@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 = {},
doi = {10.3390/toxics13060493},
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 = {},
doi = {10.3390/medsci13020067},
pmid = {40559225},
issn = {2076-3271},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Ultrasonography/methods ; *Peripheral Nerves/diagnostic imaging/pathology ; *Spinal Nerve Roots/diagnostic imaging/pathology ; Middle Aged ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to nerve atrophy. Ultrasonography has a significant role in the diagnosis of ALS.

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

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

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

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

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

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

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

@article {pmid40557915,
year = {2025},
author = {Ranieri, F and Senerchia, G and Bonan, L and Casali, S and Cabona, C and Cantone, M and De Marchi, F and Diamanti, L and Doretti, A and Fini, N and Filosto, M and Fortuna, A and Iovino, A and Iuzzolino, VV and Lanza, G and Lunetta, C and Maderna, L and Mandrioli, J and Mazzini, L and Musumeci, G and Nuredini, A and Sorarù, G and Toriello, A and Ticozzi, N and Todisco, M and Vacchiano, V and Zinno, L and Silani, V and Rossi, S and Di Lazzaro, V and Dubbioso, R and , },
title = {Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.27305},
pmid = {40557915},
issn = {1531-8249},
abstract = {OBJECTIVE: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival.

METHODS: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan-Meier curves and Cox regression models.

RESULTS: The MEP:CMAP ratio differed significantly across phenotypes (p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages (p < 0.0001). Hyperexcitable patients had shorter survival (p = 0.004), including when tested within 1 year of onset (p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12-3.03, p = 0.016).

INTERPRETATION: This real-world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025.},
}

@article {pmid40555967,
year = {2025},
author = {Ahmed, AB and Draz, ME and Asad, H and Naguib, IA and Edrees, FH},
title = {Innovative Synchronous Spectrofluorometric Method for Assessing a Novel Drug Combination in Amyotrophic Lateral Sclerosis: In Vivo Human Application With Greenness and Sustainability Evaluation.},
journal = {Luminescence : the journal of biological and chemical luminescence},
volume = {40},
number = {6},
pages = {e70222},
doi = {10.1002/bio.70222},
pmid = {40555967},
issn = {1522-7243},
support = {TU-DSPP-2024-49//Taif University/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Spectrometry, Fluorescence/methods ; *Celecoxib/analysis/therapeutic use/administration & dosage/blood ; *Ciprofloxacin/analysis/therapeutic use/blood/administration & dosage ; Drug Combinations ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder that causes damage to sensory neurons, then paralysis and death. A novel combination of celecoxib (CXP) and ciprofloxacin (CIP) has recently been used to enhance both motor performance and CNS cell morphology, alterations in the rate of disease progression, quality of life, and survival, which passed phase IIb RCT study. Celecoxib is classified as a non-steroidal anti-inflammatory drug; ciprofloxacin is a fluoroquinolone antibiotic that has a synergistic effect for the treatment of ALS, which is a severe neurological disorder. A new sustainable, simple, sensitive, and environmentally friendly synchronous spectrofluorimetric approach (SSF) was established to simultaneously estimate celecoxib and ciprofloxacin in pure form and biological fluids. The approach depends on synchronous fluorescence spectroscopy, where CXP and CIP were detected at 364 and 438 nm, correspondingly, using Δλ of 80-nm utilizing sodium dodecyl sulphate (SDS) micellar system, which considerably improved synchronous fluorescence intensity. The approach was validated and revealed excellent linearity with concentrations varying from 10 to 10,000 and 5 to 20,000 ng/mL for CXP and CIP; correspondingly, CXP and CIP showed extremely low limits of detection (LODs) 0.58-0.24 ng/mL, which guarantee the sensitivity of the proposed approach. The suggested approach was successfully implemented to analyze the co-administered pharmaceuticals in their pure form and actual human plasma after concurrent oral administration of both drugs, which may be employed in an inquiry on the pharmacokinetics and bioavailability of human plasma to the new coming PrimeC pharmaceutical formulation. Ultimately, the method's remarkable greenness was proved by evaluating its greenness profile using various assessment strategies. The findings revealed that the SSF approach is a sustainable and environmentally friendly analytical approach.},
}

*Amyotrophic Lateral Sclerosis/drug therapy
Humans
Spectrometry, Fluorescence/methods
*Celecoxib/analysis/therapeutic use/administration & dosage/blood
*Ciprofloxacin/analysis/therapeutic use/blood/administration & dosage
Drug Combinations

@article {pmid40555518,
year = {2025},
author = {Zanella, P and Loss, I and Parlato, R and Weishaupt, JH and Sala, C and Verpelli, C and Boeckers, TM and Catanese, A},
title = {ALS mutations shift the isoelectric point of the KIF5A C-terminal inducing protein aggregation and TDP-43 mislocalization.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1658-24.2025},
pmid = {40555518},
issn = {1529-2401},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by death of lower and upper motor neurons. Although the mechanism behind the selective neuron loss is still unclear, several heterogenous genes have been causally linked to ALS. KIF5A encodes for a neuronally enriched kinesin involved in protein transport and mutations within this gene have been causally linked to different motor neuron diseases. The mutations identified in ALS patients are mostly predicted to alter its mRNA splicing, leading to a frameshift mutation and an aberrant 39 amino acid-long sequence in the C-terminal domain of KIF5A.Here we found that ALS-related KIF5A mutations induce the accumulation of the mutant form of the protein in human motoneurons, which are also characterized by the cytosolic mislocalization of TDP-43. This ALS hallmark was even exacerbated upon overexpression of the ALS-KIF5A protein in cells differentiated from healthy controls and primary neurons, suggesting a pathological connection between the cellular load of the mutant protein and TDP-43 pathology. While the terminal domain of the WT isoform is characterized by an acid isoelectric point (pI), the ALS variant presents a basic pI due to the altered aminoacidic composition of this sequence. We thus generated a KIF5A ALS isoform that retained part of the aberrant sequence but with lower pI. The overexpression of this mutated variant led to significantly lower protein aggregation and TDP-43 mislocalization than the ALS mutant. Our data show that re-establishing the correct pI rescues KIFA aggregation and significantly reduces the cytoplasmic mislocalization of TDP-43.Significance Statement Amyotrophic Lateral Sclerosis is a lethal neurodegenerative disease to which no cure is still known. Heterogenous genes have been causally linked to ALS, yet, the exact pathomechanism responsible for neuronal death remains unclear. One such gene is KIF5A which encodes for a neuronally enriched kinesin. Identified mutations cause incorrect mRNA splicing resulting in an aberrant C-terminal aminoacidic sequence. Here, we identified TDP-43 cytosolic enrichment, a hallmark common to many ALS models, in two distinct hiPSC-derived motoneuron lines harboring the ALS mutation KIF5A[c2993-1 G>A] Moreover, we generated a KIF5A isoform that retained most of the aberrant sequence but did not promote protein aggregation nor TDP-43 mislocalization upon overexpression. These results shed further light on the pathobiochemistry of the ALS-KIF5A cases.},
}

@article {pmid40555284,
year = {2025},
author = {Park, KH and Kim, KW},
title = {Optogenetics to Biomolecular Phase Separation in Neurodegenerative Diseases.},
journal = {Molecules and cells},
volume = {},
number = {},
pages = {100247},
doi = {10.1016/j.mocell.2025.100247},
pmid = {40555284},
issn = {0219-1032},
abstract = {Neurodegenerative diseases involve toxic protein aggregation. Recent evidence suggests that biomolecular phase separation, a process in which proteins and nucleic acids form dynamic, liquid-like condensates, plays a key role in this aggregation. Optogenetics, originally developed to control neuronal activity with light, has emerged as a powerful tool to investigate phase separation in living systems. This is achieved by fusing disease-associated proteins to light-sensitive oligomerization domains, enabling researchers to induce or reverse condensate formation with precise spatial and temporal control. This review highlights how optogenetic systems such as OptoDroplet are being used to dissect the mechanisms of neurodegenerative disease. We examine how these tools have been applied in models of neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's disease. These studies implicate small oligomeric aggregates as key drivers of toxicity and highlight new opportunities for therapeutic screening. Finally, we discuss advances in light-controlled dissolution of condensates and future directions for applying optogenetics to combat neurodegeneration. By enabling precise, dynamic control of protein phase behavior in living systems, optogenetic approaches provide a powerful framework for elucidating disease mechanisms and informing the development of targeted therapies.},
}

@article {pmid40554516,
year = {2025},
author = {Castro, J and de Carvalho, M},
title = {Nerve Conduction Studies of Phrenic Nerve: Normative Data.},
journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNP.0000000000001181},
pmid = {40554516},
issn = {1537-1603},
abstract = {INTRODUCTION: In neuromuscular diseases, respiratory failure is a major complication. Pulmonary function tests are generally used to assess respiratory function but can be influenced by a number of factors. Nerve conduction studies of the phrenic nerve (PN) is a simple, noninvasive, and safe method to assess diaphragm compromise in neuromuscular diseases.

METHODS: A group of 132 (78 males) healthy subjects, aged between 23 and 90 years, was studied, with bilateral stimulation of the PN, with recording of diaphragm motor responses. Anthropometric variables (sex, age, height, and weight) were collected, and their influence on diaphragm motor response was assessed. Side-to-side differences were also analyzed.

RESULTS: PN compound muscle action potential (CMAP) had significantly higher amplitude and area on the left side. Men had longer latency, and higher amplitude and area when compared with women, on both sides. Age was a significant factor influencing CMAP latency, with an average increase of 0.25 ms per decade of life. In men, a latency longer than 9.5 ms and a CMAP amplitude lower than 0.62 mV should be considered abnormal, while in women, the values are 8.5 ms and 0.48 mV, respectively.

CONCLUSIONS: PN conduction studies offer a simple and reliable technique readily applicable in clinical settings. Diaphragm CMAP parameters are significantly influenced by the anthropometric variables of sex and age. Notably, CMAP amplitude and area are greater for the left PN.},
}

@article {pmid40554439,
year = {2025},
author = {Fan, Y and Wang, Z and Wu, M and Lin, L and Chen, L and Zheng, B},
title = {Bidirectional Causal Relationship Between Myopia and Neurodegenerative Diseases: Two-Sample Mendelian Randomization Analyses.},
journal = {British journal of hospital medicine (London, England : 2005)},
volume = {86},
number = {6},
pages = {1-19},
doi = {10.12968/hmed.2025.0183},
pmid = {40554439},
issn = {1750-8460},
mesh = {Humans ; Mendelian Randomization Analysis ; *Myopia/genetics/epidemiology ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/epidemiology ; Genetic Predisposition to Disease ; Parkinson Disease/genetics/epidemiology ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics/epidemiology ; Amyotrophic Lateral Sclerosis/genetics/epidemiology ; },
abstract = {Aims/Background Myopia is highly prevalent in certain neurodegenerative diseases (NDDs), and both conditions demonstrate genetic susceptibility. This study investigated the potential bidirectional causal relationships between myopia and four NDDs, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), using Mendelian randomization (MR). We aimed to determine whether myopia contributes to the risk of NDDs and vice versa. Methods We analyzed data from two independent, large-scale genome-wide association study (GWAS) cohorts on myopia, comprising 212,571 participants in the first cohort (finn-b-H7_MYOPIA) and 95,619 in the second (GCST009521). GWAS summary statistics for the four NDDs, encompassing 589,439 samples, were also incorporated. Bidirectional MR was employed to investigate causal relationships between myopia and each of the four NDDs. The inverse variance-weighted (IVW) method served as the primary analytical approach. Sensitivity analyses, including MR-Egger regression, weighted median, weighted mode, and simple mode, were conducted to assess the robustness of the findings. Horizontal pleiotropy was evaluated using the MR-Egger regression intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, while heterogeneity was assessed via Cochran's Q test. Leave-one-out analyses were conducted to evaluate the influence of individual single nucleotide polymorphisms (SNPs). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and statistical significance was set at p < 0.05. Results MR analyses identified no evidence of a causal relationship between myopia and refractive error and increased risk of any of the four NDDs (all p > 0.05). Similarly, none of the NDDs were associated with an increased risk of myopia or refractive error (all p > 0.05). Sensitivity analyses revealed no SNPs with significant influence on the causal associations (all p > 0.05), supporting the robustness of the findings. Conclusion This study provides no evidence of a bidirectional causal relationship between myopia and the four NDDs among individuals of European ancestry. Future research should extend beyond direct causal inference to investigate potential mediating biological mechanisms.},
}

Humans
Mendelian Randomization Analysis
*Myopia/genetics/epidemiology
Genome-Wide Association Study
*Neurodegenerative Diseases/genetics/epidemiology
Genetic Predisposition to Disease
Parkinson Disease/genetics/epidemiology
Polymorphism, Single Nucleotide
Alzheimer Disease/genetics/epidemiology
Amyotrophic Lateral Sclerosis/genetics/epidemiology

@article {pmid40553568,
year = {2025},
author = {Bekier Ii, ME and Pinarbasi, ES and Krishnan, G and Mesojedec, JJ and Hurley, M and Harikumar Sheela, H and Collins, CA and Ghaffari, LT and de Majo, M and Ullian, EM and Koontz, M and Coleman, S and Li, X and Tank, EM and Waksmacki, J and Gao, FB and Barmada, SJ},
title = {Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI188138},
pmid = {40553568},
issn = {1558-8238},
abstract = {Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK) - a proline-directed serine/threonine kinase - promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.},
}

@article {pmid40553535,
year = {2025},
author = {Ramachandra, K and Narayana, AR and Induraj, A and Pai, R},
title = {Unilateral Vocal Cord Palsy as Presenting Feature of Amyotrophic Lateral Sclerosis.},
journal = {The Journal of the Association of Physicians of India..},
volume = {73},
number = {5},
pages = {83-84},
doi = {10.59556/japi.73.0931},
pmid = {40553535},
issn = {0004-5772},
mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; Aged ; *Vocal Cord Paralysis/etiology/diagnosis ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative pathology marked by the degeneration of upper and lower motor neurons, resulting in muscle weakness and atrophy, impairing motor function. Bulbar-onset ALS is a distinct clinical subtype, with initial involvement of bulbar motor neurons, often causing severe speech and swallowing difficulties. Despite its impact, bulbar-onset ALS, especially with rare symptoms like unilateral vocal cord palsy (UVCP), lacks extensive research. Here, we detail the case of a 79-year-old nonambulatory diabetic male with a 1-year history of hoarseness of voice, diagnosed with bulbar-onset ALS with UVCP. This underscores the importance of recognizing unusual presentations of ALS, particularly in geriatric populations, urging tailored medical evaluations for optimal care and improved outcomes in this challenging neurological condition.},
}

Humans
Male
*Amyotrophic Lateral Sclerosis/diagnosis/complications
Aged
*Vocal Cord Paralysis/etiology/diagnosis

@article {pmid40551967,
year = {2025},
author = {Berdyński, M and Safranow, K and Andersen, PM and Żekanowski, C},
title = {Phenotypic Characterization of ALS-Causing SOD1 Mutations Affecting Polypeptide Length.},
journal = {Human mutation},
volume = {2025},
number = {},
pages = {9792233},
pmid = {40551967},
issn = {1098-1004},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/mortality ; Humans ; *Superoxide Dismutase-1/genetics/chemistry ; Phenotype ; *Mutation ; Middle Aged ; Female ; Male ; Adult ; Age of Onset ; Aged ; },
abstract = {Background: Some 234 mutations in the small SOD1 gene have been reported to cause amyotrophic lateral sclerosis. However, the pathogenic mechanisms, particularly of those mutations affecting polypeptide length, are contested. It is presently unknown whether all reported nonsense mutations in SOD1 are causative for ALS. The emergence of promising new anti-SOD1 drugs has made it imperative to gain further insight into clinical-genetic aspects of ALS for deciding which patients to treat in clinical practice and include in drug trials. Objective: This study is aimed at comprehensively analyzing the clinical phenotypes associated with ALS-causing SOD1 mutations that alter the polypeptide length. The specific focus is on the age at which symptoms manifest and the survival duration. Methods: Data were collected from web databases, published reports, conference presentations, and personal communications up to November 2023. The clinical endpoints, including age at symptom onset and age at death, were subjected to survival analysis. Comparative analyses were performed between frameshift and nonframeshift variants. Results: A cohort of 146 ALS patients harboring 38 different nonmissense SOD1 variants was analyzed. The mean age of disease onset was 46.9 years, with a mean survival duration of 49 months. Significant heterogeneity was observed in clinical outcomes, with earlier disease onset and reduced survival associated with specific mutations. Notably, frameshift mutations proximal to the N-terminus showed a higher risk of early ALS onset compared to more distal mutations. Conclusions: The clinical phenotypes of ALS patients with nonmissense SOD1 mutations are highly variable and dependent on the specific mutation. These findings underscore the necessity of including diverse SOD1 mutation carriers in therapeutic trials and suggest that both loss-of-function and gain-of-function mechanisms may contribute to ALS pathology.},
}

*Amyotrophic Lateral Sclerosis/genetics/mortality
Humans
*Superoxide Dismutase-1/genetics/chemistry
Phenotype
*Mutation
Middle Aged
Female
Male
Adult
Age of Onset
Aged

@article {pmid40550228,
year = {2025},
author = {Tiwari, A and Singh, B and Singh, GK and Meena, J and Agrawal, AK and Kumar, S and Modi, G},
title = {Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.5c00096},
pmid = {40550228},
issn = {2576-6422},
abstract = {Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.},
}

@article {pmid40550045,
year = {2025},
author = {Lei, C and Chen, J and Chen, Z and Xiao, Y and Chen, J and Ma, C and Yang, M and Wu, D and Xie, L},
title = {Amyotrophic lateral sclerosis and neurodegenerative diseases: A Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {25},
pages = {e42847},
doi = {10.1097/MD.0000000000042847},
pmid = {40550045},
issn = {1536-5964},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/epidemiology ; Parkinson Disease/genetics ; Alzheimer Disease/genetics ; Frontotemporal Dementia/genetics ; },
abstract = {In this study, we used the Mendelian randomization (MR) method to systematically examine whether there is a bidirectional causal relationship between amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). We analyzed data from 6,44,924 participants using MR to evaluate causality. We employed inverse variance weighted and MR-Egger regression tests for MR analysis. Additionally, we performed sensitivity analyses using the MR-Egger test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. The inverse variance weighted analysis found no evidence of a risk effect between ALS and the neurodegenerative diseases AD, PD, FTD, MSA, and DLB. However, the MR-Egger analysis showed that both AD (odds ratio: 1.079, 95% confidence interval: 1.017-1.145, P = .029) and PD (odds ratio: 1.210, 95% confidence interval: 1.046-1.401, P = .020) have a risk effect on ALS, indicating that AD and PD increase the risk of ALS. Our MR analysis suggests that AD and PD may have a potential causal relationship with ALS. Conversely, ALS does not appear to have a causal relationship with the other neurodegenerative diseases examined (FTD, MSA, DLB).},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
*Mendelian Randomization Analysis
*Neurodegenerative Diseases/genetics/epidemiology
Parkinson Disease/genetics
Alzheimer Disease/genetics
Frontotemporal Dementia/genetics

