OR = 1.23; 95% CI: 1.02 - 1.47, per IQR increase of 0.14 ppb) in adjusted direct effect models, but not associated with exposure to NO2 (OR = 1.09; 95% CI: 0.87 - 1.41, per IQR increase of 2.79 ppb), ozone (O3) (OR = 0.99; 95% CI: 0.80 - 1.22, per IQR increase of 2.31 ppb), fine particulate matter (PM2.5) (OR = 0.99; 95% CI: 0.80 - 1.23, per IQR increase of 0.52 μg/m[3]) or PM2.5(smoke) (OR = 1.05; 95% CI: 0.83 - 1.35, per IQR increase of 0.68 μg/m[3]). As for recency models, SO2 remained significantly associated with ALS in both 5-year (OR = 1.21; 95% CI: 1.03 - 1.43) and 10-year prior to onset sensitivity models (OR = 1.23; 95% CI: 1.02 - 1.47). Our findings support the association between long-term exposure to air pollutants, particularly SO2, and the development of ALS, supporting the need for improved air pollution control measures.},
}

@article {pmid40569529,
year = {2025},
author = {Shin, M and Ha, T and Lee, S and Li, C and Choi, JH and Choi, JW},
title = {Biohybrid motor neuron spheroid composed of graphene/HUVEC/neural cell for 3D biosensing system to evaluate drug of amyotrophic lateral sclerosis.},
journal = {Nano convergence},
volume = {12},
number = {1},
pages = {29},
pmid = {40569529},
issn = {2196-5404},
support = {RS-2023-00259341//the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT/ ; RS-2024-00344633//the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)/ ; NRF-2022M3H4A1A01005271//the National R&D Program through the NRF funded by the Ministry of Science and ICT/ ; },
abstract = {A 3D motor neuron (MN) spheroid has been developed to investigate neurodegenerative and neuromuscular junction (NMJ) disease. However, core necrosis and reduced neurogenesis, impairing neural network formation, were observed as the MN spheroid matured. In this study, to enhance neural network formation, a biohybrid MN spheroid composed of neural cells/reduced graphene oxide (rGO)/human umbilical vein endothelial cells (HUVECs) was generated for the first time and applied to 3D biosensing system for MNJ disease. By incorporating rGO and HUVECs at the onset of human neural stem cell (hNSC) culture, rGO and HUVECs were evenly distributed within MN spheroid generated by differentiation of hNSC, which improved oxygen- and nutrient- supply by reduction of core necrosis, and enhanced neurogenesis. The fabricated biohybrid MN spheroid improved neural network formation and electrophysiological signal. This method was also applied to generate biohybrid cerebral organoids from human induced pluripotent stem cells (hiPSCs), emphasizing its versatility for diverse 3D neural models. Then, a 3D NMJ biosensing system was fabricated by positioning the biohybrid MN spheroid with muscle bundles to evaluate its utility in neuromuscular disease modeling. Biohybrid MN spheroids generated from induced pluripotent stem cells of sporadic amyotrophic lateral sclerosis (ALS) patients were used to make NMJ. Reduced contraction of the connected muscle bundle due to ALS could be restored by upon treatment with the bosutinib, ALS drug, demonstrating the potential use for drug screening. The method to generate biohybrid spheroid can be applied to generation of various biohybrid brain organoids, and the proposed 3D NMJ biosensing system can be used to drug screening of diverse neuromuscular diseases.},
}

@article {pmid40569409,
year = {2025},
author = {Thissen, J and Klassen, MD and Fischer, B and Hacker, MC and Breitkreutz, J and Teutenberg, T and Cunha, R},
title = {StreamFind: data processing workflows for qualification and quantification of biopharmaceutical drug products analyzed by size exclusion chromatography coupled to capillary-enhanced Raman spectroscopy.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {40569409},
issn = {1618-2650},
support = {16DKWN138//Bundesministerium für Bildung und Forschung/ ; KK5312603KA1//Bundesministerium für Wirtschaft und Klimaschutz/ ; },
abstract = {Innovative hyphenated technologies, such as size exclusion chromatography coupled with capillary-enhanced Raman spectroscopy (SEC-CERS), enable more comprehensive analyses of biopharmaceutical drug products. However, specialized software for processing and analyzing data from these advanced techniques is often lacking. This study introduces the R package StreamFind, which is designed to help users seamlessly process both chromatographic and Raman spectroscopic data within an integrated workflow. We detail the implementation and structure of StreamFind and demonstrate its ability in the in-depth analysis of biopharmaceutical products. The study shows its capability to differentiate monoclonal antibodies and entire biopharmaceutical formulations and to quantify various components based on their Raman spectra. Principal component analysis (PCA) identified significant differences among the biopharmaceutical products analyzed, while multivariate curve resolution-alternating least squares (MCR-ALS) proved to be an effective method for quantifying different components within these products. The StreamFind platform is designed to be extensible, to facilitate contributions from new users and to support the future integration of additional algorithms to process different types of complex analytical data.},
}