@article {pmid40548824,
year = {2025},
author = {Leykam, L and Jonsson, PA and Forsberg, KME and Andersen, PM and Brännström, T and Marklund, SL and Zetterström, P},
title = {SOD1 Protein Content in Human Central Nervous System and Peripheral Tissues.},
journal = {Journal of neurochemistry},
volume = {169},
number = {6},
pages = {e70136},
doi = {10.1111/jnc.70136},
pmid = {40548824},
issn = {1471-4159},
support = {//Olsson och Olsson Välgörenhetsstiftelse/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Fort Knox Välgörenhetsstiftelse/ ; 2.1.12-1605-14//Umeå University Insamlingsstiftelsen/ ; 2.1.6-452-20//Umeå University Insamlingsstiftelsen/ ; 223-1881-13//Umeå University Insamlingsstiftelsen/ ; 223-2808-12//Umeå University Insamlingsstiftelsen/ ; //Västerbotten Läns Landsting/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; //Neuroförbundet/ ; 2012-3167//Vetenskapsrådet/ ; 2017-03100//Vetenskapsrådet/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; 2012-0262//Swedish brain foundation/ ; 2012-0305//Swedish brain foundation/ ; 2013-0279//Swedish brain foundation/ ; 2016-0303//Swedish brain foundation/ ; 2020-0353//Swedish brain foundation/ ; },
mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/enzymology ; Male ; Female ; *Central Nervous System/enzymology/metabolism ; Middle Aged ; Aged ; Adult ; *Superoxide Dismutase/metabolism ; Muscle, Skeletal/enzymology ; },
abstract = {Gene silencing therapy is an effective treatment for amyotrophic lateral sclerosis (ALS) patients carrying mutations in the superoxide dismutase-1 (SOD1) gene aiming to reduce noxious forms of SOD1 in the central nervous system (CNS). The normal steady-state level of SOD1 protein in human CNS is therefore of interest but is contested. In this work we have analyzed SOD1 protein content, total protein content, and SOD1 enzymatic activity in six areas of the CNS as well as in four peripheral tissues from sporadic and familial ALS patients and non-ALS controls. Our results show that SOD1 in the human CNS constitutes around 100 μg/g wet weight corresponding to about 0.16% of the total protein in the studied areas. Of the peripheral tissues analyzed, kidney and erythrocytes contain roughly equal amounts, liver higher, and skeletal muscle lower levels of SOD1 compared to the CNS. This data shows SOD1 protein levels around 10 times lower compared to previously published figures. However, SOD1 can still be considered an abundant protein considering that > 12 000 proteins are expressed in human cells. There was no difference in SOD1 protein content between sporadic or familial ALS patients and control individuals. The level and activity of SOD1 are not deviating in the areas of the CNS that are most vulnerable to ALS. Instead, insufficient control of SOD1 structure and aggregation could be important factors behind the vulnerability of motor areas to SOD1 proteotoxicity.},
}

Humans
*Superoxide Dismutase-1/metabolism
Amyotrophic Lateral Sclerosis/metabolism/genetics/enzymology
Male
Female
*Central Nervous System/enzymology/metabolism
Middle Aged
Aged
Adult
*Superoxide Dismutase/metabolism
Muscle, Skeletal/enzymology

@article {pmid40547142,
year = {2025},
author = {Kumar, S},
title = {Esophageal squamous cell carcinoma susceptibility of activin A receptor type 1C variants in Chinese population.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {6},
pages = {102687},
pmid = {40547142},
issn = {1948-5204},
abstract = {Lin et al's investigation on the association of activin A receptor type 1C (ACVR1C) (transforming growth factor beta type I receptor) single nucleotide polymorphisms (SNPs) with esophageal squamous cell carcinoma (ESCC) risk in the Chinese population is a scientific approach. This study explores the susceptibility of ACVR1C polymorphism towards ESCC in the Chinese population, highlighting the polymorphism's potentiality as an early diagnostic and therapeutic target. The author assessed about a thousand ESCC Chinese patients' samples for ACVR1C SNPs in a hospital-based cohort study using the ligation detection reaction method. Further, the hypothesis was tested using appropriate statistical genetic models and stratified analysis. ACVR1C SNPs can help assess ESCC susceptibility stratification and provide valuable information for individual diagnosis and treatment of ESCC patients. In order to account for confounding variables, find genuine SNP-disease relationships, boost statistical power, and make biological interpretation easier, it is imperative that genetic association studies of ESCC incorporate pertinent clinical aspects.},
}

@article {pmid40544342,
year = {2025},
author = {Rodríguez-García, V and Venta-Sobero, JA and Chima-Galán, MDC},
title = {A novel heterozygous variant of FUS gene associated with juvenile ALS and premature tremor onset: a case report.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/21678421.2025.2522403},
pmid = {40544342},
issn = {2167-9223},
abstract = {Juvenile amyotrophic lateral sclerosis (JALS) is neurodegenerative disease of the upper and lower motor neurons of rare incidence. Although fused in sarcoma (FUS) mutations in JALS patients have been associated with movement disorders, here we described the case of a young girl with very early onset of tremor, years before commencement of weakness; once symptoms of JALS were stablished, a typical rapid disease progression from spinal to bulbar symptoms were noticed. Genetic testing revealed a novel mutation in FUS gene causative of a protein dysfunction. This case emphasizes the fact that some mutations within the FUS in JALS patients may produce a symptom onset with tremor.},
}

@article {pmid40545904,
year = {2025},
author = {Mitsumoto, H and Cheung, K and Oskarsson, B and Jang, GE and Andrews, HF and Johnson, S and Shah, JS and Fernandes, JA and Andrews, JA and Rao, M and McElhiney, M},
title = {Placebo-Controlled, Randomized Double-Blind N-Of-1 Trial to Study Safety and Potential Efficacy of TJ-68 for Improving Muscle Cramps in Patients With Amyotrophic Lateral Sclerosis: A Pilot Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28459},
pmid = {40545904},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Muscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ-68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ-68 in ALS.

METHODS: This study was a double-blind, randomized, placebo-controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years.

RESULTS: The enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ-68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance.

DISCUSSION: The study revealed that N-of-1 trial design can detect changes in a small sample size, and TJ-68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ-68.},
}

@article {pmid40544973,
year = {2025},
author = {Thakur, N and Kumar, T and Singh, C and Kumar, R and Kumar, A},
title = {Cell membrane-coated nanoparticles in neurodegenerative disorders management.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {125875},
doi = {10.1016/j.ijpharm.2025.125875},
pmid = {40544973},
issn = {1873-3476},
abstract = {Neurodegenerative disorders (ND) are accompanied by neuronal death because of progressive destruction in neuronal structure and function. Due to various neurological conditions, there is a significant number of deaths every year around the world. The healthcare burden is also increasing each year. Development and progress in nanotechnology enable the creation of nanocarriers that transport drugs to the site of disease, thereby enhancing the therapeutic performance of the drug. However, the transport of nanocarrier-based therapeutics to the brain is restricted by barriers such as the Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCFB), which are further impeded by P-glycoproteins. Hence, current research and development focus on overcoming these obstacles. A biomimetic drug delivery system is one of the best ways to overcome these challenges. One of the promising biomimetic drug delivery systems is cell membrane-coated nanoparticles. In this review, we have comprehensively reviewed the recent progress and development in various cell membranes coated nanoparticle-based drug delivery systems for the effective management of a range of neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Glioblastoma, Ischemic Stroke, Huntington's Disease, Amyotrophic Lateral Sclerosis, Glioma, Peripheral Nerve Injury, and Motor Neuron Disorder. We also reviewed the challenges associated with cell membrane-coated nanoparticles, such as biosafety hurdles, toxicity, regulatory requirements, and clinical translation. Ultimately, we provided the conclusions and future research directions that must be investigated to overcome the current limitations.},
}

@article {pmid40544661,
year = {2025},
author = {Zelek, WM and Tenner, AJ},
title = {Complement therapeutics in neurodegenerative diseases.},
journal = {Immunobiology},
volume = {230},
number = {4},
pages = {153089},
doi = {10.1016/j.imbio.2025.153089},
pmid = {40544661},
issn = {1878-3279},
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis pose considerable therapeutic challenges, not only due to their complex pathophysiology, but also because any effective drug must be capable of penetrating the brain. Inflammation is a key feature of NDDs. Increasingly, the complement system, long studied in the context of host defence, has emerged as a central player in the brain, with roles extending far beyond its classical immune functions. Complement contributes to synaptic pruning and immune surveillance, but when dysregulated, it can drive chronic inflammation, synapse loss, and neurodegeneration. Complement is also implicated in neurodevelopmental and neuropsychiatric diseases, including schizophrenia and mood disorders, where overactivation of the cascade impacts brain maturation and circuit stability. In this review, we take a broad view of roles of the complement system in both health and disease in the central nervous system (CNS). We summarise key mechanisms through which complement contributes to pathology, discuss emerging therapeutic strategies, and consider major hurdles in CNS drug development, including brain delivery and the need for patient stratification. As our understanding of the pathological roles of the complement system in the brain advances, it is becoming clear that complement therapeutics may offer a novel approach in slowing neurodegeneration, and in addressing a broader spectrum of disorders affecting the brain.},
}

@article {pmid40544604,
year = {2025},
author = {Jonk, SM and Nicol, A and Chrysostomou, V and Lardner, E and Yu, SC and Stålhammar, G and Crowston, JG and Tribble, JR and Swoboda, P and Williams, PA},
title = {Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans.},
journal = {Redox biology},
volume = {85},
number = {},
pages = {103732},
doi = {10.1016/j.redox.2025.103732},
pmid = {40544604},
issn = {2213-2317},
abstract = {Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in C. elegans assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in C. elegans provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in C. elegans models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.},
}

@article {pmid40543477,
year = {2025},
author = {Scott, J and Crook-Rumsey, M and Carobin, A and Bilgorai, J and Kelly, G and Sreedharan, J and Shaw, C and Bashford, J},
title = {Noninvasive quantification of fasciculations to track tofersen therapy in superoxide dismutase 1 amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {177},
number = {},
pages = {2110791},
doi = {10.1016/j.clinph.2025.2110791},
pmid = {40543477},
issn = {1872-8952},
}

@article {pmid40443243,
year = {2025},
author = {Adhya, A and Uppula, S and Raidas, S and Gupta, A and Singh, RK and Vibha, D and Garg, A and Tripathi, M},
title = {Midbrain Atrophy in Mills Syndrome: A Rare Finding Pointing to Diagnosis.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-2},
doi = {10.1017/cjn.2025.10135},
pmid = {40443243},
issn = {0317-1671},
}

@article {pmid40543321,
year = {2025},
author = {Zou, T and Hou, M and Han, H and Wang, X and Chen, H and Tang, Y and Li, R and Hu, S},
title = {Medulla oblongata dominated synaptic density network degeneration in amyotrophic lateral sclerosis.},
journal = {NeuroImage. Clinical},
volume = {47},
number = {},
pages = {103814},
doi = {10.1016/j.nicl.2025.103814},
pmid = {40543321},
issn = {2213-1582},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a brain network disorder closely associated with synaptic loss in the upper and lower motor neurons. However, the in vivo synaptic network changes and their progressive processes remain unclear. Here, we aim to investigate the synaptic density network connectivity and the likely sequences of synaptic loss in patients with ALS.

METHODS: We examined data from 21 patients diagnosed with ALS and 25 sex- and age-matched healthy controls (HCs) who underwent PET imaging with the SV2A radioligand [[18]F]SynVesT-1. The individual synaptic density similarity network was constructed for each patient by calculating the similarity between interregional synaptic density distributions. The synaptic network connectivity changes were investigated, followed by an examination of the local synaptic density in regions that showed significant network alterations. Finally, we constructed the voxel-wise and ROI-wise causal synaptic covariance network (cSCN) by applying Granger causality analysis. This allowed us to identify the sequence of synaptic loss in these brain regions.

RESULTS: We observed an overall decrease in synaptic density network connectivity in ALS patients compared to controls, with the highest nodal degree in the right medulla oblongata. Specifically, the reduced connections were dominantly between the medulla oblongata and the striatum, frontal lobe, occipital lobe, as well as between the striatum and the frontal lobe, occipital lobe. Furthermore, patients with ALS displayed significantly synaptic loss in those brain regions. The cSCN analyses showed that as the disease progresses, the cortical synaptic loss sequences of ALS extend from the medulla oblongata to the regions including the striatum, frontal lobe, occipital lobe, and parietal lobe.

CONCLUSIONS: These findings suggest that synaptic density network degeneration in ALS may follow a bottom-up transmission pattern, primarily involving in the medulla oblongata-striatum-neocortex network, which have the potential to capture new network-based targets for clinical therapy in the progression of ALS.},
}

@article {pmid40542195,
year = {2025},
author = {Zhang, J and Hu, J and Liu, R and Zhou, T and Luo, X and Liang, P and Xie, Z and Zhao, Q and Chen, Y and Du, D and Liu, C and Zheng, Y and Li, D and Wang, B},
title = {YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates.},
journal = {Nature cell biology},
volume = {},
number = {},
pages = {},
pmid = {40542195},
issn = {1476-4679},
support = {32470726//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32000727//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82188101//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32171236//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32370731//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170683//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82372788//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2023J01024//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; JCYJ20220531100204010//Shenzhen Science and Technology Innovation Commission/ ; 20XD1425000//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 22JC1410400//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; },
abstract = {Recent studies exploring the underlying pathomechanisms of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, have focused on biomolecular condensates. Here we reveal an unexpected function for YAP, a central component of the Hippo pathway, in regulating the dynamic behaviour of stress granules and TDP-43 condensates, a role that is independent of its transcriptional activity in the Hippo pathway. YAP directly binds to TDP-43. This interaction directly promotes the homotypic multimerization and phase separation of TDP-43 while inhibiting its hyperphosphorylation and solidification under stress conditions. Remarkably, YAP, whose messenger RNA levels are reduced in patients with ALS, is found to co-localize with pathological hyperphosphorylated TDP-43 aggregates in the brains of patients with ALS. In addition, elevation of YAP/Yorkie (a fly homologue of mammalian YAP) expression substantially reduces TDP-43 toxicity in primary neuron and transgenic fly models of ALS. Our findings highlight an unexpected role of YAP in managing ALS-associated biomolecular condensates, presenting important implications for potential ALS treatments.},
}

@article {pmid40542104,
year = {2025},
author = {Temp, AGM and Tarakdjian, GN and Kasper, E and Machts, J and Kaufmann, J and Vielhaber, S and Prudlo, J and Cole, JH and Dyrba, M and Teipel, S and Hermann, A},
title = {The role of cognitive and brain reserve in the clinical presentation and progression of amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {20232},
pmid = {40542104},
issn = {2045-2322},
abstract = {Recent research has shown that cognitive reserve is associated with better cognitive abilities in ALS/MND, and that a slow brain ageing speed is associated with intact cognition in ALS. This study compares the effects of cognitive reserve and the predicted brain age difference (PAD) on the risk of being diagnosed with ALS, the risk of having cognitive or behavioral impairment, or even fronto-temporal dementia, and on disease duration.Our results indicated that neither PAD nor cognitive reserve was associated with an increased risk of ALS, but that higher PAD was associated with an increased risk of cognitive impairments and FTD, as well as a shortened disease duration. Higher cognitive reserve on the other hand was associated with a lower risk of cognitive impairment and a longer disease duration.Brain age as a proxy of brain reserve influences disease progression and presentation more strongly than cognitive reserve.},
}

@article {pmid40541317,
year = {2025},
author = {Frecska, E and Kovács, A and Szabo, A},
title = {The protective effect of DMT against neurodegeneration.},
journal = {International review of neurobiology},
volume = {181},
number = {},
pages = {395-420},
doi = {10.1016/bs.irn.2025.04.010},
pmid = {40541317},
issn = {2162-5514},
abstract = {This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of our previous preclinical (in vitro and in vivo) DMT studies aiming at mitigating IRI and related cellular neuropathologies. We conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest. The multiple neuroprotective mechanisms facilitated by DMT may position it as a model molecule for developing pharmacological treatments for neurodegenerative disorders.},
}

@article {pmid40541245,
year = {2025},
author = {Vázquez, MC and Perna, A and Legnani, M and Saona, G},
title = {Prognostic factors in ALS: different approaches to the same problem.},
journal = {Arquivos de neuro-psiquiatria},
volume = {83},
number = {6},
pages = {1-7},
doi = {10.1055/s-0045-1809407},
pmid = {40541245},
issn = {1678-4227},
abstract = {The natural history of amyotrophic lateral sclerosis (ALS), the prognoses, and the survival times are fields of considerable interest that are scarcely studied in South American countries.To describe the survival of a representative cohort of Uruguayan ALS patients, and to identify covariates associated with survival using different analyses.Survival was assessed using the Kaplan-Meier method. Different Cox proportional hazards functions were used to identify independent prognostic predictors since the diagnosis: classic, stratified, and truncated.We included 166 definite and probable ALS patients. The median follow-up was of 13.6 years. An analysis was performed according to the recruitment groups: prevalent, exhaustive incident, and non-exhaustive incident cases. The median survival since the diagnosis was longer in the prevalent group (33 months) than in the exhaustive incident (22 months) and non-exhaustive incident (14 months) groups. The median survival time of the entire cohort from onset to death was 37 months and 23 months from the diagnosis. Factors related to survival from diagnosis to death were: age at onset, bulbar region onset, clinical form, and progression rate.The present study described the role of clinical and demographic factors in ALS survival in the Uruguayan population and shed light on differences involving survival models and the temporal bias produced by the lack of precision in determining the onset of the disease.},
}