@article {pmid40568280,
year = {2025},
author = {Bouabdallaoui, A and Taouihar, S and Yahya, N and Adali, N and Nassik, H},
title = {Bulbar-Onset Amyotrophic Lateral Sclerosis Unmasked by General Anesthesia: A Case Report.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e84823},
pmid = {40568280},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects the motor neurons in the brain and spinal cord, resulting in severe muscular weakness, atrophy, and loss of motor control. Patients with ALS are often highly sensitive to anesthetic drugs, specifically neuromuscular blocking agents, which can exacerbate muscle weakness and contribute to prolonged postoperative recovery times. In this article, we report a case of bulbar ALS diagnosed after postoperative extubation failure in a 51-year-old patient. Practitioners should consider this disease in cases of difficult postoperative ventilatory weaning and should be aware of the impact of surgery and anaesthesia on disease progression.},
}

@article {pmid40568112,
year = {2025},
author = {Calco, B and Sweeney, CL and Steiner, J and Wang, T and Markowitz, TE and Paul, S and Palicha, B and Dinges, S and Yoo, K and Henderson, L and McDonald, V and De Ravin, SS and Greenberg, B and Zerbe, CS and Notarangelo, LD and Holland, SM and Nath, A and Safavi, F},
title = {A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS).},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.23.655625},
pmid = {40568112},
issn = {2692-8205},
abstract = {Mutations in PIK3R1 , a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in PIK3R1 in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis. Induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs) demonstrated that this mutation resulted in PIK3R1 haploinsufficiency, with downstream activation of AKT, disruption of neuronal electrical function and increased apoptosis in iPSC-derived motor neurons. Single-cell RNA sequencing (scRNA-seq) and pathway analysis of differentially expressed genes showed apoptosis pathways were upregulated in neuronal clusters from iMNs harboring the PIK3R1 c.1710 dup mutation. Mutated iPSC-derived brain organoids were smaller than matched controls. scRNA-seq of brain organoids showed more active apoptosis in neuronal clusters of patient-derived brain organoids. These findings identify a critical and novel role for PIK3R1 haploinsufficiency in neuronal function and survival.},
}

@article {pmid40568026,
year = {2025},
author = {Peggion, C and Bonadio, RS and Stella, R and Scalabrin, S and Pasetto, L and Millino, C and Camporeale, L and Pacchioni, B and Bonetto, V and Bertoli, A and Cagnin, S and Massimino, ML},
title = {Restoration of myogenesis in ALS-myocytes through miR-26a-5p-mediated Smad4 inhibition and its impact on motor neuron development.},
journal = {Molecular therapy. Nucleic acids},
volume = {36},
number = {3},
pages = {102581},
pmid = {40568026},
issn = {2162-2531},
abstract = {Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized primarily by a progressive loss of motor neurons (MNs) in which degeneration skeletal muscle involvement has been demonstrated. Skeletal muscle is a plastic tissue that responds to insults through proliferation and differentiation of satellite cells. Skeletal muscle degeneration and regeneration are finely regulated by signals that regulate satellite cell proliferation and differentiation. It is known that satellite cell differentiation is impaired in ALS, but little is known about the involvement of microRNAs (miRNAs) and their role in intercellular communication in ALS. Here we demonstrated impaired differentiation of satellite cells derived from ALS mice related to the impairment of myogenic p38MAPK and protein kinase A (PKA)/pCREB signaling pathways that can be regulated by miR-882 and -134-5p. These miRNAs participate in autocrine signaling in association with miR-26a-5p that, secreted from wild-type (WT) and captured by ALS myoblasts, enhances ALS-related myoblast differentiation by repressing Smad4-related signals. Moreover, miR-26a-5p and -431-5p work in a paracrine way ameliorating motoneuron differentiation. These findings emphasize the need to better understand intercellular communication and its role in ALS pathogenesis and progression. They also suggest that miRNAs could be targeted or used as therapeutic agents for myofiber and MN regeneration.},
}

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

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

@article {pmid40566837,
year = {2025},
author = {Massey, C and Griffiths, AW and McDermott, C and Hobson, E},
title = {How healthcare professionals support cough and secretion management in amyotrophic lateral sclerosis (ALS): a UK national survey.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/21678421.2025.2522401},
pmid = {40566837},
issn = {2167-9223},
abstract = {OBJECTIVE: To understand the practices of healthcare professionals supporting people with Amyotrophic Lateral Sclerosis (ALS) to manage cough and secretion issues. This includes utilization of and confidence in assessment and treatment techniques and barriers and enablers of care.