@article {pmid40541176,
year = {2025},
author = {Sonustun, B and Vahsen, BF and Ledesma-Terrón, M and Li, Z and Tuffery, L and Xu, N and Calder, EL and Jungverdorben, J and Weber, L and Zhong, A and Miguez, DG and Monetti, M and Zhou, T and Giacomelli, E and Studer, L},
title = {Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102535},
doi = {10.1016/j.stemcr.2025.102535},
pmid = {40541176},
issn = {2213-6711},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron (MN) loss. The most common genetic cause, a hexanucleotide repeat expansion in C9orf72 (C9-ALS), disrupts microglial function, contributing to neuroinflammation, a key disease driver. To investigate this, we developed a three-dimensional spinal microtissue (SM) model incorporating human induced pluripotent stem cell (hiPSC)-derived MNs, astrocytes, and microglia. Screening 190 Food and Drug Administration (FDA)-approved compounds, we identified sartans-angiotensin II receptor I blockers (ARBs)-as potent inhibitors of neuroinflammation. Telmisartan, a highly brain-penetrant ARB, significantly reduced the levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and rescued MN loss in C9-ALS SMs. Our findings suggest that C9-ALS microglia drive MN toxicity and that telmisartan can effectively mitigate inflammation and preserve MN viability. This work lays the groundwork for modeling disease-related neuroinflammation and points to telmisartan as a therapeutic candidate worth further exploration for treating C9-ALS.},
}

@article {pmid40540646,
year = {2025},
author = {Au, CK and Chin, ML and Luk, WL and Wong, KW and Che, LY and Yuan, BF and Ilić, G and Pavlović, M and Chan, HW and Yu, JZ and Pavlović, NM and Cai, Z and Chan, W},
title = {Analysis of Honey and Environmental Samples from BEN Endemic Villages in Serbia: Identification of a Novel Human Exposure Pathway for Aristolochic Acids and Aristolactams.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c06473},
pmid = {40540646},
issn = {1520-5118},
abstract = {Dietary exposure to aristolochic acids (AAs) through AA-tainted flour is closely linked to the development of Balkan endemic nephropathy (BEN), a chronic kidney disease that is prevalent in rural farming villages in the Balkan region; however, additional exposure pathways would better explain the incidence rate of BEN. This study reveals for the first time that inhalation of AA-contaminated air, which often contains aristolactams (ALs)─genotoxic metabolites of AAs─represents an unrecognized exposure route. The presence of AAs was confirmed in local honey, and subsequent analysis of face masks worn by volunteers near flowering Aristolochia clematitis (A. clematitis) weeds indicated that AAs may be airborne. Further investigation into the transport of AA-containing particles was conducted by analyzing outdoor residential surfaces (e.g., windowsills) in Serbia, detecting AA-I or AL-I in more than 20% of the samples, with concentrations ranging from 13 to 2470 pg and 1 to 8985 pg per 225 cm[2], respectively. Additionally, it was found that burning A. clematitis generates particle-bound ALs. Given that A. clematitis weeds are often burned alongside wheat remnants for cooking, heating, and fertilizer production, these findings highlight airborne AAs and ALs as potentially key agents in the induction of BEN. In conjunction with the WHO's notice that biomass burning significantly contributes to the high prevalence of respiratory diseases in the Balkans, this study identifies AAs and their analogs as air pollutants. Therefore, it is imperative to eliminate A. clematitis weeds from affected areas and to cease their use as heating and cooking fuel.},
}

@article {pmid40540128,
year = {2025},
author = {Bonan, L and Bombardi, M and Di Lionardo, A and Vitiello, M and Morresi, S and Longoni, M},
title = {Co-occurence of amyotrophic lateral sclerosis and sarcoidosis: a case report and systematic review of the literature.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40540128},
issn = {1590-3478},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, with 90% of cases being sporadic. Sarcoidosis is an inflammatory disease affecting multiple organs, with neurological complications occurring in 5-10% of patients. Only isolated cases of this extremely rare combination of the two diseases have been reported.

METHODS: We present the case of a 45-year-old man diagnosed with ALS after a 2-year history of progressive upper limb weakness who was incidentally found to be affected by thoraco-abdominal lymphadenopathy. The biopsy confirmed the co-presence of sarcoidosis. We also make a systematic review of the literature of this rare combination.

RESULTS: The patient showed stabilization of the neurological condition and the pneumological disease after administration of immunosuppressive treatment.

CONCLUSION: Our case report and literature review highlight peculiar clinical characteristics of this extremely rare combination of diseases, deepening the understanding of this peculiar phenotype.},
}

@article {pmid40539764,
year = {2025},
author = {Adler, GL and Kiernan, MC and Tan, RH},
title = {The FindMNDBiomarker Program: Protein Changes in Motor Neuron Disease/Amyotrophic Lateral Sclerosis Postmortem Tissue and Biofluids.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.27300},
pmid = {40539764},
issn = {1531-8249},
support = {IM-202403-01257//FightMND/ ; MCR-77//FightMND/ ; },
abstract = {OBJECTIVE: Biomarkers of disease pathogenesis are critically needed for amyotrophic lateral sclerosis (ALS) to facilitate diagnosis and patient stratification into appropriate therapeutic trials. Proteomic studies offer significant potential to advance this, but reproducibility across laboratories is a key component toward identifying protein changes that can be translated into clinical applications.

METHODS: A combined analysis of 25 proteomic studies in human ALS biospecimens was performed to identify proteins consistently altered in ALS postmortem tissue, cerebrospinal fluid, or blood, as well as across primary regions of ALS pathology and peripheral biofluids. We consolidated these datasets into a user-friendly database "FindMND Biomarker," which is an accessible search tool that allows users to quickly determine how often, and in which biospecimen types, their proteins of interest are dysregulated in patients with ALS.

RESULTS: Our combined analysis identified 1,458 altered proteins in ALS, and revealed consistent dysregulation in mitochondrial, cytoplasmic, and RNA binding proteins in primary and later affected regions of ALS pathology. Remarkable consistency in the direction and dysregulation of chitinases and gelsolin proteins were observed across ALS biofluids. Comparisons of postmortem tissue and biofluids reinforce several known protein changes, and highlighted novel proteins of interest that may drive disease pathogenesis.

INTERPRETATION: The biospecimen type in which protein dysregulation is most consistently identified provides important insight into disease, and whether these represent potential measures of disease pathogenesis or systemic changes. By streamlining proteins by reproducibility and biospecimen type, FindMNDBiomarker is a useful resource that provides new mechanistic insights, and facilitates the prioritization of ALS-associated proteins for further validation and investigation. ANN NEUROL 2025.},
}

@article {pmid40538061,
year = {2025},
author = {Guo, Z and Zhang, X and Li, Y and Chen, Y and Xu, Y},
title = {Splicing to keep splicing: A feedback system for cellular homeostasis and state transition.},
journal = {Clinical and translational medicine},
volume = {15},
number = {6},
pages = {e70369},
doi = {10.1002/ctm2.70369},
pmid = {40538061},
issn = {2001-1326},
support = {82173292//National Natural Science Foundation of China/ ; 62171365//National Natural Science Foundation of China/ ; 62471378//National Natural Science Foundation of China/ ; 2024SF-GJHX-40//the Key Research and Development Projects of Shaanxi Province/ ; QCYRCXM-2022-209//the Key Research and Development Projects of Shaanxi Province/ ; YX6J021//Young Talent Support Plan of Xi'an Jiaotong University/ ; 2022-11//Basic-Clinical Medical Integration & Innovation Project of Xi'an Jiaotong University/ ; },
abstract = {BACKGROUND: Alternative splicing (AS) plays a crucial role in regulating gene expression and governing proteomic diversity by generating multiple protein isoforms from a single gene. Increasing evidence has highlighted the regulation for pre-mRNA splicing of the splicing factors (SFs). This review aims to examine featured mechanisms and examples of SF regulation by AS, focusing on paradigmatic feedback loops and their biological implications.

MAIN BODY OF THE ABSTRACT: We specifically focus on the autoregulation and inter-regulation of SFs through AS machinery. These interactions give rise to a feedback system, where the negative feedback loops aid in maintaining cellular homeostasis, and the positive feedback loops play roles in triggering cellular state transitions. We examine the growing evidence highlighting the specific mechanisms employed by SFs to autoregulate their own splicing, including AS-coupled nonsense-mediated mRNA decay (AS-NMD), nuclear retention, and alternative 3'UTR regulation. We showcase the influence of AS feedback in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and cancer. Furthermore, we discuss how master splicing factors can dominantly orchestrate splicing cascades, leading to widespread impacts in cellular processes. We also discuss how non-coding RNAs, particularly circular RNAs and microRNAs, engage in the splicing regulatory networks. Lastly, we showcase how negative and positive feedback loops can collaboratively achieve remarkable biological functions during the cell fate decision.

SHORT CONCLUSION: This review highlights the regulation of SFs by AS, providing enriched information for future investigations that aim at deciphering the intricate interplay within splicing regulatory networks.

KEY POINTS: Negative feedback of alternative splicing maintains cellular homeostasis. Positive feedback of alternative splicing triggers cellular state transitions. Alternative splicing forms integrated feedback networks with circRNAs and microRNAs to reciprocally regulate their expression and function. The coordinated interplay of distinct splicing feedback mechanisms orchestrates precise cell fate transitions. Future directions and therapeutic possibilities that could transform alternative splicing research into treatments.},
}

@article {pmid40537251,
year = {2025},
author = {Verde, F and Vávra, J and Dorst, J and Elmas, Z and Wiesenfarth, M and De Gobbi, A and Ratti, A and Poletti, B and Tumani, H and Weishaupt, J and Silani, V and Ticozzi, N and Otto, M and Ludolph, AC and Oeckl, P},
title = {CSF levels of the somatodendritic protein MAP2 are increased in ALS and predict shorter survival.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336208},
pmid = {40537251},
issn = {1468-330X},
abstract = {BACKGROUND: Previous proteomic work has identified the somatodendritic protein MAP2 as a new candidate cerebrospinal fluid (CSF) biomarker for amyotrophic lateral sclerosis (ALS).

METHODS: We measured CSF levels of MAP2 and neurofilament light chain (NFL) in a retrospective cohort of 251 patients with ALS and 108 neurological controls (NCs).

RESULTS: Patients with ALS had a higher median CSF MAP2 level compared with NCs, leading to an area under the curve (AUC) of 0.7080 (p<0.0001). They also had a higher median CSF NFL level (p<0.0001), resulting in an excellent diagnostic performance (AUC=0.9641; p<0.0001). Among patients with ALS, CSF MAP2 correlated with disease progression rate (DPR) (r=0.3099; p<0.0001) and was negatively associated with survival (HR=3.174). CSF NFL also correlated with DPR (r=0.4936; p<0.0001) and was negatively associated with survival (HR=2.759). The association of MAP2 with DPR was independent from NFL (p=0.0037). Stratifying patients based on median levels of both biomarkers resulted in significant differences in median survival times (low NFL/low MAP2, 66 months; high NFL/low MAP2 and vice versa, 35 months; high NFL/high MAP2, 26 months; p<0.0001). MAP2 was also associated with genetic status in patients with ALS, as patients with no mutations in C9ORF72 or in SOD1, as well as C9ORF72-positive ones, had higher median levels compared with NCs (p<0.0001), while patients with SOD1 mutations did not significantly differ from NCs (p>0.9999).

CONCLUSIONS: Our study shows that the somatodendritic protein MAP2 is a promising candidate CSF biomarker for ALS.},
}

@article {pmid40536996,
year = {2025},
author = {Yañez, IM and Torres-Cuevas, I and Corral-Debrinski, M},
title = {Neuroglobin: A promising candidate to treat neurological diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01503},
pmid = {40536996},
issn = {1673-5374},
abstract = {Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide. Altogether, the burden of neurological disorders has increased considerably over the past 30 years because of population aging. Overall, neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow. Autism spectrum disorder, motor neuron disease, encephalopathy, epilepsy, stroke, ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease represent a non-exhaustive list of neurological illnesses. These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system. Among the common features of neurological handicaps, we find protein aggregation, oxidative stress, neuroinflammation, and mitochondrial impairment in the target tissues, e.g., the brain, cerebellum, and spinal cord. The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis, are responsible for their dependence on functional mitochondria for their integrity. Reactive oxygen species, produced along with the respiration process within mitochondria, can lead to oxidative stress, which compromises neuronal survival. Besides having an essential role in energy production and oxidative stress, mitochondria are indispensable for an array of cellular processes, such as amino acid metabolism, iron-sulfur cluster biosynthesis, calcium homeostasis, intrinsic programmed cell death (apoptosis), and intraorganellar signaling. Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases, therapies that are effective to diminish or halt neuronal dysfunction/death are rare. Given the genetic complexity responsible for neurological disorders, the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life. A promising candidate is the neuroglobin, a globin superfamily member of 151 amino acids, which is found at high levels in the brain, the eye, and the cerebellum. The protein, which localizes to mitochondria, is involved in electron transfer, oxygen storage and defence against oxidative stress; hence, possessing neuroprotective properties. This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions, which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.},
}

@article {pmid40536931,
year = {2025},
author = {Li, K and Chen, R and Wang, R and Fan, W and Zhao, N and Yang, Z and Yan, J},
title = {Neuroinflammation in neurodegenerative diseases: Focusing on the mediation of T lymphocytes.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01539},
pmid = {40536931},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system, leading to a decline in patients' cognitive, motor, and emotional abilities. Neuroinflammation plays a significant role in the progression of these diseases. However, there is limited research on therapeutic approaches to specifically target neuroinflammation. The role of T lymphocytes, which are crucial mediators of the adaptive immune response, in neurodegenerative diseases has been increasingly recognized. This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases. The pathogenesis of neurodegenerative diseases is complex, involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons, and T cells are a key component of these processes. One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells, including microglia, astrocytes, B cells, and natural killer cells. Different subsets of CD4+ T cells, such as Th1, Th2, Th17, and regulatory T cells, can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases. Additionally, CD8+ T cells, which can directly regulate immune responses and kill target cells, also play several important roles in neurodegenerative diseases. Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that, while some patients respond positively, others may not respond as well and may even experience adverse effects. Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system, which can lead to undesirable side effects. However, with new insights into the pathophysiology of neurodegenerative diseases, there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.},
}

@article {pmid40536530,
year = {2025},
author = {Pensato, V and Peverelli, S and Tiloca, C and Magri, S and Brusati, A and Pingue, M and Morelli, C and Dalla Bella, E and Manini, A and Tannorella, P and Doretti, A and Mandrioli, J and Terenghi, F and Prelle, A and Riva, N and Verde, F and Eleopra, R and Taroni, F and Lauria Pinter, G and Silani, V and Ticozzi, N and Gellera, C and Ratti, A},
title = {Exploring NEK1 genetic variability in Italian amyotrophic lateral sclerosis patients.},
journal = {Journal of neurology},
volume = {272},
number = {7},
pages = {469},
pmid = {40536530},
issn = {1432-1459},
support = {GR-2016-02364373//Ministero della Salute/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *NIMA-Related Kinase 1/genetics ; Male ; Female ; Italy ; Middle Aged ; Aged ; Adult ; Mutation/genetics ; *Genetic Variation/genetics ; Cohort Studies ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Mutations in NEK1, encoding for a serine/threonine kinase which regulates several biological processes, are associated with amyotrophic lateral sclerosis (ALS).

METHODS: NEK1 was analysed by amplicon deep sequencing in a cohort of 1016 Italian sporadic and familial ALS patients previously screened for C9orf72, SOD1, TARDBP and FUS mutations.

RESULTS: We identified 28 rare NEK1 variants in 29 patients (2.85%) of whom 20/782 were sporadic (2.5%), 6/107 familial (5%) and 3/127 of unknown aetiology (2.3%). Variants were classified as pathogenic (P; n = 1), likely pathogenic (LP; n = 6 in 7 patients) and of unknown significance (VUS; n = 21) according the American College of Medical Genetics and Genomics criteria. Notably, 64% of the identified variants (18/28, including 4 LP and 14 VUS) were novel. Among the 29 patients with rare NEK1 variants, 7 (of whom 5 were familial cases) had additional variants in one of the four main ALS causative genes. Moreover, 23 patients carried the already reported NEK1 p.Arg261His risk variant (VUS) alone or in addition to SOD1 mutations (n = 1) or C9orf72 repeat expansion (n = 2) and to the NEK1 p.Asp128Val variant (n = 1). Genotype-phenotype correlation analysis showed no significant differences in age at onset or survival in NEK1 variant carriers, independently on the variant type. No flail arm phenotype, but atypical features, including sensory symptoms, were present in NEK1 carriers.