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

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

CONCLUSION: Cough and secretion management is complex and involves numerous professional groups. There is a need for clinical and educational interventions that address knowledge and skill gaps in managing cough and secretion issues, which will help increase healthcare professionals' confidence in assessing and treating these complex problems.},
}

@article {pmid40566744,
year = {2025},
author = {Bai, J and Cheng, K and Zhang, N and Chen, Y and Ni, J and Wang, Z},
title = {Research advances in dysphagia animal models.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70054},
pmid = {40566744},
issn = {2576-2095},
support = {82172531//National Natural Science Foundation of China/ ; 2021Y9105//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; },
abstract = {Dysphagia is a common complication of stroke, Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The construction of animal models of dysphagia is an important way to explore its pathogenesis and treatment. At present, the animal models of dysphagia mainly include rodents, nonhuman primates, and other mammals, such as pigs and dogs. This review systematically summarizes the establishment and evaluation of dysphagia animal models in stroke, PD, and ALS in three kinds of experimental animals, providing a basis for the selection of appropriate animal models of dysphagia.},
}

@article {pmid40566588,
year = {2025},
author = {Martinelli, I and Gianferrari, G and Santarelli, R and Zucchi, E and Simonini, C and Fini, N and Ghezzi, A and Gessani, A and Ferri, L and Smolik, K and Ferraro, D and Bedin, R and Gizzi, M and Sette, E and Vacchiano, V and Bonan, L and Zinno, L and De Massis, P and Canali, E and Medici, D and Terlizzi, E and Morresi, S and Santangelo, M and Patuelli, A and Currò Dossi, M and Longoni, M and Pugliatti, M and Filippini, T and Ferro, S and Errals Study Group, and Mandrioli, J},
title = {Exploring the Role of Diabetes in ALS: A Population-Based Cohort Study.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {6},
pages = {},
pmid = {40566588},
issn = {2075-1729},
support = {GPG/2022/1343//The Emilia Romagna Registry for ALS (ERRALS) is supported by a grant from the Emilia Romagna Regional Health Authority/ ; },
abstract = {Type 2 diabetes mellitus (T2DM) as a comorbidity in amyotrophic lateral sclerosis (ALS) has sparked interest for its potential impact on disease expression and prognosis. In this retrospective cohort study, we investigated the prevalence and clinical correlates of T2DM in a large cohort of patients from the ALS registry of a Northern Italy region, Emilia Romagna, established in 2009. Out of 1756 ALS patients enrolled up to 2021, 145 were affected by T2DM (diALS). Patients with diALS were older than those without T2DM (ndALS) (71.56 vs. 65.76 years, p < 0.001), had a higher body mass index (25.63 vs. 24.23, p < 0.001), but experienced greater weight loss at diagnosis (6.87% vs. 5.44%, p < 0.007). Respiratory onset (6.2% vs. 2.6%, p = 0.013) and respiratory phenotype (4.2% vs. 1.4%, p = 0.04) were more frequent among diALS. Coherently, diALS presented a lower forced vital capacity (74.9% vs. 87.9%, p ≤ 0.001) and more frequently adopted Non-Invasive Ventilation (NIV) (50.35% vs. 37.61%, p = 0.003), with significant influence on time to NIV (HR 1.71, 95% CI 1.07-2.74, p = 0.024). Exploring genetic background, among all the genes examined C9ORF72 emerged as underrepresented among diALS (7.64% in ndALS vs. 0% in diALS, p = 0.039). In conclusion, we confirmed a more severe respiratory dysfunction in diALS, suggesting a specific frailty in respiratory muscles, together with some peculiar clinical features consistent with the previous literature data, such as a later onset. The lower prevalence of C9ORF72 expansion in this population may hint towards a specific role of the gene in metabolism and inflammation, granting more space to non-genetic causes, warranting further studies for confirmation.},
}

@article {pmid40565582,
year = {2025},
author = {Rother, F and Parmar, AR and Bodenhagen, JS and Marvaldi, L and Hartmann, E and Bader, M},
title = {Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice.},
journal = {Genes},
volume = {16},
number = {6},
pages = {},
pmid = {40565582},
issn = {2073-4425},
support = {2021 Grant//Rita Levi Montalcini 2021 Grant (MIUR, Italy)/ ; MIUR project "Dipartimenti di Eccellenza 2023-2027"//Ministero dell'Istruzione dell'Università e della Ricerca/ ; },
mesh = {Animals ; *alpha Karyopherins/genetics/deficiency ; *Attention Deficit Disorder with Hyperactivity/genetics/pathology/metabolism ; Mice ; Mice, Knockout ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Male ; },
abstract = {Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (Kpna3-KO) or KPNA4 (Kpna4-KO). The motoric abilities and locomotion at different time points in ageing were tested to study the role of these two genes on motor neuron function. While we did not find deficits related to motor neurons in both mouse models, we discovered a hypermotoric phenotype in KPNA4-deficient mice. Attention deficit/hyperactivity disorder (ADHD) is caused by a combination of genetic, environmental and neurobiological factors and a number of genes have been suggested in genome-wide association studies to contribute to ADHD, including KPNA4. Here we provide supportive evidence for KPNA4 as a candidate pathogenic factor in ADHD, by analysing Kpna4-KO mice which show ADHD-like symptoms.},
}

Animals
*alpha Karyopherins/genetics/deficiency
*Attention Deficit Disorder with Hyperactivity/genetics/pathology/metabolism
Mice
Mice, Knockout
Disease Models, Animal
Motor Neurons/metabolism/pathology
Male

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

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

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

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

@article {pmid40565135,
year = {2025},
author = {Bono, N and Fruzzetti, F and Farinazzo, G and Candiani, G and Marcuzzo, S},
title = {Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
pmid = {40565135},
issn = {1422-0067},
support = {//Italian Ministry of Health (RRC)/ ; T4-AN-09 prog. ZRPOS2//CALabria HUB per Ricerca Innovativa ed Avanzata- CALHUB.RIA "Creazione di Hub delle Sci-enze della Vita"/ ; ZRA124//AriSLA foundation, "Bulb-Omics"/ ; PNRR-MCNT2-2023-12377336//the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics/diagnosis/metabolism ; Humans ; *Genetic Therapy/methods ; *Biomarkers/metabolism ; C9orf72 Protein/genetics ; Animals ; Gene Editing ; Superoxide Dismutase-1/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches transforming ALS research and clinical management. We explore emerging biomarkers, including the fluid-based markers such as neurofilament light chain, exosomes, and microRNAs in biological fluids, alongside the non-fluid-based biomarkers, including neuroimaging and electrophysiological markers, for early diagnosis and patient stratification. The integration of multi-omics data reveals complex molecular mechanisms underlying ALS heterogeneity, potentially identifying novel therapeutic targets. We highlight current gene therapy strategies, including antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 gene editing systems, alongside advanced delivery methods for crossing the blood-brain barrier. By bridging molecular neuroscience with bioengineering, these technologies promise to revolutionize ALS diagnosis and treatment, advancing toward truly disease-modifying interventions for this previously intractable condition.},
}

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

@article {pmid40564215,
year = {2025},
author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Chun, JU and Chung, JH and Lee, SY and Lee, JH and Chae, YR},
title = {Multi-Metal Exposure Profiling in ALS Patients in South Korea via Hair Analysis: A Cross-Sectional Study.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
pmid = {40564215},
issn = {2227-9059},
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with an unclear etiology. This study aimed to assess chronic heavy metal exposure in ALS patients in South Korea by comparing hair concentrations of common (Hg, Pb, Cd) and rare (U, Th, Pt) metals with healthy controls.

METHODS: Hair samples were collected from 66 ALS patients and 70 healthy individuals at Rodem Hospital between 2022 and 2025. Metal concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) following standardized washing and digestion protocols.

RESULTS: ALS patients showed significantly higher levels of Hg, Pb, Cd, Al, As, and U than controls (p < 0.05). Notably, 40% of ALS patients had Hg levels exceeding 50% of the reference upper limit, compared to only 10% of controls. Elevated levels of uranium and other rare metals were also observed in specific ALS cases.

CONCLUSIONS: These findings suggest a possible association between heavy metal exposure and ALS in South Korea. Hair analysis may serve as a useful tool for identifying environmental factors contributing to ALS pathogenesis.},
}

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

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

@article {pmid40563773,
year = {2025},
author = {Swash, M and de Carvalho, M},
title = {Dynamics of Onset and Progression in Amyotrophic Lateral Sclerosis.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
pmid = {40563773},
issn = {2076-3425},
abstract = {This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease's pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised.},
}

@article {pmid40563772,
year = {2025},
author = {Artioli, G and Guardamagna, L and Succi, N and Guasconi, M and Diamanti, O and Dellafiore, F},
title = {Relational, Ethical, and Care Challenges in ALS: A Systematic Review and Qualitative Metasynthesis of Nurses' Perspectives.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
pmid = {40563772},
issn = {2076-3425},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to severe functional decline and death, imposing significant physical, emotional, and ethical burdens on patients and healthcare providers. With no curative treatment, ALS care depends on the early and sustained integration of palliative care to address complex and evolving needs. Nurses play a pivotal role in this process, yet their lived experiences remain underexplored. This study aimed to synthesize qualitative evidence on nurses' experiences in ALS care, with a focus on emotional, ethical, and palliative dimensions.

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

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

CONCLUSION: Nurses in ALS care face complex emotional and ethical challenges that call for strong institutional support and palliative training. Enhancing palliative care integration from diagnosis, alongside targeted education and psychological support, is crucial to improving care quality and sustaining the well-being of both patients and nurses.},
}

@article {pmid40563439,
year = {2025},
author = {Marini, C and Riondato, M and Dighero, E and Democrito, A and Losacco, S and Emionite, L and Nobbio, L and Di Patrizi, I and Camera, M and Ghersi, C and Ghelardoni, M and Lanfranchi, F and Vitale, F and Carta, S and Chiesa, S and Torazza, C and Milanese, M and Bauckneht, M and Hamedani, M and Zaottini, F and Schenone, A and Martinoli, C and Grillo, F and Sambuceti, G},
title = {Increased [[18]F]DPA-714 Uptake in the Skeletal Muscle of SOD1[G93A] Mice: A New Potential of Translocator Protein 18 kDa Imaging in Amyotrophic Lateral Sclerosis.},
journal = {Biomolecules},
volume = {15},
number = {6},
pages = {},
pmid = {40563439},
issn = {2218-273X},
support = {RF-2018-12366238//Italian Ministry of Health/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/genetics/pathology ; Mice ; Mice, Transgenic ; *Muscle, Skeletal/metabolism/diagnostic imaging ; Positron-Emission Tomography/methods ; *Receptors, GABA/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Pyrimidines/pharmacokinetics ; *Pyrazoles/pharmacokinetics ; Fluorine Radioisotopes ; Disease Models, Animal ; Humans ; Tissue Distribution ; Brain/metabolism/diagnostic imaging ; Male ; },
abstract = {PURPOSE: The skeletal muscle has been proposed to contribute to the progressive loss of motor neurons typical of amyotrophic lateral sclerosis (ALS). However, this mechanism has not yet been clarified due to the lack of suitable imaging tools. Here, we aimed to verify whether PET imaging of the translocator protein 18 kDa (TSPO) can detect a muscular abnormality in an experimental model of ALS.