CONCLUSION: Our study further expands NEK1 genetic variability by identifying novel rare variants and confirming ALS oligogenic nature since 19.6% of NEK1 patients also carried mutations in one of the four main ALS-associated genes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*NIMA-Related Kinase 1/genetics
Male
Female
Italy
Middle Aged
Aged
Adult
Mutation/genetics
*Genetic Variation/genetics
Cohort Studies
Genetic Predisposition to Disease

@article {pmid40535632,
year = {2025},
author = {Tang, X and Wang, C and Tian, S and Wen, H and Zhang, H},
title = {Acupuncture for neurodegenerative diseases: mechanisms, efficacy, and future research directions.},
journal = {American journal of translational research},
volume = {17},
number = {5},
pages = {3703-3717},
pmid = {40535632},
issn = {1943-8141},
abstract = {In recent years, acupuncture has shown good therapeutic efficacy in treating neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Studies have demonstrated that acupuncture alleviates symptoms primarily by suppressing neuroinflammation, enhancing autophagy, improving synaptic plasticity, and optimizing mitochondrial function. As molecular research advances, the underlying mechanisms of acupuncture in these conditions have become increasingly clear. This review summarizes recent progress in understanding the efficacy and molecular mechanisms of acupuncture in neurodegenerative diseases, providing a theoretical support for its clinical application.},
}

@article {pmid40534726,
year = {2025},
author = {Kissling, WD and Mulder, W and Wang, J and Shi, Y},
title = {Data of vegetation structure metrics retrieved from airborne laser scanning surveys for European demonstration sites.},
journal = {Data in brief},
volume = {60},
number = {},
pages = {111548},
pmid = {40534726},
issn = {2352-3409},
abstract = {This dataset provides a standardized collection of rasterized Light Detection And Ranging (LiDAR) metrics in GeoTIFF format, derived from country-wide airborne laser scanning (ALS) data across seven demonstration sites in five European countries: Mols Bjerge National Park (Denmark), Reserve Naturelle Nationale du Bagnas (France), Oostvaardersplassen (Netherlands), Salisbury Plain (United Kingdom), Knepp Estate (United Kingdom), Monks Wood (United Kingdom), and the island of Comino (Malta). The sites range in areal size from 0.08 km[2] to 54 km[2] and include habitat types such as forests, broadleaf and conifer woodlands, small plantations, dry and wet grasslands, marshes, reedbeds, arable fields, farmland, scrublands and mediterranean garigue. A total of 35 LiDAR metrics were calculated, of which 28 represent vegetation structural attributes. These include vegetation height (seven metrics), vegetation cover (fourteen metrics), and vegetation vertical variability (seven metrics). Additionally, seven metrics describe point density (one metric), eigenvalues (three metrics), and normal vectors (three metrics). The rasterized LiDAR metrics have a spatial resolution of 10 m, with coverage and extent defined by shapefiles corresponding to each demonstration site. The raw ALS point clouds were clipped to the site boundaries and processed with the 'Laserfarm' workflow, a standardized computational workflow that includes modular pipelines for re-tiling, normalization, feature extraction, and rasterization. Laserfarm employs the feature extraction module of the open-source 'Laserchicken' software to compute the LiDAR metrics. The workflow was implemented using the IT services of the Dutch national facility for information and communication technology, SURF. The clipped LiDAR point clouds are available through a public repository, except for the LiDAR point clouds from Comino, Malta, which are not publicly available. The 35 rasterized LiDAR metrics (GeoTIFF files, 10 m resolution) from all sites, including Comino, as well as the corresponding site boundary shapefiles (geospatial vector format), are provided in a Zenodo repository. Additionally, the Jupyter Notebooks with Python code for executing the Laserfarm workflow are available to facilitate reproducibility and further computational applications. Users should note that the rasterized LiDAR metrics may contain zero or NA values, particularly over water surfaces, with the pulse penetration ratio metric potentially indicating false high vegetation cover over water. Users may reclassify or mask areas with zero values accordingly. Some pixels exhibit abnormal vegetation height values, which can be filtered before analysis. Certain striping patterns, likely resulting from overlapping flight lines and increased point density, are present in some metrics, though their overall impact appears minimal. This dataset enables diverse applications, including canopy height measurements, mapping of hedgerows, treelines, and forest patches, as well as characterizing vegetation density, vertical stratification, and habitat openness. It supports landscape-scale habitat analysis and contributes to the standardization of vegetation metrics from ALS data for site-specific ecological monitoring (e.g., Natura 2000). Moreover, the dataset demonstrates the automated execution of LiDAR data processing workflows, which is crucial for establishing a transnational and multi-site biodiversity and ecosystem observation network.},
}

@article {pmid40534528,
year = {2025},
author = {Ertural, B and Çiçek, BN and Kurnaz, IA},
title = {RNA Therapeutics: Focus on Antisense Oligonucleotides in the Nervous System.},
journal = {Biomolecules & therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.4062/biomolther.2025.022},
pmid = {40534528},
issn = {1976-9148},
abstract = {RNA therapeutics present a disruptive technology that has changed the drug discovery and manufacturing landscape, which established itself more prominently upon the recent COVID-19 pandemic. RNA therapeutics encompass diverse molecules like antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), RNA aptamers, and messenger RNAs (mRNAs), which can function through different mechanisms. RNA therapeutics are witnessing expanding applications across a range of diseases, notably in the treatment of neurological disorders. For instance, ASO therapies like nusinersen for spinal muscular atrophy and eteplirsen for Duchenne muscular dystrophy exemplify successful RNA therapeutic strategies. Emerging ASO treatments for Huntington's disease and amyotrophic lateral sclerosis are also promising, with ongoing clinical trials demonstrating significant reductions in disease-associated proteins. Still, delivery of these molecules remains a pivotal challenge in RNA therapeutics, especially for ASOs in penetrating the blood-brain barrier to target neurological disorders effectively. Nanoparticlebased formulations have emerged as leading strategies to enhance RNA stability, reduce immunogenicity, and improve cellular uptake. Despite these advances, significant hurdles remain, including optimizing pharmacokinetics, minimizing off-target effects, and ensuring sustained therapeutic efficacy. Regulatory frameworks are evolving to accommodate the unique challenges of RNAbased therapies, including ASOs with efforts underway to establish comprehensive guidelines for RNA therapeutics, yet there are also sustainable manufacturing issues that need to be considered for long-term feasibility. By addressing these challenges, RNA therapeutics hold immense potential to revolutionize treatment paradigms for neurological disorders. Looking forward, the future of RNA therapeutics in neurology appears promising but requires continued interdisciplinary collaboration and technological innovation.},
}

@article {pmid40533880,
year = {2025},
author = {Liu, W and Wang, S and Zhang, T and Zhu, H and Chang, N and Zhang, L and Hu, Z},
title = {A Review of Preparation of Low-Carbon Cementitious Materials from Chemically Activated Red Mud: Synergy, Hydration Mechanism, Rheological Properties and Applications.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.5c01088},
pmid = {40533880},
issn = {1520-5827},
abstract = {Red mud, a byproduct of the alumina refining process, is generated at a rate of 1-2.5 tonnes per tonne of alumina produced. In 2022, China's alumina production totaled 77.475 million tonnes, contributing over 4 billion tonnes of accumulated red mud, which is the third-largest industrial solid waste in the country. Red mud's high alkalinity and presence of toxic elements pose environmental challenges, particularly in terms of disposal. This review provides a comprehensive examination of red mud-based cementitious materials, focusing on their preparation, properties, and environmental impact. By combining red mud with high-calcium and silica-aluminum solid wastes and enhancing its reactivity through mechanical grinding or thermal activation, red mud's cementitious activity can be significantly improved. Optimized compositions, with a Ca/Si ratio of 2.05 and Al/S ratio of 0.70, have achieved compressive strengths of up to 63.9 MPa at 28 day. Durability studies highlight the material's resistance to chloride ion penetration and sulfate attack, with reduced permeability enhancing long-term performance. Additionally, environmental assessments confirm that stabilization and solidification techniques effectively mitigate heavy metal leaching, ensuring compliance with EPA standards. Despite these advancements, challenges remain in optimizing red mud activation processes, improving rheological properties, and reducing production costs. Future research should focus on refining activation methods, enhancing hydration mechanisms, and developing scalable industrial applications. By addressing these gaps, red mud-based cementitious materials can become a sustainable solution for eco-friendly construction, supporting global efforts to repurpose industrial byproducts into low-carbon, durable building materials.},
}

@article {pmid40531663,
year = {2025},
author = {Ralston, CY and Gupta, S and Del Mundo, JT and Soe, AC and Russell, B and Rad, B and Tyler, J and Paul, S and Kahan, DN and Kristensen, LG and Subramanian, S and Kidd, S and Burnett, K and Sankaran, B and Classen, S and Progozhin, D and Taylor, JR and Dickert, JM and Royal, KB and Rozales, A and Ortega, SL and Allaire, M and Nix, JC and Hura, GL and Holton, JM and Hammel, M and Adams, PD},
title = {ALS-ENABLE: creating synergy and opportunity at the Advanced Light Source synchrotron structural biology beamlines.},
journal = {Journal of synchrotron radiation},
volume = {},
number = {},
pages = {},
doi = {10.1107/S1600577525004205},
pmid = {40531663},
issn = {1600-5775},
support = {GM124169//National Institutes of Health, National Institute of General Medical Sciences/ ; GM126218//National Institutes of Health, National Institute of General Medical Sciences/ ; DE-AC02-05CH1123//US Department of Energy, Office of Science/ ; },
abstract = {ALS-ENABLE is an integrated NIH P30 resource at the Advanced Light Source synchrotron at Lawrence Berkeley National Laboratory in Berkeley, California, USA. The resource provides a single portal to the combined mature structural biology technologies of macromolecular crystallography, small-angle X-ray scattering and X-ray footprinting mass spectrometry, and includes beamlines 2.0.1, 3.3.1, 4.2.2, 5.0.1, 5.0.2, 5.0.3, 8.2.1, 8.2.2, 8.3.1 and 12.3.1. This paper describes the organizational structure and the technologies of ALS-ENABLE. A case study showcasing the main technologies of the resource applied to the characterization of the SpyCatcher-SpyTag protein system is presented.},
}

@article {pmid40531650,
year = {2025},
author = {Zeng, W and Peng, Z and Chen, Y and Du, S},
title = {Multi-Scale Temporal Analysis with a Dual-Branch Attention Network for Interpretable Gait-Based Classification of Neurodegenerative Diseases.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3580944},
pmid = {40531650},
issn = {2168-2208},
abstract = {The accurate diagnosis of neurodegenerative diseases (NDDs), such as Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Parkinson's Disease (PD), remains a clinical challenge due to the complexity and subtlety of gait abnormalities. This paper proposes the Dual-Branch Attention-Enhanced Residual Network (DAERN), a novel deep learning architecture that integrates Dilated Causal Convolutions (DCCBlock) for local gait pattern extraction and Multi-Head Self-Attention (MHSA) for long-range dependency modeling. A CrossAttention Fusion module enhances feature integration, while SHapley Additive exPlanations (SHAP) and Integrated Gradients (IG) improve interpretability, providing clinically relevant insights into gait-based NDD classification. Uniform Manifold Approximation and Projection (UMAP) visualizations reveal well-separated clusters corresponding to distinct NDDs categories, demonstrating the model's ability to capture discriminative features. Comprehensive ablation studies validate the contributions of model components and preprocessing strategies, highlighting the significance of each in achieving state-of-the-art classification performance. Experimental evaluations on the Gait in Neurodegenerative Disease (GaitNDD) dataset demonstrate that DAERN achieves an accuracy of 99.64%, an F1-score of 99.65%, and an AUC of 0.9997, significantly outperforming conventional deep learning and machine learning baselines. These findings suggest that DAERN could be a valuable and interpretable tool for clinical gait assessment, aiding in early-stage monitoring and automated screening of NDDs, with potential applications in real-time wearable sensor-based gait analysis.},
}

@article {pmid40531486,
year = {2025},
author = {Berry, JD and Maragakis, N and Paganoni, S},
title = {CNM-Au8 in Amyotrophic Lateral Sclerosis-Reply.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.5825},
pmid = {40531486},
issn = {1538-3598},
}

@article {pmid40531483,
year = {2025},
author = {Endo, M and Kami, M},
title = {CNM-Au8 in Amyotrophic Lateral Sclerosis.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.5822},
pmid = {40531483},
issn = {1538-3598},
}

@article {pmid40451305,
year = {2025},
author = {Cho, SW and Sontam, T and Chen, A and Limmer, EE and Tolkachjov, SN},
title = {Response to Thang et al's "Response to Cho et al's 'GLP-1 receptor agonist use is associated with increased rates of acne vulgaris diagnosis in non-diabetic obese women but not men: A retrospective cohort study'".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.04.085},
pmid = {40451305},
issn = {1097-6787},
}

@article {pmid40530462,
year = {2025},
author = {Raymond, J and Oskarsson, B and Larson, T and Mohidul, S and Horton, DK and Mehta, P},
title = {Place of Death in Patients with Motor Neuron Disease and the Association with Comorbidities During the Coronavirus Disease 2019 Pandemic: A Population-Based Analysis.},
journal = {Journal of palliative care},
volume = {},
number = {},
pages = {8258597251349627},
doi = {10.1177/08258597251349627},
pmid = {40530462},
issn = {2369-5293},
abstract = {ObjectiveMotor neuron disease (MND) is a progressive neurological disorder with no known cure that damages motor neurons. The purpose of this analysis is to examine the place of death for MND patients in the United States during the coronavirus disease 2019 (COVID-19) pandemic and to investigate the extent of specific comorbidities.MethodsWe obtained death certificate and associated comorbidities data for all U.S. MND deaths from 2018 to 2021 and conducted a population-based cross-sectional analysis of the deaths pre-COVID-19 (2018-2019) and during COVID-19 (2020-2021). We hypothesized that place of death and comorbidities associated with place of death for MND patients in the United States were altered during the COVID-19 pandemic in comparison to the 2 years period before the pandemic.ResultsWe analyzed 30 066 MND deaths (14 562 pre-COVID-19 and 15 504 during COVID-19) aged 20 years and older. During COVID-19, MND deaths at home increased (54.4% vs 45.5% pre-COVID). Hispanic individuals had an increased likelihood of dying at home compared to a nursing home or hospice (OR = 1.57, 95%CI: 1.22-2.02), but a decreased likelihood compared to a hospital (OR = 0.61, 95% CI: 0.51-0.72). Among the top comorbidities listed, there was a 27.8% increase in diabetes mellitus and a 20.2% increase in essential hypertension during COVID-19. During COVID-19, diabetes mellitus was more commonly reported as a comorbidity for deaths occurring in hospitals (OR = 1.40, 95%CI: 1.03-1.89) or at home (OR = 1.26, 95%CI: 1.03-1.55), while essential hypertension was more commonly reported with deaths at home (OR = 1.17, 95%CI: 1.01-1.36).ConclusionOur analysis showed an increase in at-home MND deaths as well as certain comorbidities during the COVID-19 pandemic, suggesting MND patients had a higher likelihood of death from non-COVID-19 comorbidities.},
}

@article {pmid40529392,
year = {2025},
author = {Pfaff, AL and Kõks, S},
title = {Retrotransposition-competent L1s are increased in the genomes of individuals with amyotrophic lateral sclerosis.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {250},
number = {},
pages = {10575},
pmid = {40529392},
issn = {1535-3699},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Long Interspersed Nucleotide Elements/genetics ; *Genome, Human ; Female ; Male ; Middle Aged ; Genetic Predisposition to Disease ; Retroelements ; },
abstract = {An individual's genetics contributes to their risk of developing amyotrophic lateral sclerosis (ALS); however, there is still a large proportion of the heritability of ALS to be understood. Part of this missing heritability may lie in complex variants, such as the long interspersed element 1 (L1) retrotransposon, which have yet to be evaluated. The majority of L1 insertions in the human genome are no longer able to retrotranspose, but to date 279 retrotransposition-competent (RC) L1s have been reported. Many RC-L1s are polymorphic for their presence/absence; therefore, each individual will have a different number and complement of RC-L1s. These elements have been hypothesized to be involved in disease processes by multiple mechanisms such as somatic mutation by retrotransposition, the triggering of neuroinflammation and DNA damage. We hypothesize that L1s may influence disease development either through their effects on endogenous genes or through the properties that enable them to retrotranspose. Whole genome sequencing data from the New York Genome Center ALS consortium were used to characterize L1 variation identifying 2,803 polymorphic L1 elements and association analysis was performed in European individuals (ALS/ALS with other neurological disorder (ALSND) n = 2,653, controls n = 320). There were no individual L1 elements associated with disease, but we did identify a significant increase in the number of RC-L1s in ALS/ALSND genomes (p = 0.01) and the presence of ≥46 RC-L1s showed the most significant association (OR = 1.09 (1.02-1.16), p = 0.01) with disease. Analysis of individual L1s and their association with age at onset and survival identified one L1 whose presence was significantly associated with a lower age at onset (52.7 years) compared to homozygous absent individuals (59.2 years) (padj = 0.009). Our study has identified novel genetic factors for both disease risk and age at onset in ALS providing further evidence for the role of L1 retrotransposons in neurodegenerative diseases.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Long Interspersed Nucleotide Elements/genetics
*Genome, Human
Female
Male
Middle Aged
Genetic Predisposition to Disease
Retroelements

@article {pmid40528459,
year = {2025},
author = {Yang, M and Zhang, A and Chen, M and Cao, J},
title = {Advances in Circulating Biomarkers for Neurodegenerative Diseases, Traumatic Brain Injuries, and Central Nervous System Tumors.},
journal = {Annals of laboratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.3343/alm.2024.0611},
pmid = {40528459},
issn = {2234-3814},
abstract = {Neurological disorders, including neurodegenerative diseases, traumatic brain injuries (TBI), and central nervous system (CNS) tumors, are complex conditions that significantly impact patients globally. Timely diagnosis and monitoring are critical for improving outcomes, driving the need for reliable biomarkers. Specifically, biomarkers detectable in cerebrospinal fluid (CSF) and blood offer important insights into disease presence and progression. This review explores the evolution of circulating blood biomarkers for neurodegenerative diseases, TBI, and CNS tumors, highlighting advanced detection technologies from enzyme-linked immunosorbent assays (ELISAs) to electrochemiluminescence (ECL) assays, single-molecule arrays (Simoa), and mass spectrometry. Advanced technologies with enhanced sensitivity and specificity, particularly in detecting low-abundance analytes, facilitate the investigation of CSF biomarkers for various neurological disorders. We also describe the progress in blood-based biomarkers for , emerging as less invasive alternatives to CSF sampling. Clinically, the implementation of Alzheimer's disease (AD) blood biomarkers Aβ42/Aβ40 ratio and Apolipoprotein E isoform-specific peptide can aid the diagnosis, while p-tau181 and p-tau217 differentiates AD dementia from non-AD neurodegenerative diseases. Blood glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are used in ruling out mild TBI. Despite these innovations, challenges remain, including assay standardization, sensitivity/specificity trade-offs, and the requirement for longitudinal studies to understand biomarker utility over time. Future research should focus on addressing these challenges to fully realize the potential of blood-based biomarkers in neurological disorder diagnostics and patient care.},
}

@article {pmid40528238,
year = {2025},
author = {Huang, X and Zhang, Z and Chen, L and Yang, S and Liu, X and Bi, J and Zhang, Z and Wang, Y and Wei, N and Zhu, W and Chen, N and Hua, L and Li, Y and Wang, Y and Jing, J and Pan, H},
title = {Diagnostic value of the motor band sign in amyotrophic lateral sclerosis: a 7T magnetic resonance imaging study.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {30},
pmid = {40528238},
issn = {2047-9158},
}

@article {pmid40527647,
year = {2025},
author = {Thijs, Z and Calzada, A and Sosa, M and Dumican, M},
title = {The Association Between Bilingualism and Voice Quality in Spanish-English Bilingual Speakers: A Systematic Review.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jvoice.2025.05.027},
pmid = {40527647},
issn = {1873-4588},
abstract = {OBJECTIVE/HYPOTHESIS: The vast majority of the global population speaks more than one language. In the United States, Spanish-English bilingual speakers are the largest bilingual group. Yet, the potential effect of being bilingual, specifically a Spanish-English speaker, on voice quality is poorly understood. The current study consequently set out to systematically review the literature on the association between being a Spanish-English bilingual speaker and voice quality.

STUDY DESIGN: Systematic review.

METHODS: A systematic review of association was conducted using Moola et al's guidelines. A search string was developed and run in May 2024 across three databases: MEDLINE (via PubMed), CINAHL via EBSCOhost, and Scopus. After duplicate removal, title, and abstract screening, full-text screening was performed, and peer-reviewed articles considering voice quality measures in Spanish-English bilingual speakers were included. Data were extracted and presented in table format, and the quality of the articles was assessed using the Checklist for Analytical Cross-Sectional Studies.

RESULTS: In total, 685 records were retrieved, with 485 remaining after duplicate removal. After title and abstract screening, 25 full texts were screened, including 8 articles in the review. Five studies included acoustic measures describing voice quality, with only three including auditory-perceptual analysis. The most commonly considered vocal trait in Spanish-English bilinguals was vocal fry, with the included studies pointing to increased vocal fry use when speaking English.

CONCLUSIONS: Only a few articles discuss potential vocal changes in Spanish-English bilinguals. Further research is needed to elucidate any potential vocal changes related to being a bilingual speaker, as the current small number of studies and mixed findings make drawing conclusions difficult. More standardization across voice and language assessment could be beneficial.},
}

@article {pmid40527529,
year = {2025},
author = {Cassidy-Seyoum, SA and Adhikari, B and Chheng, K and Chanpheakdey, P and Meershoek, A and Hsiang, MS and von Seidlein, L and Tripura, R and Ley, B and Price, RN and Dysoley, L and Thriemer, K and Engel, N},
title = {Acceptability and feasibility of glucose-6-phosphate dehydrogenase (G6PD) testing using SD Biosensor by village malaria workers in Cambodia: a qualitative study.},
journal = {BMJ global health},
volume = {10},
number = {6},
pages = {},
doi = {10.1136/bmjgh-2025-019615},
pmid = {40527529},
issn = {2059-7908},
mesh = {Humans ; Cambodia ; Qualitative Research ; Feasibility Studies ; *Glucosephosphate Dehydrogenase/blood/analysis ; Female ; *Community Health Workers ; *Biosensing Techniques/methods ; Focus Groups ; Male ; *Glucosephosphate Dehydrogenase Deficiency/diagnosis ; *Patient Acceptance of Health Care/statistics & numerical data ; *Malaria, Vivax/drug therapy ; Adult ; Interviews as Topic ; Point-of-Care Testing ; Middle Aged ; Malaria ; Primaquine/therapeutic use ; },
abstract = {INTRODUCTION: Plasmodium vivax is the predominant cause of malaria in the Greater Mekong Subregion. To ensure safe treatment with primaquine, point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing was rolled out in Cambodia at the health facility level, although most malaria patients are diagnosed in the community. The current study aims to explore the acceptability and feasibility of implementing community-level G6PD testing in Cambodia.

METHODS: Semistructured interviews and focus group discussions (FGD) were conducted. Across eight study sites in three provinces, 142 respondents, including policymakers, programme officers, healthcare providers and patients, participated in 67 interviews and 19 FGDs in 2022 and 2023. Data were analysed thematically using an adapted framework derived from Bowen et al's feasibility framework and Sekhon et al's acceptability framework.

RESULTS: All stakeholders attributed value to the intervention. Acknowledging an intervention's different values can help discern policy implications for an intervention's successful implementation. Building and maintaining confidence in the device, end users, infrastructure and health systems were found to be key elements of acceptability. In general, health centre workers and village malaria workers (VMWs) had confidence that VMWs could conduct the test and administer treatment given appropriate initial training, monthly refresher training and the test's repeated use. More is required to build policymakers' confidence, while some implementation challenges, including the test's regulatory approval, stability above 30°C and cost, need to be overcome.

CONCLUSION: Implementation of G6PD testing at the community level in Cambodia is an acceptable and potentially feasible option but requires addressing implementation challenges and building and maintaining confidence among stakeholders.},
}

Humans
Cambodia
Qualitative Research
Feasibility Studies
*Glucosephosphate Dehydrogenase/blood/analysis
Female
*Community Health Workers
*Biosensing Techniques/methods
Focus Groups
Male
*Glucosephosphate Dehydrogenase Deficiency/diagnosis
*Patient Acceptance of Health Care/statistics & numerical data
*Malaria, Vivax/drug therapy
Adult
Interviews as Topic
Point-of-Care Testing
Middle Aged
Malaria
Primaquine/therapeutic use

@article {pmid40527446,
year = {2025},
author = {Zhang, Z and Guo, X and Liu, Y and Ke, P and Meng, Y and Gu, J and Hu, L and Yuan, Z and Duan, R and Luo, J and Xiao, F},
title = {PKM2 Alleviates Mitochondrial Oxidative Stress and Neuronal Apoptosis through Metabolic and Non-metabolic Pathways to Protect SOD1[G93A] Mice.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.06.012},
pmid = {40527446},
issn = {1873-4596},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron death. Dysregulated energy metabolism is implicated in ALS pathogenesis, yet the role of pyruvate kinase M2 (PKM2), a key glycolytic enzyme, remains elusive. Here, we demonstrated that PKM2 expression was upregulated in the spinal neurons of SOD1[G93A] mice during early stages of disease. Pharmacological inhibition of PKM2 with compound 3k (C3k) shortened survival times, exacerbated motor deficits, and amplified mitochondrial oxidative stress and neuronal apoptosis in mice with ALS. Mechanistically, PKM2 mitigated mitochondrial dysfunction via its enzymatic activity, promoting lactate metabolism to reduce reactive oxygen species (ROS) accumulation. Concurrently, nuclear PKM2 directly bound to the Nrf2 promoter, enhancing Nrf2 transcription to strengthen antioxidant defenses. Our findings unveil PKM2 as a multifunctional neuroprotectant in ALS, offering novel therapeutic directions through metabolic and transcriptional modulation.},
}

@article {pmid40525139,
year = {2025},
author = {Abou Izzeddine, N and Ahmad, K and Bacha, C and Jabbour, M and Najjar, M and Salhab, S and Ghadieh, HE and Kanaan, A and Azar, S and Khattar, ZA and Harb, F},
title = {The microbial guardians: Unveiling the role of gut microbiota in shaping neurodegenerative disease.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {17-37},
pmid = {40525139},
issn = {2667-2421},
abstract = {The gut microbiota, a complex community of microorganisms residing in the digestive tract, plays a pivotal role in human health. Recent studies have highlighted its significant impact on neurodegenerative diseases, conditions that pose profound challenges to affected individuals and society at large. This review explores the intricate relationship between gut microbiota and the progression of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. We delve into the dynamic ecosystem of gut microbiota, examining factors influencing its composition and the bidirectional communication established via the gut-brain axis. Emerging evidence suggests that gut microbiota can modulate neurodegenerative disease progression through mechanisms including inflammatory responses, production of neuroactive substances, and regulation of neurotransmitters. Furthermore, we discuss the potential therapeutic implications of targeting gut microbiota with probiotics, prebiotics, and postbiotics. While promising, these interventions face challenges and limitations that must be addressed through ongoing research. Understanding the role of gut microbiota in neurodegenerative diseases is crucial for developing innovative therapeutic strategies and improving patient outcomes.},
}

@article {pmid40524150,
year = {2025},
author = {Cozzi, M and Tedesco, B and Ferrari, V and Chierichetti, M and Pramaggiore, P and Cornaggia, L and Magdalena, R and Brodnanova, M and Mohamed, A and Milioto, C and Piccolella, M and Galbiati, M and Rusmini, P and Crippa, V and Gellera, C and Magri, S and Taroni, F and Cristofani, R and Poletti, A},
title = {One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {287},
pmid = {40524150},
issn = {1478-811X},
support = {Travelling Fellowship n. JCSTF2205742//Company of Biologists/ ; Scientific Exchange Grant n. 9643//European Molecular Biology Organization/ ; 2025 grant//CureHSPB8,USA/ ; piano di sviluppo della ricerca (PSR) UNIMI//Università degli Studi di Milano/ ; piano di sviluppo della ricerca (PSR) UNIMI//Università degli Studi di Milano/ ; piano di sviluppo della ricerca (PSR) UNIMI//Università degli Studi di Milano/ ; R21AR080407/AR/NIAMS NIH HHS/United States ; R21AR080407/AR/NIAMS NIH HHS/United States ; 2020 grant//Kennedy's Disease Association/ ; 2018 grant//Kennedy's Disease Association/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; PRIN- Progetti di ricerca di interesse nazionale - bando 2022, PNRR finanziato dall'Unione europea- Next Generation EU, componente M4C2, investimento 1.1 n. P20225R4Y5//Ministero dell'Università e della Ricerca/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022EFLFL8//Ministero dell'Università e della Ricerca/ ; 739510//European Network for Rare Neurological Disorders/ ; 739510//European Network for Rare Neurological Disorders/ ; 739510//European Network for Rare Neurological Disorders/ ; RF-2018-12367768//Ministero della Salute/ ; CP 20/2018 (Care4NeuroRare)//Fondazione Regionale per la Ricerca Biomedica/ ; . 2021-1544//Fondazione Cariplo/ ; 23236//AFM-Téléthon/ ; },
abstract = {UNLABELLED: Kinesin family member 5 A (KIF5A) is a neuron-specific molecular motor involved in anterograde transport. KIF5A mediates a wide range of trafficking processes that are only partially shared with the other members of the KIF5 family. Since 2002, several disease-causing mutations have been found in the KIF5A gene and a link between the specific domain in the encoded protein affected by mutations and the associated phenotype has become evident. Point mutations targeting KIF5A motor and stalk domains, that are expected to impair KIF5A motility, mainly associate with spastic paraplegia type 10 (SPG10) and axonal Charcot-Marie-Tooth (CMT) disease. Oppositely, translational frameshifts causing the elongation of KIF5A tail enhance KIF5A migration towards cell periphery, induce kinesin aggregation, and are linked to amyotrophic lateral sclerosis (ALS) or neonatal intractable myoclonus (NEIMY). This review correlates KIF5A structure and roles in neuronal trafficking with its involvement in the above-mentioned neurodegenerative and neurodevelopmental conditions.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02277-x.},
}

@article {pmid40524084,
year = {2025},
author = {Ticozzi, N and Padovani, A and Filosto, M and , },
title = {ALS global day 2025: research and clinical advances.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40524084},
issn = {1590-3478},
}

@article {pmid40524081,
year = {2025},
author = {Uygun, Ö and Unkun, R and Asan, F and Gündüz, A},
title = {Facial onset sensory-motor neuronopathy: diagnostic challenges and insights from a case report.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40524081},
issn = {1590-3478},
}

@article {pmid40523602,
year = {2025},
author = {Horikawa, I and Yamada, L and Harris, BT and Harris, CC},
title = {Δ133p53α-mediated inhibition of astrocyte senescence and neurotoxicity as a possible therapeutic approach for neurodegenerative diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.06.031},
pmid = {40523602},
issn = {1873-7544},
abstract = {Non-neuronal glial cells in the brain, such as astrocytes, play essential roles in maintaining the functional integrity of neuronal cells. A growing body of evidence suggests that cellular senescence of astrocytes, characterized by loss of proliferative potential and secretion of neurotoxic cytokines, makes significant contribution to neurotoxicity in Alzheimer's disease and a wide range of other neurodegenerative diseases. This review discusses the beneficial effects of Δ133p53α, a natural p53 protein isoform that inhibits p53-mediated cellular senescence, thereby protecting astrocytes from senescence, highlights its potential as a therapeutic target, and underscores the need for continued research in this area. Both in senescent human astrocytes in culture, whether induced by replicative exhaustion, irradiation or exposure to amyloid-β, and in brain tissues with increased senescent astrocytes from patients with Alzheimer's disease, the expression levels of endogenous Δ133p53α protein were consistently and significantly reduced. The lentiviral vector-driven expression of Δ133p53α protected cultured human astrocytes from cellular senescence and neurotoxic secretory phenotype, leading to their cellular reprogramming to a neuroprotective state associated with neurotrophic growth factors. We thus propose that Δ133p53α is worth testing as a therapeutic target that can be enhanced in a wide range of neurodegenerative diseases with accumulated senescent astrocytes, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and chronic traumatic encephalopathy due to traumatic brain injury. We hypothesize that a Δ133p53α-mediated cellular reprogramming approach and a senolytic or senomorphic approach, both targeting non-neuronal cells, may be complementary with each other, and may cooperate with neuron-protecting or amyloid-β-targeting therapies currently in use.},
}

@article {pmid40523537,
year = {2025},
author = {Risby-Jones, G and Marallag, J and Jagaraj, CJ and Atkin, JD and Walker, AK and Woodruff, TM and Lee, JD and Fung, JN},
title = {IL-6 trans-signalling is elevated in ALS models and drives TDP-43 induced inflammatory responses in microglia.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.06.021},
pmid = {40523537},
issn = {1090-2139},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by chronic inflammation in both the central nervous system (CNS) and peripheral tissues. Interleukin-6 (IL-6) has been implicated in ALS pathology; however, IL-6 exhibits both anti-inflammatory and pro-inflammatory functions. Notably, IL-6 trans-signalling possesses pro-inflammatory properties and is emerging as a key contributor to neuroinflammation during neurodegeneration. In this study, we aimed to characterize the expression of the IL-6 trans-signalling pathway in ALS mouse models and investigate its role in ALS protein aggregate-mediated inflammation in microglia and peripheral immune cells. Our results revealed that the protein expression level of a key IL-6 trans-signalling component, soluble IL-6 receptor (sIL-6R), was significantly increased in the spinal cord and tibialis anterior (TA) muscles of both SOD1[G93A] and rNLS8 TDP-43 transgenic mice. Additionally, using mouse primary microglia, human monocyte-derived microglia-like cells (MDMi), and blood peripheral immune cells, we demonstrated that recombinant TDP-43 protein elicits robust pro-inflammatory cytokine responses, including IL-6, TNF-α, IL-23, and MCP-1. These responses were attenuated when treated with a specific IL-6 trans-signalling inhibitor, sgp130Fc. Our findings suggest that the TDP-43-induced inflammatory response is, in part, IL-6 trans-signalling-dependent and highlight the role of IL-6 trans-signalling as a potential driver of chronic inflammation contributing to ALS pathology. These results support IL-6 trans-signalling as a promising therapeutic target for mitigating inflammation and slowing disease progression. Future research should explore the broader implications of modulating IL-6 trans-signalling in ALS.},
}

@article {pmid40522761,
year = {2026},
author = {Fan, T and Peng, J and Liang, H and Chen, W and Wang, J and Xu, R},
title = {Potential common pathogenesis of several neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {21},
number = {3},
pages = {972-988},
doi = {10.4103/NRR.NRR-D-24-01054},
pmid = {40522761},
issn = {1673-5374},
abstract = {With the gradual advancement of research methods and technologies, various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases. However, current descriptions of these biological processes do not fully explain the onset, progression, and development of these conditions. Therefore, exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research. This review summarizes the potential common pathogeneses of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal lobar dementia, and Lewy body disease. Research findings have indicated that several common biological processes, including aging, genetic factors, progressive neuronal dysfunction, neuronal death and apoptosis, protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis, are involved in the pathogenesis of these six neurodegenerative diseases. Based on current information derived from diverse areas of research, these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases. Furthermore, promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed. Hence, these potential common biological processes may represent only very small, limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases. In clinical treatment, interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases. Therefore, future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks, rather than isolating individual biological processes. Based on this, therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions, as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.},
}

@article {pmid40521002,
year = {2025},
author = {Wei, Y and Rhee, H and Najafi, H and Blair, S and Kim, NC and Kim, WJ},
title = {Glial subtype-specific modulation of disease pathogenesis in Drosophila models of ALS.},
journal = {Genes & diseases},
volume = {12},
number = {5},
pages = {101631},
pmid = {40521002},
issn = {2352-3042},
}

@article {pmid40520109,
year = {2025},
author = {Evangelista, BA and Ragusa, JV and Pellegrino, K and Wu, Y and Quiroga-Barber, IY and Cahalan, SR and Arooji, OK and Madren, JA and Schroeter, S and Cozzarin, J and Xie, L and Chen, X and White, KK and Ezzell, JA and Iannone, MA and Cohen, S and Phanstiel, DH and Meeker, RB and Cohen, TJ},
title = {ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation.},
journal = {iScience},
volume = {28},
number = {6},
pages = {112648},
pmid = {40520109},
issn = {2589-0042},
abstract = {Amyotrophic lateral sclerosis (ALS) is the most common and fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, transactive response DNA binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 aggregates elicit immune responses remains underexplored. In this study, we demonstrate that TDP-43 aggregates are internalized by antigen-presenting cell populations, cause vesicle rupture, and drive innate and adaptive immune cell activation by way of antigen presentation. Using a multiplex imaging platform, we observed enrichment of activated microglia/macrophages in ALS white matter that correlated with phosphorylated TDP-43 accumulation, CD8 T cell infiltration, and major histocompatibility complex expression. Taken together, this study sheds light on a novel cellular response to TDP-43 aggregates through an immunological lens.},
}

@article {pmid40519505,
year = {2025},
author = {Funo, K and Fukutake, T and Takeuchi, R and Uzawa, Y},
title = {Importance of Individualized Pressure Settings in Mechanical Insufflation-Exsufflation for Lung Volume Recruitment: A Case Report.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e84211},
pmid = {40519505},
issn = {2168-8184},
abstract = {Lung volume recruitment (LVR) has been proposed as a treatment to maintain respiratory health in patients with neuromuscular diseases who frequently develop restrictive ventilatory impairment due to muscle weakness. LVR applies noninvasive mechanical pressure techniques to maintain and improve pulmonary and chest wall compliance and to preserve vital capacity. Various methods of LVR have been developed, which can be classified into two types: the stacked-breath method and the single-breath method. Mechanical insufflation-exsufflation (MI-E) is one approach categorized under the single-breath method. Although the clinical use of pressure settings in MI-E varies, inspiratory pressure levels around 40 cmH2O are sometimes applied in practice. However, such settings may result in patient discomfort and raise safety concerns. Given the limited clinical guidance available, it may be more appropriate to determine individualized settings based on each patient's impairment level, pulmonary mechanics, and tolerance. This case report describes such an approach to LVR using the single-breath method with MI-E in a patient with amyotrophic lateral sclerosis (ALS). To determine the optimal inspiratory pressure, three parameters were assessed at each pressure level: expiratory volume, subjective perception of lung expansion, and immediate subjective effects following inspiration. As the patient reported discomfort at 30 cmH2O, the final inspiratory pressure was set at 25 cmH2O. This level of inspiratory assistance led to improvements in vocal loudness and alleviated breathlessness during speech. These positive effects contributed to the patient's acceptance of the intervention and its continued use after discharge to home care. This case highlights the importance of tailoring LVR settings to optimize effectiveness, patient comfort, and safety, based on pulmonary mechanics, bedside volume assessment, and patient-reported respiratory status.},
}

@article {pmid40518845,
year = {2025},
author = {Erdal, Y and Mahmutoglu, AS and Yavuz, N and Mahmutoglu, O and Emre, U},
title = {Assessment of cervical skeletal muscle index in early and late phases of amyotrophic lateral sclerosis.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/01616412.2025.2520010},
pmid = {40518845},
issn = {1743-1328},
abstract = {OBJECTIVES: The diagnosis of Amyotrophic Lateral Sclerosis (ALS) can be challenging when clinical and electrophysiological findings are insufficient. We aimed to investigate the potential role of cervical Skeletal Muscle Index (SMI), as a supportive diagnostic marker in ALS, particularly in relation to disease duration.