METHODS: In vivo biodistribution and kinetics of [[18]F]DPA-714 were analyzed in skeletal muscle and brain of SOD1[G93A] transgenic mice and in wildtype (WT) littermates. Both cohorts were divided into three groups (n = 6 each) to be studied at 60, 90 and 120 days. After microPET imaging, animals were sacrificed to evaluate inflammatory infiltrates by hematoxylin/eosin staining and TSPO expression by immunohistochemistry and Western blot in both quadriceps and brain.

RESULTS: [[18]F]DPA-714 uptake was higher in the skeletal muscles of SOD1[G93A] than in WT mice in the preclinical phase (60 and 90 days) and further increased up to the symptomatic late stage (120 days). Inflammatory cells were absent in the quadriceps of SOD1[G93A] mice whose myocytes, instead, showed a progressive increase in TSPO expression with advancing age. By contrast, brain tracer uptake and TSPO expression were comparably low in both groups, regardless of age and genotype.

CONCLUSION: Upregulation of TSPO expression is characteristic of skeletal muscle, but not the brain, in the experimental SOD1[G93A] mouse model of ALS. Tracers targeting this pathway have been mostly proposed for the evaluation of inflammatory processes within the central nervous system. Nevertheless, the ubiquitous nature of TSPO expression and its responsiveness to various signals may broaden the diagnostic potential of these tracers to include disease conditions beyond inflammation.},
}

Animals
*Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/genetics/pathology
Mice
Mice, Transgenic
*Muscle, Skeletal/metabolism/diagnostic imaging
Positron-Emission Tomography/methods
*Receptors, GABA/metabolism
*Superoxide Dismutase-1/genetics/metabolism
*Pyrimidines/pharmacokinetics
*Pyrazoles/pharmacokinetics
Fluorine Radioisotopes
Disease Models, Animal
Humans
Tissue Distribution
Brain/metabolism/diagnostic imaging
Male

@article {pmid40563328,
year = {2025},
author = {Chong, ZZ and Souayah, N},
title = {Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
pmid = {40563328},
issn = {2076-3921},
abstract = {Oxidative stress has become a common impetus of various diseases, including neurodegenerative diseases. This review introduces the generation of reactive oxygen species (ROSs) in the nervous system, the cellular oxidative damage, and the high sensitivity of the brain to ROSs. The literature review focuses on the roles of oxidative stress in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Oxidative stress occurs when excessively produced free radicals are beyond the capability of endogenous antioxidants to scavenge, leading to the oxidation of proteins, lipids, and nucleic acids, stimulating neuroinflammatory responses, causing neuronal dysfunction, senescence, and death. The dysfunctional mitochondria and aberrant activities of metabolic enzymes are the major source of ROSs. The high vulnerability of the nervous system to ROSs underlies the critical roles of oxidative stress in neurodegenerative diseases. Gene mutations and other risk factors promote the generation of ROSs, which have been considered a crucial force causing the main pathological features of AD, PD, HD, and ALS. As a result, antioxidants hold therapeutic potential in these neurodegenerative diseases. The elucidation of the pathogenic mechanisms of oxidative stress will facilitate the development of antioxidants for the treatment of these diseases.},
}

@article {pmid40563288,
year = {2025},
author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP},
title = {Inhibition of Triacylglycerol Accumulation and Oxidized Hydroperoxides in Hepatocytes by Allium cepa (Bulb).},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
pmid = {40563288},
issn = {2076-3921},
abstract = {Recent studies have demonstrated that dietary plant extracts can inhibit the development of lipid droplets (LDs) and oxidized LDs (oxLDs) in hepatic cells. These findings suggest that such extracts may be beneficial in combating metabolic dysfunction-associated fatty liver disease (MAFLD) and its more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH). We examined nine Allium extracts (ALs: AL1-9) to assess their capacity to decrease lipid droplet accumulation (LDA) and oxidative stress by suppressing lipid formation and oxidation in liver cells. Among the Allium extracts tested, AL6 exhibited significant inhibitory effects against LDA. Furthermore, we employed our lipidomic method to assess the accumulation and suppression of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] by AL6 in liver cells under oleic acid (OA) and linoleic acid (LA) loading conditions. These findings indicate that foods derived from Allium species prevent the formation of lipid droplets by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. Analysis of the metabolome of bioactive lipid droplet accumulation inhibition (LDAI) AL6 using LC-MS/MS and 1D-NMR [[1]H, [13]C, DEPT 90, and 135] techniques revealed that AL6 is primarily composed of carbohydrates, glucosidic metabolites, and organosulfur compounds, with small amounts of polyols, fatty acyls, small peptides, and amino acids. This implies that AL6 could be a valuable resource for developing functional foods and drug discovery targeting metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH) and related disorders.},
}

@article {pmid40562771,
year = {2025},
author = {Amado, DA and Robbins, AB and Whiteman, KR and Smith, AR and Chillon, G and Chen, Y and Fuller, JA and Patty, NA and Izda, A and Cheng, C and Nelson, S and Dichter, AI and Mazzoni, EO and Monteys, AM and Davidson, BL},
title = {AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5334},
pmid = {40562771},
issn = {2041-1723},
support = {K08 NS114106/NS/NINDS NIH HHS/United States ; UH3 NS094355/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *Dependovirus/genetics ; Motor Neurons/metabolism/pathology ; Mice ; *Ataxin-2/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; *RNA Interference ; Genetic Vectors ; Disease Models, Animal ; Genetic Therapy/methods ; Male ; MicroRNAs/genetics ; Female ; },
abstract = {Amyotrophic lateral sclerosis (ALS) involves motor neuron death due to mislocalized TDP-43. Pathologic TDP-43 associates with stress granules (SGs), and lowering the SG-associated protein ataxin-2 (ATXN2) using Atxn2-targeting antisense oligonucleotides prolongs survival in TAR4/4 sporadic ALS mice but failed in clinical trials likely due to poor target engagement. Here we show that an AAV with potent motor neuron transduction delivering Atxn2-targeting miRNAs reduces Atxn2 throughout the central nervous system at doses 40x lower than published work. In TAR4/4 mice, miAtxn2 increased survival (50%) and strength, and reduced motor neuron death, inflammation, and phosphorylated TDP-43. TAR4/4 transcriptomic dysregulation recapitulated ALS gene signatures that were rescued by miAtxn2, identifying potential therapeutic mechanisms and biomarkers. In slow progressing hemizygous mice, miAtxn2 slowed disease progression, and in ALS patient-derived lower motor neurons, our AAV vector transduced >95% of cells and potently reduced ATXN2 at MOI 4 logs lower than previously reported. These data support AAV-RNAi targeting ATXN2 as a translatable therapy for sporadic ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism
*Dependovirus/genetics
Motor Neurons/metabolism/pathology
Mice
*Ataxin-2/genetics/metabolism
*DNA-Binding Proteins/metabolism/genetics
Humans
*RNA Interference
Genetic Vectors
Disease Models, Animal
Genetic Therapy/methods
Male
MicroRNAs/genetics
Female

@article {pmid40562529,
year = {2025},
author = {Ferese, R and Suppa, A and Campopiano, R and Scala, S and Sammarone, F and Di Pilla, L and Di Pardo, A and Chiaravalloti, MA and Griguoli, AM and Cannella, M and D'Alessio, C and Storto, M and Fanelli, M and Zampogna, A and Patera, M and Inghilleri, M and Ceccanti, M and Cambieri, C and Buttari, F and Peconi, C and Giardina, E and Zampatti, S and Centonze, D and Gambardella, S},
title = {New variants and genotype-phenotype correlation in KIF5A mutation: the contribution of a large Italian cohort.},
journal = {Journal of medical genetics},
volume = {},
number = {},
pages = {},
doi = {10.1136/jmg-2025-110801},
pmid = {40562529},
issn = {1468-6244},
abstract = {BACKGROUND: Variants in the Kinesin-family member 5A (KIF5A) gene are associated with a range of motor diseases, and a strong correlation between the protein domains (motor, stalk and tail) and the clinical phenotype has been proposed. However, several studies have reported exceptions contributing to a complex genotype-phenotype correlation in recent years. Further studies are needed to improve our knowledge about the prevalence of KIF5A variants and their genotype-phenotype correlation.

METHODS: 390 patients (220 hereditary spastic paraplegia, 80 Charcot-Marie-Tooth disease type 2 and 90 amyotrophic lateral sclerosis) have been selected for next-generation sequencing Clinical Exome.

RESULTS: Five patients have been found to carry causative variants in the KIF5A gene. Of these, three are familiar cases, and two are sporadic. Segregation analysis was performed on the familiar probands. The five patients with pathogenic variants represent 4% of the studied population, and the clinical and genetic analysis of these five families allowed us to examine different scenarios.Some of these data support the hypothesis of a complex correlation between domains and disease.

CONCLUSION: These data confirm the complex genotype-phenotype correlation, both in terms of clinical heterogeneity associated with a specific domain and variability within the members of the same family, but also suggest a strong genotype-phenotype correlation, both intrafamiliar and interfamiliar, produced by a few variants.},
}