METHODS: A total of 22 ALS patients and 25 age- and sex-matched controls were retrospectively included. The cross-sectional area (CSA) of cervical muscles was measured on axial T1-weighted magnetic resonance imaging (MRI) at the C3 vertebra level. SMI was calculated by normalizing the total CSA to patient height (mm[2]/m[2]). ALS patients were stratified based on the timing of MRI: within six months of symptom onset and after six months.

RESULTS: There were no significant differences in age, sex, BMI, or total muscle volume between patients and controls. Although mean SMI was slightly lower in ALS patients (p = 0.177), this difference was not statistically significant. Among ALS patients, those who underwent MRI more than six months after symptom onset had significantly lower SMI values compared to both those who underwent MRI within six months and controls (respectively, p = 0.014, p = 0.018). No significant SMI difference was observed between ALS patients who underwent MRI within six months and controls (p = 0.626).

CONCLUSION: Cervical SMI measurements at the C3 vertebral level may support ALS diagnosis, particularly in patients with longer disease duration. SMI may also provide insight into early muscle loss due to denervation.},
}

@article {pmid40518671,
year = {2025},
author = {Del Val, G and Gauye, F and Audrain, M and Menant, S and Ratnam, M and Chevalier, E and Ollier, R and Bhatia, D and Seredenina, T and Afroz, T and Pfeifer, A and Kosco-Vilbois, M and Nevoltris, D},
title = {A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2025.06.026},
pmid = {40518671},
issn = {1525-0024},
abstract = {TAR DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated as a vectorized full-length antibody (vmAb) and evaluated for brain delivery using adeno-associated virus 9 (AAV9). Among the expression cassettes explored, the selected construct utilized an internal ribosome entry site (IRES), which produced high expression yields in vitro (>200 mg/L) with comparable quality, binding and functional properties to the conventionally produced mAb. A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid and brain of mice. In a mouse model of ALS/FTD, treatment with a vmAb reduced the amount of pathological phospho-TDP-43 in neurons by 58% and 68% when expressed either using a ubiquitous promoter or a brain-selective promoter, respectively. This innovative approach sufficiently delivers effective immunotherapy with a single dose and illustrates the enormous potential of using vectorized antibodies to target neuropathology, including TDP-43 in patients suffering from ALS, FTD and other TDP-43 proteinopathies.},
}

@article {pmid40518263,
year = {2025},
author = {Alali, S and Dubin, J and Hobin, F and Das, S and Lambrechts, C and Stoops, E and Vanmechelen, E and van Damme, P and Poesen, K},
title = {Serum neuronal pentraxin 2 levels are associated with shorter survival in amyotrophic lateral sclerosis.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336198},
pmid = {40518263},
issn = {1468-330X},
}

@article {pmid40517187,
year = {2025},
author = {Haro-Martínez, E and Muscolino, E and Moral, N and Duran, J and Fornaguera, C},
title = {Crossing the blood-brain barrier: nanoparticle-based strategies for neurodegenerative disease therapy.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {40517187},
issn = {2190-3948},
support = {2021 SGR 00537//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 2024-LLAV-00042//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; ICREA Acadèmia 2024//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 202207-31//Fundació la Marató de TV3/ ; PID2020-118699GB-100//Agencia Estatal de Investigación/ ; Not specified//Fundación Ramón Areces/ ; FISDUR-2024//Departament d'Universitats, Recerca i Societat de la Informació/ ; },
abstract = {Neurodegenerative conditions, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease, represent a critical medical challenge due to their increasing prevalence, severe consequences, and absence of curative treatments. Beyond the need for a deeper understanding of the fundamental mechanisms underlying neurodegeneration, the development of effective treatments is hindered by the blood-brain barrier, which poses a major obstacle to delivering therapeutic agents to the central nervous system. This review provides a comprehensive analysis of the current landscape of nanoparticle-based strategies to overcome the blood-brain barrier and enhance drug delivery for the treatment of neurodegenerative diseases. The nanocarriers reviewed in this work encompass a diverse array of nanoparticles, including polymeric nanoparticles (e.g. micelles and dendrimers), inorganic nanoparticles (e.g. superparamagentic iron oxide nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, selenium and cerium oxide nanoparticles), lipid nanoparticles (e.g. liposomes, solid lipid nanoparticles, nanoemulsions), as well as quantum dots, protein nanoparticles, and hybrid nanocarriers. By examining recent advancements and highlighting future research directions, we aim to shed light on the promising role of nanomedicine in addressing the unmet therapeutic needs of these diseases.},
}

@article {pmid40516772,
year = {2025},
author = {Rawat, E and Sharma, S and Vyas, S and Alsaidan, OA and Kapoor, DU and Prajapati, BG},
title = {Advances in alginate-based nanoformulations: Innovative and effective strategies for targeting and treating brain disorders.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {125851},
doi = {10.1016/j.ijpharm.2025.125851},
pmid = {40516772},
issn = {1873-3476},
abstract = {Brain disorders, encompassing neurodegenerative conditions and intracranial neoplasms, present formidable obstacles in the realm of pharmacological delivery due to the existence of athe blood-brain barrier (BBB) and the restricted bioavailability of therapeutic agents. Alginate-derived nanoformulations have emerged as highly promising systems for drug delivery, offering attributes such as biocompatibility, regulated release, and improved targeting efficacies. This review investigates contemporary advancements in alginate-based nanoformulations, with a particular emphasis on their efficacy in surmounting obstacles to successful pharmacological delivery to the brain. Initially, we furnish a comprehensive overview of alginate, underscoring its pertinent properties, biomedical applications, and inherent limitations. Subsequently, the discourse progresses to strategies for nanoformulation, which encompass lipid-based, polymeric, and inorganic methodologies, with a focus on their benefits in relation to cerebral targeting. Moreover, this review entails the therapeutic potential of alginate-based nanoformulations in addressing significant neurological disorders, including Alzheimer's disease, Parkinson's disease, brain tumours, traumatic brain injury, epilepsy, and amyotrophic lateral sclerosis. By amalgamating cutting-edge nanotechnology with the distinctive properties of alginate, these formulations signify a promising pathway for the advancement of efficacious therapies aimed at brain targeting. Additionally, prospective research trajectories and challenges associated with the optimization of alginate-based nanocarriers for clinical applications are also elucidated.},
}

@article {pmid40516596,
year = {2025},
author = {Kitamura, K and Tsukui, I and Sasaki, F and Shiramasa, Y and Arayama, M and Morishita, M and Oshima, A and Kitazawa, S and Kameda, T and Kitahara, R},
title = {ATP as a key modulator of fused-in-sarcoma phase separation and aggregation: Insights into amyotrophic lateral sclerosis pathogenesis.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169295},
doi = {10.1016/j.jmb.2025.169295},
pmid = {40516596},
issn = {1089-8638},
abstract = {Fused in sarcoma (FUS) is an RNA-binding protein, the aberrant aggregation of which is linked to amyotrophic lateral sclerosis (ALS). Liquid-liquid phase separation (LLPS) of FUS facilitates functional condensate formation and can drive pathological aggregation under certain conditions. The aggregation-inhibitory effects of ATP, a key cellular hydrotrope, have been reported for multiple proteins; however, how ATP, present at approximately 1-12 mM concentrations in cells, regulates LLPS and amyloid fibril formation remains unclear. Therefore, we investigated how ATP modulates the LLPS behavior and aggregation of FUS and its ALS-linked variants, R495X and P525L. ATP destabilized both normal LLPS and aberrant high-pressure LLPS (HP-LLPS), with a relatively strong inhibitory effect on HP-LLPS. Pressure-jump experiments demonstrated that ATP reduced the irreversible aggregation propensity of HP-LLPS, particularly in ALS variants that exhibited enhanced aggregation compared to that by wild-type FUS. Molecular dynamic simulations further revealed that the triphosphate and adenosine moieties of ATP synergistically disrupted intermolecular interactions that were crucial for phase separation, leveraging its amphipathic properties. Notably, ATP concentrations within the physiological range (1-12 mM) significantly inhibited FUS aggregation, suggesting a protective role in cellular environments. These results indicate that decreased intracellular ATP levels may exacerbate aberrant phase transitions of FUS, contributing to ALS onset. This study underscores the potential of ATP as a therapeutic modulator of protein phase separation and aggregation, providing valuable insights into the molecular mechanisms of ALS. Our findings open new avenues for targeting ATP-regulated pathways for treating neurodegenerative disorders.},
}

@article {pmid40516449,
year = {2025},
author = {Yadav, AJ and Padhi, AK},
title = {Synergizing multiresolution simulations, interface redesign, and hotspot mapping to decipher pathogenic mutation-driven structural modulation in VCP.},
journal = {Computers in biology and medicine},
volume = {194},
number = {},
pages = {110560},
doi = {10.1016/j.compbiomed.2025.110560},
pmid = {40516449},
issn = {1879-0534},
abstract = {Valosin-containing protein (VCP/p97), a pivotal AAA[+] ATPase, orchestrates proteostasis via ER-associated degradation (ERAD), ubiquitin-mediated proteolysis, and organelle surveillance. Pathogenic missense mutations, notably Arg95Gly (R95G) within the evolutionarily conserved double-ψ β-barrel (DPBB) of its N-terminal domain, are implicated in proteinopathies including IBMPFD and ALS. To decode the structural-dynamics perturbations underpinning R95G-driven dysfunction, we integrated AlphaFold3-based modeling, protein-peptide docking, and multiscale enhanced-sampling molecular dynamics (MD) simulations-spanning 1.2 μs all-atom, 12 μs coarse-grained, and umbrella sampling regimes. Our findings reveal that R95G disrupts the β-barrel integrity, destabilizes long-range domain coupling, and engenders conformational heterogeneity deleterious to gp78 cofactor recruitment. Free-energy landscapes of the mutant highlight enthalpically disfavored, low-occupancy binding conformers, corroborated by MM/PBSA-based end-state binding free energy and potential of mean force (PMF) analyses, which indicate impaired binding thermodynamics. Interface hotspot mapping pinpoints dynamic perturbations at critical residues that propagate allosteric decoupling and morphological distortion of the binding interface. Collectively, our results delineate a mechanistic cascade-from local β-barrel destabilization to global interaction network disruption-underlying VCP's functional impairment in disease states. This work provides a computationally derived structural framework to inform targeted biophysical validation and the rational design of therapeutic strategies aimed at rescuing VCP function in IBMPFD and ALS.},
}

@article {pmid40515975,
year = {2025},
author = {Zhu, Y and Neyrinck, K and Burg, T and Chai, YC and Nami, F and Ahuja, K and Swinnen, JV and Van Den Bosch, L and Verfaillie, C},
title = {Altered Lipid Homeostasis in Mutant FUS[R521H] Astrocytes from HiPSCs.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40515975},
issn = {1559-1182},
support = {201908440360//China Scholarship Council/ ; 12AIK24N//Fonds Wetenschappelijk Onderzoek/ ; FWO-SBO-S001221N -ORGAN-ID//Fonds Wetenschappelijk Onderzoek/ ; C14-17-107//University of Leuven C1 grants/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss, leading to paralysis and death. Mutations in the fused in sarcoma (FUS) gene cause early-onset ALS with rapid disease progression. Although motor neuron degeneration is central to ALS, recent studies highlight a significant role for dysfunctional glial cells, particularly astrocytes, in disease progression. In this study, we generated astrocytes from FUS[R521H] mutant and isogenic human induced pluripotent stem cells (hiPSCs) by inducible overexpressing SOX9. Lipidomic analysis revealed marked glycerophospholipid deficiencies in FUS[R521H] mutant astrocytes, especially reduced phosphatidylcholine (PC) and phosphatidylinositol (PI) levels. This reduction in PC was also observed in FUS[R521H] mutant oligodendroglial progenitors and motor neurons, suggesting a potential dysregulation of glycerophospholipid metabolism across multiple central nervous system (CNS) cell types in FUS-ALS. These observations highlight the need for further investigation into lipid dysregulation and its relevance to FUS-ALS pathogenesis.},
}

@article {pmid40515812,
year = {2025},
author = {Jellinger, KA},
title = {Prevalence and impact of comorbidities in amyotrophic lateral sclerosis.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40515812},
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 = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of multifaceted nature and variable progression that poses considerable challenges to our understanding of its evolution and interplay with different comorbid conditions. The etiopathogenesis of ALS is still unexplained and multimorbidity is common, but its influence on the ALS susceptibility and disease course is a matter of discussion. This study using medical databases tries to find diseases associated with ALS and their impact on disease onset and progression. Diseases associated with the risk of ALS include diabetes mellitus, dyslipidemias and cardiovascular comorbidities that may play an important role in the prognosis of ALS. Hypometabolic disorders and cardiovascular diseases may have a protective effect on ALS incidence, while coronary heart disease and hypertension have a negative effect on disease progression. Other comorbidities include Parkinson disease, TDP-43 pathology, progressive supranuclear palsy, progressive aphasia, myasthenia gravis, cancer and autoimmune disorders, while there is no evidence for a shared genetic background of common risk variants in ALS and multiple sclerosis. Among non-motor manifestations of ALS, cognitive and behavioral impairments are important. Other comorbidities include sleep disorders, traumatic encephalopathy, sarcoidosis, prionopathies, schizophrenia, cervical spondylotic myelopathy, psoriasis and others. The tremendous heterogeneity of concomitant pathologies and comorbidities observed across the ALS spectrum may be caused by a complex interplay between genetic, pathogenetic, inflammatory and other risk factors that are still poorly understood. Further research should provide increasing insight into their relationship with motor system disorders in order to find better diagnostic tools and probable effective therapies for these disease-modifying comorbidities.},
}

@article {pmid40514455,
year = {2025},
author = {Hu, YQ and Zhang, XX and Zhao, TT and Wu, XH},
title = {Using proteomics and single-cell sequencing to analyze the pathogenesis of recurrent implantation failure associated with uterine natural killer cells.},
journal = {Archives of gynecology and obstetrics},
volume = {},
number = {},
pages = {},
pmid = {40514455},
issn = {1432-0711},
support = {H2023106006//Natural Science Foundation of Hebei Province/ ; 213777102D//The Key Research and Development project of Hebei Province/ ; 20251109//Medical Science Research Project of Hebei/ ; },
abstract = {PROBLEM: Recurrent implantation failure (RIF) affects about 10% of infertility patients and may involve mid-luteal phase endometrial natural killer (NK) cells. The pathogenesis of NK cells in RIF remains unclear.

METHOD OF STUDY: Our study integrated proteomics data from endometrial tissues of six RIF patients and six controls, with single-cell sequencing insights.

RESULTS: Our proteomics analysis identified 1366 differentially expressed proteins (DEPs) between RIF and control groups, highlighting alterations in cellular processes, such as cytoplasmic translation and mRNA processing. Functional enrichment analysis revealed significant associations with pathways involved in amyotrophic lateral sclerosis and proteasomes. The DEPs were transformed into differentially expressed genes1 (DEGs1) by ID-transformation. 33 candidate genes were detected when ID-transformed 1210 DEGs1 were intersected with 752 DEGs2 from NK cells. After that, the proteomics sequencing data validation showed that the expression of AMPD3, H6PD, and PAK2 was consistent and significantly different from the GSE111974 dataset and classified as crucial genes. In addition, analysis of single-cell sequencing data annotated fibroblast-like stromal cells, NK cells, T cells, and endothelial cells, and these three essential genes showed that they were expressed in NK cells. Crossing the signaling pathways of key genes with those enriched for DEPs yielded the 'Escherichia coli infection' possibly associated with RIF. Finally, the transcription factor HR had a strong regulatory effect on the PAK2.

CONCLUSION: Finally, identifying three key genes (AMPD3, H6PD and PAK2) associated with RIF and the regulatory solid roles of HR and PAK2 provided a basis for understanding the molecular mechanism of RIF. Our findings may pave the way for developing targeted therapies to improve pregnancy outcomes in patients with RIF.},
}

@article {pmid40514097,
year = {2025},
author = {Artuğ, NT and Sirin, NG and Baslo, SA and Orhan, EK and Baslo, MB and Oge, AE},
title = {Automated step analysis algorithm for CMAP scan study.},
journal = {Medical engineering & physics},
volume = {141},
number = {},
pages = {104353},
doi = {10.1016/j.medengphy.2025.104353},
pmid = {40514097},
issn = {1873-4030},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Algorithms ; Automation ; *Action Potentials ; Aged ; Adult ; Software ; Reproducibility of Results ; Case-Control Studies ; *Electromyography/methods ; },
abstract = {OBJECTIVE: To create an automated method for step analysis in compound muscle action potential (CMAP) scan curves and compare the step parameters calculated using the conventional semi-automated and the new automated method between patients with amyotrophic lateral sclerosis (ALS) and controls.

METHODS: Twenty ALS patients and fifteen controls were enrolled into the study. Median nerve was stimulated at the wrist to record CMAP scans from abductor pollisis brevis muscle. Automated step analysis software revealed gaps on CMAP scan graphics by using new parameters indicating the steps. New parameters were calculated and compared with the conventional semi-automated step analysis. Intra-class correlation coefficients (ICC) were measured for reliability between methods.

RESULTS: Step parameters calculated by two methods showed no significant difference in patients with ALS, except step%, but their similarities were less favorable in controls. The reliability of parameters between two methods was good-to-excellent in patient group, but controls did not show a significant ICC for any of the parameters.