@article {pmid40562281,
year = {2025},
author = {Sharma, J and Thakur, A and Rain, M and Khosla, R and Maity, K and Mathur, GR and Anand, A},
title = {Interplay between exercise and neuregulin in providing neuroprotection.},
journal = {Behavioural brain research},
volume = {493},
number = {},
pages = {115710},
doi = {10.1016/j.bbr.2025.115710},
pmid = {40562281},
issn = {1872-7549},
abstract = {Exercise has been shown to have a positive impact on brain health including neuroprotective function. It has been demonstrated to increase the synthesis of neurotrophic factors, support neuronal survival, and improve neuroplasticity. Concurrently, neuregulin plays a vital role in the development, maintenance, and repair of both the central and peripheral nervous system. The link between exercise and neuregulin in mediating neuroprotection has been the subject of increased research to better understand the possible applications for the deterrence of neurodegenerative disorders. Understanding this link is of great interest because it has the potential to lead to new strategies for preventing or slowing the progression of neurodegenerative diseases. With an emphasis on exercise-induced neuregulin-mediated neuroprotection, this article reviews the literature on the neuroprotective effects of exercise and neuregulin. The synergistic effects of exercise and neuregulin on neuroprotection will be clarified and valuable insights will be gained from this review, with potential implications for the development of novel therapeutic strategies for neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD).},
}

@article {pmid40562033,
year = {2025},
author = {Lall, D and Workman, MJ and Sances, S and Ondatje, BN and Bell, S and Lawless, G and Woodbury, A and West, D and Meyer, A and Matlock, A and Vaibhav, V and Van Eyk, JE and Svendsen, CN},
title = {An organ-chip model of sporadic ALS using iPSC-derived spinal cord motor neurons and an integrated blood-brain-like barrier.},
journal = {Cell stem cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.stem.2025.05.015},
pmid = {40562033},
issn = {1875-9777},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder in which motor neurons (MNs) of the brain and spinal cord degenerate, leading to paralysis. Generating MNs from patient-specific induced pluripotent stem cells (iPSCs) may help elucidate early stages of disease. Here, we combined MNs from patients with early-onset disease with brain microvascular endothelial-like cells in a microfluidic device we termed spinal cord chips (SC-chips) and added media flow, which enhanced neuronal maturation and improved cellular health. Bulk transcriptomic and proteomic analyses of SC-chips revealed differences between control and ALS samples, including increased levels of neurofilaments. Single-nuclei RNA sequencing revealed the presence of two MN subpopulations and an ALS-specific dysregulation of glutamatergic and synaptic signaling. This ALS SC-chip model generates a diversity of mature MNs to better understand ALS pathology in a model that has an active blood-brain barrier-like system for future drug screening.},
}

@article {pmid40560963,
year = {2025},
author = {Pang, C and Li, Y and Jiang, W and Xie, H and Cao, W and Yu, H and Lin, Z and Cheng, Y and Fan, D and Deng, B},
title = {Analysis of retinal markers and incident amyotrophic lateral sclerosis: An optical coherence tomography-based cohort study.},
journal = {PLoS medicine},
volume = {22},
number = {6},
pages = {e1004545},
pmid = {40560963},
issn = {1549-1676},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnostic imaging/diagnosis/pathology ; *Tomography, Optical Coherence ; Male ; Female ; Middle Aged ; *Retina/diagnostic imaging/pathology ; Biomarkers ; Aged ; Incidence ; Cohort Studies ; Adult ; United Kingdom/epidemiology ; Risk Factors ; },
abstract = {BACKGROUND: Biomarkers are widely recognized as crucial breakthroughs in tackling amyotrophic lateral sclerosis (ALS). Among them, retina markers may hold promise due to the close retina-brain connection and non-invasive, portable detection methods. Thus, using optical coherence tomography (OCT), we investigated the link between baseline cell-level retinal features and future ALS risk.

METHODS AND FINDINGS: Participants from the UK Biobank underwent OCT scans to assess retinal layers, macula, and optic disc parameters. Follow-up commenced two years after the baseline period (2006-2010), during which ALS cases were identified using International Classification of Diseases (ICD) codes from medical and assessment records. Cox proportional hazards models were applied to examine the relationship between retinal markers and incident ALS. Over a median follow-up of 14.11 years, 70 ALS cases occurred among 53,824 participants (incidence 10.58 per 100,000 person-years). Most participants were White (94.6%), 44.8% male, with a median age of 58 years. After adjusting for demographics and comorbidities affecting the retina, a standard deviation (SD) decrease of 15.19 µm in photoreceptor layer (PRL) thickness was associated with a 19% (95% confidence interval [7, 29]; p = 0.002) increased risk of ALS, while a SD increase of 26.11 µm in retinal pigment epithelium (RPE) thickness corresponded to a 20% (95% CI [7, 34]; p = 0.002) higher risk. Sensitivity analyses excluding follow-ups of less than 4 and 6 years yielded consistent results. Subgroup analyses showed these findings were more pronounced in smokers. The main limitation of this study is its single time point observational design.

CONCLUSION: A thinner PRL and thicker RPE may precede the clinical diagnosis of ALS, offering potential clues for early diagnosis and insights into the disease's pathogenesis.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/diagnostic imaging/diagnosis/pathology
*Tomography, Optical Coherence
Male
Female
Middle Aged
*Retina/diagnostic imaging/pathology
Biomarkers
Aged
Incidence
Cohort Studies
Adult
United Kingdom/epidemiology
Risk Factors

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

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

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

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

@article {pmid40560468,
year = {2025},
author = {Sumra, V and Hadian, M and Dilliott, AA and Farhan, SMK and Frank, AR and Lang, AE and Roberts, AC and Troyer, A and Arnott, SR and Marras, C and Tang-Wai, DF and Finger, E and Rogaeva, E and Orange, JB and Ramirez, J and Zinman, L and Binns, M and Borrie, M and Freedman, M and Ozzoude, M and Bartha, R and Swartz, RH and Munoz, D and Masellis, M and Black, SE and Dixon, RA and Dowlatshahi, D and Grimes, D and Hassan, A and Hegele, RA and Kumar, S and Pasternak, S and Pollock, B and Rajji, T and Sahlas, D and Saposnik, G and Tartaglia, MC and , },
title = {Regional free-water diffusion is more strongly related to neuroinflammation than neurodegeneration.},
journal = {Journal of neurology},
volume = {272},
number = {7},
pages = {478},
pmid = {40560468},
issn = {1432-1459},
mesh = {Humans ; Male ; Aged ; Female ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Diffusion Magnetic Resonance Imaging/methods ; *Neuroinflammatory Diseases/diagnostic imaging/metabolism ; Middle Aged ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Biomarkers/blood ; Aged, 80 and over ; Cognitive Dysfunction/diagnostic imaging ; },
abstract = {INTRODUCTION: Recent research has suggested that neuroinflammation may be important in the pathogenesis of neurodegenerative diseases. Free-water diffusion (FWD) has been proposed as a non-invasive neuroimaging-based biomarker for neuroinflammation.

METHODS: Free-water maps were generated using diffusion MRI data in 367 patients from the Ontario Neurodegenerative Disease Research Initiative (108 Alzheimer's Disease/Mild Cognitive Impairment, 42 Frontotemporal Dementia, 37 Amyotrophic Lateral Sclerosis, 123 Parkinson's Disease, and 58 vascular disease-related Cognitive Impairment). The ability of FWD to predict neuroinflammation and neurodegeneration from biofluids was estimated using plasma glial fibrillary-associated protein (GFAP) and neurofilament light chain (NfL), respectively.

RESULTS: Recursive Feature Elimination (RFE) performed the strongest out of all feature selection algorithms used and revealed regional specificity for areas that are the most important features for predicting GFAP over NfL concentration. Deep learning models using selected features and demographic information revealed better prediction of GFAP over NfL.

DISCUSSION: Based on feature selection and deep learning methods, FWD was found to be more strongly related to GFAP concentration (measure of astrogliosis) over NfL (measure of neuro-axonal damage), across neurodegenerative disease groups, in terms of predictive performance. Non-invasive markers of neurodegeneration such as MRI structural imaging that can reveal neurodegeneration already exist, while non-invasive markers of neuroinflammation are not available. Our results support the use of FWD as a non-invasive neuroimaging-based biomarker for neuroinflammation.},
}

Humans
Male
Aged
Female
*Neurodegenerative Diseases/diagnostic imaging/metabolism
*Diffusion Magnetic Resonance Imaging/methods
*Neuroinflammatory Diseases/diagnostic imaging/metabolism
Middle Aged
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood
Biomarkers/blood
Aged, 80 and over
Cognitive Dysfunction/diagnostic imaging

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

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

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

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

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

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

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

@article {pmid40558500,
year = {2025},
author = {Mai, HA and Thomas, CM and Nge, GG and Elefant, F},
title = {Modulating Cognition-Linked Histone Acetyltransferases (HATs) as a Therapeutic Strategy for Neurodegenerative Diseases: Recent Advances and Future Trends.},
journal = {Cells},
volume = {14},
number = {12},
pages = {},
pmid = {40558500},
issn = {2073-4409},
support = {RF1 NS095799/NS/NINDS NIH HHS/United States ; 2RF1NS095799//National Institutes of Health NINDS/ ; 2RF1NS095799/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Neurodegenerative Diseases/therapy/enzymology/drug therapy ; *Histone Acetyltransferases/metabolism ; *Cognition/physiology ; Animals ; Protein Processing, Post-Translational ; Histones/metabolism ; Epigenesis, Genetic ; Acetylation ; Aging ; },
abstract = {Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized PTMs shown to be required for neuronal function and cognition. Histone acetylation initiates neural circuitry plasticity via chromatin control, enabling neurons to respond to external environmental stimuli and adapt their transcriptional responses accordingly. While interplay between histone acetylation and deacetylation is critical for these functions, dysregulation during the aging process can lead to significant alterations in the neuroepigenetic landscape. These alterations contribute to impaired cognitive functions, neuronal cell death, and brain atrophy, all hallmarks of age-related neurodegenerative disease. Significantly, while age-related generation of DNA mutations remains irreversible, most neuroepigenetic PTMs are reversible. Thus, manipulation of the neural epigenome is proving to be an effective therapeutic strategy for neuroprotection in multiple types of age-related neurodegenerative disorders (NDs) that include Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Here, we highlight recent progress in research focusing on specific HAT-based neuroepigenetic mechanisms that underlie cognition and pathogenesis that is hallmarked in age-related NDs. We further discuss how these findings have potential to be translated into HAT-mediated cognitive-enhancing therapeutics to treat these debilitating disorders.},
}

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