CONCLUSION: A completely new automated step analysis software was developed. Analyses were done within 5 s. New step parameters were presented with supporting graphics. Results of automated step analysis were in concordance with semi-automated one for ALS patients, but not in controls.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis
Male
Middle Aged
Female
*Algorithms
Automation
*Action Potentials
Aged
Adult
Software
Reproducibility of Results
Case-Control Studies
*Electromyography/methods

@article {pmid40513650,
year = {2025},
author = {Ho, CY and Chang, YJ and Yang, CW and Shih, O and Jeng, US and Hwang, IS and Huang, WC and Chen, YR},
title = {Membrane disruption properties of poly-glycine arginine dipeptide repeats affected by peptide repeats continuity and membrane composition.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169296},
doi = {10.1016/j.jmb.2025.169296},
pmid = {40513650},
issn = {1089-8638},
abstract = {C9ORF72 hexanucleotide expansion is the most common genetic mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD). This expansion can be translated into dipeptide repeats (DPRs) through repeat-associated non-ATG (RAN) translation. Arginine-rich DPRs, i.e., poly-glycine arginine (poly-GR) and poly-proline arginine (poly-PR) are considered the most toxic ones among the five types of DPRs. We recently discovered that poly-GR forms helical conformation and is able to penetrate cell membranes, leading to cytotoxicity, but the mechanism remains unclear. Here, we investigated the membrane disruption mechanism of poly-GR related to its sequence and membrane composition. To test this, we stopped its continuously repeated sequence by inserting several proline residues to disrupt its helical structure. We found that the modification reduced its cytotoxicity and membrane disruption capability. Next, we examined the influence of lipid composition on the membrane-disrupting ability of poly-GR using various liposomes. Poly-GR caused higher leakage in the negatively charged liposomes compared to the neutral or positively charged ones. Cholesterol content affected the extent of disruption, while gangliosides had no significant effect. Using small-angle x-ray scattering (SAXS), total internal reflection fluorescence (TIRF) microscopy, and atomic force microscopy (AFM), we observed the behavior of poly-GR on lipid membranes. Finally, we directly treated mouse neuroblastoma to modulate the cholesterol content and found that cholesterol depletion inhibited the internalization of poly-GR into the cells and reduced cytotoxicity. These findings reveal that the conformation of poly-GR and the lipid composition influence its membrane penetration, offering insights into potential therapeutic strategies for C9ORF72-related diseases.},
}

@article {pmid40513028,
year = {2025},
author = {Bromberg, MB},
title = {What Is in the Literature.},
journal = {Journal of clinical neuromuscular disease},
volume = {26},
number = {4},
pages = {176-183},
doi = {10.1097/CND.0000000000000526},
pmid = {40513028},
issn = {1537-1611},
mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; },
abstract = {This issue of What Is in the Literature focuses on articles over the past year on clinical aspects of motor neuron disease, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Disease-modifying treatment for ALS remains a challenge as 2 formal drug trials did not hold up to retesting. There are new thoughts based on a multistep model to partially explain why ALS develops relatively late in life. New information on fluid biomarkers, sex differences, efficacy of medical marijuana for common symptoms, and cognitive dysfunction are discussed. For the clinic, there are updated guidelines for multidisciplinary management. Other articles address how frequently the topic of sexual health is brought up in the clinic, and insights into how patients view end-of-life issues and quality of life when using tracheal ventilation. PLS has diagnostic challenges and practical aspects, which are reviewed.},
}

Humans
*Motor Neuron Disease/therapy/diagnosis
*Amyotrophic Lateral Sclerosis/therapy/diagnosis

@article {pmid40511876,
year = {2025},
author = {Yeole, A and Khanna, L and Doshi, M and Sharma, A and Uttarwar, P and Doshi, S and Kaushik Kumar, R and Venkataramana, N and Parmar, D},
title = {A phase 2, proof-of-concept, placebo-controlled, randomized, multicenter, double-blind study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2515900},
pmid = {40511876},
issn = {2167-9223},
abstract = {Objective: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. Results: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (p > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. Conclusion: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.},
}

@article {pmid40511793,
year = {2025},
author = {Parks, ASE and Gotlib Conn, L and Amog, K and Bodmer, NS and King, JW and McLaren, AMR and Reid, M and Kishibe, T and Abrahao, A and Zinman, L and Sale, JEM},
title = {Age and life stage in the experience of amyotrophic lateral sclerosis: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/21678421.2025.2515914},
pmid = {40511793},
issn = {2167-9223},
abstract = {Objective: Understanding the experiences of people living with amyotrophic lateral sclerosis (plwALS) is necessary to appreciate their unique needs. Age and stage in the life course influence how illness is experienced; however, the extent to which age-specific complexities of living with ALS have been examined remains unexplored. This review aims to map the available evidence exploring age, age-graded role, or life-course transition with regards to the experience of ALS and to identify age-specific gaps in the literature. Methods: A scoping review guided by Joanna Briggs Institute methodology was undertaken. Eligible articles included peer-reviewed primary research studies, published in English from 2010 onward, investigating illness experience of adults with ALS with consideration for how age, age-graded roles, or life-course transitions influenced experience. Database sources included: Ovid's Medline, Embase, and PsycINFO; EBSCO CINAHL; and ProQuest Sociological Abstracts. Findings related to ALS experience and dimensions of age were summarized descriptively and categorized using qualitative content analysis. Results: Six thousand one hundred and eighty individual records were identified and screened. Forty-five articles, reporting 42 studies, were included. Findings regarding thoughts, feelings, or emotions of plwALS were most common and varied depending on whether they were in reference to chronological age or age-graded role. Despite the importance of life-course transitions for illness experience, they were not routinely considered. Conclusion: Numerous aspects of the experience of plwALS have been reported in reference to age; however, the significance of age-graded roles and life-course transitions warrants further examination. Recognition of age-related complexities of living with ALS will facilitate more personalized ALS care.},
}

@article {pmid40510242,
year = {2025},
author = {Pfaff, AL and Bubb, VJ and Quinn, JP and Kõks, S},
title = {The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {250},
number = {},
pages = {10600},
pmid = {40510242},
issn = {1535-3699},
mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Minisatellite Repeats/genetics ; Genetic Predisposition to Disease ; Male ; Female ; *Short Interspersed Nucleotide Elements/genetics ; Middle Aged ; Gene Frequency ; },
abstract = {The fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), leads to the degeneration of motor neurons in the brain and spinal cord. Many different genetic variants are known to increase the risk of developing ALS, however much of the disease heritability is still to be identified. To identify novel genetic factors, we characterised SINE-VNTR-Alu (SVA) presence/absence variation in 4403 genomes from the New York Genome Center (NYGC) ALS consortium. SVAs are a type of retrotransposon able to mobilise in the human genome generating new insertions that can modulate gene expression and mRNA splicing and to date 33 insertions are known to cause a range of genetic diseases. In the NYGC ALS consortium sequence data 2831 non-reference genome SVAs were identified and 95% of these insertions were rare with an insertion allele frequency of less than 0.01. Association analysis of the common SVAs with ALS risk, age at onset and survival did not identify any SVAs that survived correction for multiple testing. However, there were three different rare SVA insertions in the ALS associated gene NEK1 identified in four different individuals with ALS. The frequency of these rare insertions in NEK1 was significantly higher in the individuals with ALS from the NYGC ALS consortium compared to the gnomAD SV non-neuro controls (p = 0.0002). This study was the first to characterise non-reference SVA presence/absence variation in a large cohort of ALS individuals identifying insertions as potential candidates involved in disease development for further investigation.},
}

*Amyotrophic Lateral Sclerosis/genetics
Humans
*Minisatellite Repeats/genetics
Genetic Predisposition to Disease
Male
Female
*Short Interspersed Nucleotide Elements/genetics
Middle Aged
Gene Frequency

@article {pmid40510202,
year = {2025},
author = {Li, L and Lv, L and Wang, Z and Liu, X and Wang, Q and Zhu, H and Jiang, B and Han, Y and Pan, X and Zhou, X and Ren, L and Chang, Z},
title = {From copper homeostasis to cuproptosis: a new perspective on CNS immune regulation and neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1581045},
pmid = {40510202},
issn = {1664-2295},
abstract = {Copper, an essential trace element for the human body, plays a key role in energy metabolism, mitochondrial respiration, redox reactions, and neural signal transmission. The recently proposed concept of "cuproptosis" has further revealed the unique status of copper in cellular regulation: when copper abnormally accumulates within cells, it can directly bind to the lipoylated proteins of the mitochondrial TCA cycle, triggering protein aggregation and metabolic disorders, ultimately leading to cell death. This form of cell death plays an important role in various neurodegenerative diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and stroke. This review summarizes recent research on the mechanisms of cuproptosis, providing new perspectives and a theoretical basis for understanding the pathogenesis of these neurodegenerative diseases.},
}

@article {pmid40509360,
year = {2025},
author = {Chang, B and Huang, J and Xie, Q and Ruan, Y and Liu, R},
title = {Identification, Geographical Traceability, and Thermal Oxidation and Photodegradation Studies of Camellia Oil Based on Raman Spectroscopy.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {11},
pages = {},
doi = {10.3390/molecules30112473},
pmid = {40509360},
issn = {1420-3049},
support = {2024KY0802, 2023KY0217,XJ21KT29//the Middle-aged and Young Teachers' Basic Ability Promotion Project of Guangxi，The Guilin University of Aerospace Technology School Fund/ ; No. AD25069073//Guangxi Science and Technology Program Project/ ; },
mesh = {*Spectrum Analysis, Raman/methods ; *Plant Oils/chemistry/analysis ; *Camellia/chemistry ; Oxidation-Reduction ; Photolysis ; Carotenoids/chemistry/analysis ; Temperature ; Least-Squares Analysis ; Discriminant Analysis ; },
abstract = {Camellia oil, rich in monounsaturated fatty acids, squalene, tocopherols, and polyphenols, is highly valued for its nutritional benefits. However, its high market value and regional variations have led to frequent adulteration, highlighting the need for rapid, non-destructive methods for authentication, geographical traceability, and quality assessment. This study employed portable Raman spectroscopy combined with Partial Least Squares Discriminant Analysis (PLS-DA) and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to differentiate camellia oil from other edible oils and evaluate its thermal and photo-oxidative stability. PLS-DA, based on VIP-selected spectral variables, effectively distinguished camellia oil, with Raman bands near 1250 cm[-1] and 1650 cm[-1] contributing significantly. A unique peak at 1525 cm[-1], observed in samples from Gongcheng, Guangxi, was associated with carotenoids and served as a potential marker for geographical traceability. MCR-ALS modeling revealed significant reductions in the 1650 cm[-1] and 1525 cm[-1] peaks when temperatures exceeded 150 °C, indicating degradation of unsaturated fatty acids and carotenoids. Under UV exposure, the 1525 cm[-1] peak declined sharply and nearly disappeared after 24 h, suggesting rapid carotenoid degradation via photooxidation. Extended UV treatment also affected the 1650 cm[-1] peak and led to oxidative product accumulation. Overall, this study demonstrates the feasibility of integrating Raman spectroscopy with chemometric analysis for efficient oil classification, traceability, and stability monitoring, offering a valuable tool for food quality control and market supervision.},
}

*Spectrum Analysis, Raman/methods
*Plant Oils/chemistry/analysis
*Camellia/chemistry
Oxidation-Reduction
Photolysis
Carotenoids/chemistry/analysis
Temperature
Least-Squares Analysis
Discriminant Analysis

@article {pmid40508048,
year = {2025},
author = {Tolochko, C and Shiryaeva, O and Alekseeva, T and Dyachuk, V},
title = {Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms and Treatment Strategies (Part 2).},
journal = {International journal of molecular sciences},
volume = {26},
number = {11},
pages = {},
doi = {10.3390/ijms26115240},
pmid = {40508048},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/metabolism/therapy/etiology/pathology ; Humans ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/pharmacology ; Motor Neurons/metabolism/pathology/drug effects ; Glutamic Acid/metabolism ; Neuroprotective Agents/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with damage to motor neurons and leading to severe muscle weakness and, eventually, death. Over the past decade, understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy.},
}

*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/metabolism/therapy/etiology/pathology
Humans
Oxidative Stress/drug effects
Animals
Antioxidants/therapeutic use/pharmacology
Motor Neurons/metabolism/pathology/drug effects
Glutamic Acid/metabolism
Neuroprotective Agents/therapeutic use

@article {pmid40507679,
year = {2025},
author = {Zhou, Y and Ni, Y and Lan, L and Wan, H and Luo, F},
title = {Association Between Allostatic Load and Delirium in ICU Patients: A Retrospective Analysis of the MIMIC-IV Database.},
journal = {Journal of clinical medicine},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/jcm14113916},
pmid = {40507679},
issn = {2077-0383},
support = {82300118//National Natural Science Foundation of China/ ; },
abstract = {Background: Allostatic load reflects the cumulative physiological effects of chronic and repeated stress on the body and is associated with dysregulation of multiple systems. This study aimed to examine the association between the allostatic load score (ALS) and the development of delirium in intensive care unit (ICU) patients. Method: The adult patients from the Medical Information Mart for Intensive Care (MIMIC-IV) database were screened and included in this study. Allostatic load was scored by hemoglobin A1c, high-density lipoprotein, total cholesterol, systolic blood pressure, diastolic blood pressure, body mass index, C-reactive protein, and serum albumin, and varied from 0 to 8. Restricted cubic spline and multivariate logistic regression were used to assess the relationship between ALS and delirium risk in the ICU. The threshold of the ALS was determined by the decision tree approach. A sensitivity analysis was also conducted. Results: A total of 656 patients were included in the study, and the incidence of delirium was 50.6% (n = 332). In a fully adjusted restricted cubic spline model, an increase in ALS was linearly positively correlated with the occurrence of delirium in the ICU (p-overall = 0.039, p-nonlinear = 0.506). The threshold for ALS was determined to be 3. ALS ≥ 3 was associated with increased delirium rates (p < 0.001), longer hospital stays (p < 0.001), and higher in-hospital mortality (p = 0.002). Subgroup analyses revealed no significant interactions (all p values for interactions > 0.05). Conclusions: Higher ALS was linearly associated with increased risk of ICU delirium. An ALS ≥ 3 identified patients with greater delirium incidence, longer hospital stays, and higher mortality.},
}

@article {pmid40506843,
year = {2025},
author = {Ashford, BA and Simpson, JE and Dawson, C and Boche, D and Cooper-Knock, J and Heath, PR and Fillingham, D and Appleby-Mallinder, C and Wei, W and Dunning, M and Highley, JR},
title = {Human amyotrophic lateral sclerosis/motor neuron disease: The disease-associated microglial pathway is upregulated while APOE genotype governs risk and survival.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70019},
doi = {10.1111/bpa.70019},
pmid = {40506843},
issn = {1750-3639},
support = {//Bruker Spatial Biology/ ; //British Neuropathological Society/ ; //Pathological Society of Great Britain and Ireland/ ; },
abstract = {A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post-mortem frozen and formalin-fixed paraffin-embedded specimens from human sporadic ALS/MND and control cases using the nCounter® Neuroinflammation Panel. Archival data were reanalyzed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord and motor cortex and validate changes found during transcriptomic analyses. In the spinal cord, marked inflammation was observed, while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted TREM2, TYROBP, APOE, and CD163, as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity and involvement of TREM2, ApoE (encoded by APOE), and TYROBP were confirmed, suggesting the involvement of the disease-associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the APOE variant and ALS/MND risk, age of onset, and survival. We find confirmed associations between APOE ε3/ε3 and disease and between ε2/ε2 and absence of disease. Further, ε4/ε4 appears to be associated with earlier disease onset and a more aggressive course. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.},
}

@article {pmid40506548,
year = {2025},
author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Miller, LM and Hochberg, LR and Brandman, DM and Stavisky, SD},
title = {An instantaneous voice-synthesis neuroprosthesis.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {40506548},
issn = {1476-4687},
abstract = {Brain-computer interfaces (BCIs) have the potential to restore communication for people who have lost the ability to speak owing to a neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech, such as prosody and immediately hearing one's own voice. Here we demonstrate a brain-to-voice neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real time to change intonation and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.},
}

@article {pmid40505784,
year = {2025},
author = {Tang, J and Kang, Y and Chen, Q and Zhang, B and Shang, N and Lan, J and Wu, L and Peng, Y},
title = {TIMP1 inhibits Rac1-mediated ROS production to ameliorate blood-spinal cord barrier disruption in amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106987},
doi = {10.1016/j.nbd.2025.106987},
pmid = {40505784},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of motor neurons, for which therapeutic strategies and pharmacological interventions remain limited. Disruption of the blood-spinal cord barrier (BSCB) has been identified as a significant factor that may exacerbate motor neuron damage. Tissue inhibitor of metalloproteinase-1 (TIMP1), a molecule known for its dual roles in inhibiting matrix metalloproteinase (MMP) activity and exerting cytokine-like effects via receptor interactions, has been demonstrated to ameliorate endothelial barrier damage in various diseases. Here, we explored the potential of TIMP1 to restore BSCB integrity as a strategy to slow the ALS progression. Specifically, the expression of TIMP1 or its mutant variant AlaTIMP1, which lacks MMP-inhibitory activity, in spinal cord microvascular endothelial cells (SCMECs) prior to disease onset significantly reduces BSCB leakage in mice with ALS, thereby alleviating motor function deficits and delaying disease progression. Additionally, TIMP1 expression restores the expression of junctional complexes in SCMECs, as demonstrated in both in vivo and in vitro ALS models. Mechanistic studies revealed that TIMP1 suppresses ALS injury-induced integrin β1 activation independent of MMP inhibition, blocking downstream Rac1 translocation to the membrane to form a complex with NOX2. The inhibition of NOX2 activity reduces ROS-induced cytoskeletal remodeling, consequently stabilizing overall junctional alignment and preserving the BSCB integrity. Overall, our findings elucidate an MMP-independent mechanism through which TIMP1 regulates BSCB integrity in ALS context, suggesting that TIMP1 could serve as a novel tool for the treatment of ALS, particularly for prophylactic treatment in patients with familial ALS.},
}

@article {pmid40504748,
year = {2025},
author = {Andersen, TM and Conde, B and Vollsæter, M},
title = {Seeing in Synchrony: Toward Personalized Noninvasive Ventilation in Amyotrophic Lateral Sclerosis Through Dynamic Upper-Airway Visualization.},
journal = {Respiratory care},
volume = {},
number = {},
pages = {},
doi = {10.1089/respcare.13193},
pmid = {40504748},
issn = {1943-3654},
}

@article {pmid40504265,
year = {2025},
author = {Torres-Villaros, H and Streho, M and Hoa, D and Giocanti-Aurégan, A},
title = {STARGUS: a comparative study of a new swept-source biometer and B-mode ultrasound in dense cataracts.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {40504265},
issn = {1435-702X},
support = {IIT #69445453//Alcon/ ; },
abstract = {PURPOSE: This study aimed to compare a new swept-source biometer to the gold standard B-mode ultrasound biometer for measuring the axial length (AL) when standard optical biometers failed due to cataract density.

METHODS: Patients with advanced cataracts whose AL could not be measured using optical biometers available in our clinics, including the Lenstar LS-900 and IOLMaster 500 and 700, were included. The AL, anterior chamber depth (ACD), and lens thickness (LT) were measured using a new swept-source biometer (SSB) (Argos[®], Alcon) and B-mode ultrasound. The Enhanced Retinal Visualization (ERV) mode of the new SSB was used when the standard mode did not provide reliable AL measurements.

RESULTS: AL measurements failed in 183 eyes due to cataract density using available biometers. The new SSB allowed successfully measuring the AL in 89.6% of cases, and the ERV mode was needed in 15.8% of eyes. The ALs measured with the new SSB and B-mode ultrasound were comparable, with an excellent intraclass correlation coefficient (ICC) of 0.99. No significant differences in ACD measurements were observed between new SSB and ultrasound or conventional biometers, with ICC of 0.81 and 0.87, respectively. However, the LT tended to be thinner with the new SSB compared to ultrasound, suggesting a potential source of error, but no significant difference was observed with conventional biometers (ICC of 0.88).

CONCLUSIONS: The new SSB Argos[®], in particular when the ERV mode is used, could be a reliable alternative to B-mode ultrasound for measuring AL in eyes with dense cataracts. It is as effective as ultrasound in measuring the AL, and it could help to improve cataract surgery planning and outcomes.},
}

@article {pmid40504117,
year = {2025},
author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC},
title = {Visualizing nuclear pore complex plasticity with pan-expansion microscopy.},
journal = {The Journal of cell biology},
volume = {224},
number = {9},
pages = {},
doi = {10.1083/jcb.202409120},
pmid = {40504117},
issn = {1540-8140},
support = {R01 NS122236/NH/NIH HHS/United States ; F31 HL158119/NH/NIH HHS/United States ; R01 GM129308/NH/NIH HHS/United States ; R35 GM15374/NH/NIH HHS/United States ; 2420904//National Science Foundation/ ; },
mesh = {*Nuclear Pore/metabolism/ultrastructure ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Nuclear Envelope/metabolism ; *Microscopy/methods ; Membrane Glycoproteins ; },
abstract = {The exploration of cell-type and environmentally responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-expansion microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation. They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae, depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the nuclear ring to the inner ring of the NPC specifically in induced pluripotent stem cell-derived neurons from a patient with C9orf72 amyotrophic lateral sclerosis. Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.},
}

*Nuclear Pore/metabolism/ultrastructure
Humans
Induced Pluripotent Stem Cells/metabolism
Neurons/metabolism
Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
C9orf72 Protein/genetics/metabolism
Nuclear Envelope/metabolism
*Microscopy/methods
Membrane Glycoproteins

@article {pmid40503807,
year = {2025},
author = {Rudnicki, SA and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and Cudkowicz, ME and De Carvalho, M and Genge, A and Hardiman, O and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and Van Den Berg, LH and Zinman, L and Herder, KE and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Shefner, JM and , },
title = {Hospitalizations as an outcome measure in COURAGE-ALS.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2515907},
pmid = {40503807},
issn = {2167-9223},
abstract = {Objective: To describe the development of a methodology to characterize hospitalizations and their relationship to amyotrophic lateral sclerosis (ALS) and provide results using this process in a phase 3 trial of reldesemtiv in ALS. Methods: ALS clinical trialists assisted in developing a classification system to determine if a hospitalization was related to ALS (HR-ALS), unrelated (HU-ALS), or if the relationship was indeterminate (HI-ALS) and this was applied by the investigators to hospitalizations in COURAGE-ALS. Time to first hospitalization and number of hospitalizations were compared between those assigned reldesemtiv or placebo for up to 48 weeks. Demographic and clinical features were evaluated for prediction of hospitalization risk; this analysis was limited to those participants who completed the first 24-week double-blind placebo-controlled portion of the trial. Results: COURAGE-ALS terminated early due to futility. Time to first hospitalization was similar in the reldesemtiv compared to placebo arms as was the incidence, with 86 of the participants (17.6% of those originally assigned placebo and 18.0% originally on reldesemtiv) experiencing an event. The largest percentage of events was classified as HR-ALS for both placebo (64%, 18/28) and reldesemtiv (76%, 44/58). In a multivariate model, only bulbar or respiratory onset disease was a significant risk factor for hospitalization. Conclusion: While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to characterize disease burden and clinical meaningfulness of the endpoint.},
}

@article {pmid40502782,
year = {2025},
author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Coleman, MP and Barmada, SJ and Sreedha, J},
title = {Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependent manner.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6527592/v1},
pmid = {40502782},
issn = {2693-5015},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive and ultimately fatal diseases characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila . Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. Expression of TDP-43 both activated GSK3 and promoted caspase mediated cleavage of TDP-43. Conversely, GSK3 inhibition reduced the abundance of full-length and cleaved TDP-43 in neurons expressing wild-type or disease-associated mutant TDP-43, ultimately ameliorating neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity has therapeutic value.},
}

@article {pmid40502754,
year = {2025},
author = {Cheng, F and Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, A and Haines, J and Chung, M},
title = {Combining xQTL and genome-wide association studies from ethnically diverse populations improves druggable gene discovery.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6700169/v1},
pmid = {40502754},
issn = {2693-5015},
abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing new treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies (GWAS). Gene-based association tests provide a more powerful alternative to traditional single nucleotide polymorphism (SNP)-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we developed GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level GWAS data. Using GenT, we identified 16, 15, 35, and 83 druggable genes linked to Alzheimer's disease (AD), amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively. Additionally, our multi-ancestry gene-based test (MuGenT) uncovered 28 druggable genes associated with type 2 diabetes that previous trans-ancestry or ancestry-specific GWAS had missed. By integrating brain expression and protein quantitative trait loci (e/pQTLs) into our analysis, we identified 43 druggable genes (e.g., RIPK2, NTRK1, RIOK1) associated with AD that had supporting xQTL evidence. Notably, experimental assays demonstrated that the NTRK1 protein inhibitor GW441756 significantly reduced tau hyper-phosphorylation (including p-tau181 and p-tau217) in AD patient-derived iPSC neurons, thus providing mechanistic support for our predictions. Overall, our findings underscore the power of gene-based association testing as a strategic tool for informed drug target discovery and validation based on human genetic and genomic data for complex diseases.},
}

@article {pmid40502095,
year = {2025},
author = {Poch, D and Mukherjee, C and Mallik, S and Todorow, V and Kuiper, EFE and Dhingra, N and Surovtseva, YV and Schlieker, C},
title = {Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.07.658469},
pmid = {40502095},
issn = {2692-8205},
abstract = {UNLABELLED: Aberrant biomolecular condensates are implicated in multiple incurable neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and DYT1 dystonia. However, the role of condensates in driving disease etiology remains poorly understood. Here, we identify myeloid leukemia factor 2 (MLF2) as a disease-agnostic biomarker for phase transitions, including stress granules and nuclear condensates associated with dystonia. Exploiting fluorophore-derivatized MLF2 constructs, we developed a high-content platform and computational pipeline to screen modulators of NE condensates across chemical and genetic space. We identified RNF26 and ZNF335 as protective factors that prevent the buildup of nuclear condensates sequestering K48-linked polyubiquitinated proteins. Chemical screening identified four FDA-approved drugs that potently modulate condensates by resolving polyubiquitinated cargo and MLF2 accumulation. Our exploratory integrated chemical-genetics approach suggests that modulation of zinc, and potentially autophagy and oxidative stress, is critical for condensate modulation and nuclear proteostasis, offering potential therapeutic strategies for neurological disorders. Application of our platform to a genome-wide CRISPR KO screen identified strong enrichment of candidate genes linked to primary microcephaly and related neurodevelopmental disorders. Two hypomorphic microcephaly-associated alleles of ZNF335 failed to rescue nuclear condensate accumulation in ZNF335 KO cells, suggesting that aberrant condensates and impaired nuclear proteostasis may contribute to the pathogenesis of microcephaly.

HIGHLIGHTS: MLF2 emerges as a disease-agnostic condensate biomarker co-localizing with TDP-43 and G3BP1FDA-approved drugs target condensates linked to perturbed proteostasis.RNF26 and ZNF335 are identified as modulators of nuclear phase transitions.Microcephaly patient disease alleles fail to counteract aberrant condensates.},
}

@article {pmid40501612,
year = {2025},
author = {Bhuiyan, P and Yi, Y and Wei, B and Yan, A and Dong, L and Wei, H},
title = {Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.21.655232},
pmid = {40501612},
issn = {2692-8205},
abstract = {Calcium dysregulation, caused by pathological activation of ryanodine receptors, contributes to motor neuron degeneration, motor dysfunction, and muscle weakness in SOD1-G93A transgenic amyotrophic lateral sclerosis (ALS) mice. This study investigates the therapeutic efficacy of intranasally administered dantrolene nanoparticles, a ryanodine receptor antagonist, on motor neuron function, muscle strength, spinal cord degeneration, and survival outcomes. Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) IN-DAN: Intranasal administration of dantrolene in the Ryanodex formulation vehicle (RFV), at a dosage of 5mg/kg, administered daily from ages 90-120 days; 3) IN-VEH: Intranasal administration of RFV alone (as a vehicle control), following the same dosing schedule as the IN-DAN condition. Body weight and general motor function were monitored weekly, with survival recorded daily throughout the treatment period. At the treatment conclusion, neurological function was comprehensively evaluated using a standardized neurological scoring system. Motor coordination and balance were assessed using the balance beam test (beam widths of 12 mm and 6 mm) and the rotarod test. Muscle strength was evaluated by measuring grip force using the Kondziela inverted screen test. After behavioral testing, spinal cord tissues were collected for analysis. The levels of neurofilament light chain (NFL), a skeletal neuron protein, and spinal cord weight were determined to measure spinal cord degeneration. Compared to non-transgenic control mice, SOD1-G93A mice exhibited significantly elevated neurological scores, indicating severely impaired neurological function. This deterioration was robustly and significantly ameliorated by IN-DAN treatment by 90% (P<0.0001). Similarly, ALS mice demonstrated impairments in motor coordination and balance on the beam balance test, with dramatic and significant increases in crossing time and the number of foot slips. These impairments were greatly and significantly mitigated by IN-DAN treatment, by 78% in crossing time (P<0.0001) and 84% in the number of slips (P<0.0001) on the 12 mm-wide beam, but not by the vehicle control. ALS mice demonstrated progressive body weight loss as well, which was similarly reversed by IN-DAN treatment, but not by the vehicle control. Muscle strength, as measured by grip force, was significantly reduced in ALS mice but robustly preserved IN-DAN treatment, which prevented the decrease by 213% (P<0.0001), while the vehicle control had no effect. Spinal cord weight was significantly reduced in ALS mice, a trend reversed by intranasal dantrolene nanoparticle treatment, but not by the vehicle control. Survival analysis revealed that 100% of control mice survived through the 30-day treatment period (up to 120 days of age), while survival in untreated or vehicle-treated ALS mice dropped to 67%. In contrast, ALS mice treated with intranasal dantrolene nanoparticles demonstrated a significantly improved survival rate of 89%. Thus, intranasal dantrolene nanoparticle treatment significantly and robustly improved neurological outcomes in SOD1-G93A ALS mice, inhibiting neurological impairment, motor dysfunction, balance deficits, and muscle weakness. These improvements were associated with a marked inhibition of spinal cord weight loss. Additionally, dantrolene treatment reversed body weight loss and significantly improved survival probability in ALS mice.},
}

@article {pmid40501554,
year = {2025},
author = {Trautwig, AN and Shantaraman, A and Chung, M and Dammer, EB and Ping, L and Duong, DM and Petrucelli, L and Ward, ME and Glass, JD and Nelson, PT and Levey, AI and McEachin, ZT and Seyfried, NT},
title = {Molecular Subtyping Based on Hippocampal Cryptic Exon Burden Reveals Proteome-wide Changes Associated with TDP-43 Pathology across the Spectrum of LATE and Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.30.656396},
pmid = {40501554},
issn = {2692-8205},
abstract = {TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer's disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7 . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43-depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease.},
}

@article {pmid40501419,
year = {2025},
author = {Bischoff, KE and Kojimoto, G and O'Riordan, DL and Leavell, YL and Maiser, S and Grouls, A and Smith, AK and Pantilat, SZ and Kluger, BM and Mehta, AK},
title = {Strengths and Opportunities: Clinicians' Perspectives on Palliative Care for Amyotrophic Lateral Sclerosis (ALS) in the United States.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28458},
pmid = {40501419},
issn = {1097-4598},
support = {/AG/NIA NIH HHS/United States ; //ALS Association/ ; },
abstract = {INTRODUCTION/AIMS: Little is known about the state of palliative care (PC) for people with ALS (pALS) in the U.S. We aimed to examine current practice regarding PC for pALS and how it can be improved.

METHODS: ALS and PC clinicians completed surveys about: (1) strengths and limitations of PC for pALS provided by ALS and PC teams, (2) reasons for and barriers to referring to specialty PC, and (3) how PC could be improved.

RESULTS: One hundred forty-one ALS clinicians from 72 institutions and 242 PC clinicians from 96 institutions in 30 states completed surveys. Half of ALS clinicians reported they are able to manage patients' pain (55%) and mood symptoms (52%) "very well." Fewer reported managing care partner needs (43%) and spiritual/existential distress (29%) "very well." Fifty-eight percent of pALS are referred to outpatient PC and 69% to hospice at some point in the illness. Barriers to referring include that PC programs are not sufficiently available to pALS. ALS clinicians generally felt satisfied with PC teams' care, but PC clinicians were less confident managing motor symptoms (51% confident) and helping care partners understand how to provide care (51%) and use equipment (25%). Most clinicians felt the quality of PC provided by ALS (77%) and PC (90%) teams is good/excellent. However, qualitative comments highlighted that both ALS and PC clinicians have knowledge gaps, and collaboration between ALS and PC clinicians should increase.

DISCUSSION: Clinician education, expansion of PC services, strengthened collaboration, and further research about PC for pALS are needed.},
}

@article {pmid40500504,
year = {2025},
author = {Niu, J and Verkhratsky, A and Butt, A and Yi, C},
title = {Oligodendroglia in Ageing and Age-Dependent Neurodegenerative Diseases.},
journal = {Advances in neurobiology},
volume = {43},
number = {},
pages = {363-405},
pmid = {40500504},
issn = {2190-5215},
mesh = {Humans ; *Oligodendroglia/pathology/physiology/metabolism ; *Neurodegenerative Diseases/pathology/physiopathology/metabolism ; *Aging/pathology/physiology ; Animals ; },
abstract = {The central nervous system is susceptible to gradual decline with age, affecting all types of glial cells in the process. Compared to other glial cells, the oligodendroglial lineage is highly vulnerable to ageing and undergoes significant characteristic changes that impact upon its structure and impair its physiological functions. Therefore, the ageing and degeneration of oligodendroglia become major risk factors for neurodegenerative diseases. During the age-related disease process, changes in oligodendroglia lead to a decline in their ability to regenerate myelin and respond to the aged microenvironment, which are closely linked to the pathogenesis of neurodegenerative diseases, facilitating the emergence of these diseases in older populations. In this chapter, we introduce the physiological changes of oligodendroglia during ageing and the related mechanisms and then summarise their pathophysiological contributions to age-related cognitive disorders. Finally, we discuss potential therapeutic strategies that target oligodendroglia for future research on neurodegenerative diseases.},
}

Humans
*Oligodendroglia/pathology/physiology/metabolism
*Neurodegenerative Diseases/pathology/physiopathology/metabolism
*Aging/pathology/physiology
Animals

@article {pmid40499018,
year = {2025},
author = {Yadav, V and Singh, R and Chaturvedi, M and Siddhanta, S and Chaturvedi, R},
title = {Multivariate and Machine Learning-Derived Virtual Staining and Biochemical Quantification of Cancer Cells through Raman Hyperspectral Imaging.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c01028},
pmid = {40499018},
issn = {1520-6882},
abstract = {Advances in virtual staining and spatial omics have revolutionized our ability to explore cellular architecture and molecular composition with unprecedented detail. Virtual staining techniques, which rely on computational algorithms to map molecular or structural features, have emerged as powerful tools to visualize cellular components without the need for physical dyes, thereby preserving sample integrity. Similarly, spatial omics enable the mapping of biomolecules across tissue or cell surfaces, providing spatially resolved insights into biological processes. However, traditional dye-based staining methods, while widely used, come with significant limitations. In this context, Raman spectroscopy offers a robust, label-free alternative for probing molecular composition at a high resolution. We present a novel algorithm that reconstructs super-resolved Raman images by extracting spectral patterns from surrounding pixels, enabling detailed, label-free visualization of cellular structures. By employing Raman spectroscopy in conjunction with chemometric tools such as principal component analysis (PCA), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural network (ANN), we performed a quantitative analysis of key biomolecular components, including collagen, lipids, glycogen, and nucleic acids, and classify the different cancer cell lines with an accuracy of nearly 99%. This approach not only enabled the identification of distinct molecular fingerprints across the different cancer types but also provided a powerful tool for understanding the biochemical variations that underlie tumor heterogeneity. This innovative combination of virtual staining, spatial omics, and advanced chemometrics highlights the potential for more accurate diagnostics and personalized treatment strategies in oncology.},
}

@article {pmid40498717,
year = {2025},
author = {Komolafe, OO and Mustofa, J and Daley, MJ and Walton, D and Tawiah, A},
title = {Current applications and outcomes of AI-driven adaptive learning systems in physical rehabilitation science education: A scoping review protocol.},
journal = {PloS one},
volume = {20},
number = {6},
pages = {e0325649},
doi = {10.1371/journal.pone.0325649},
pmid = {40498717},
issn = {1932-6203},
mesh = {Scoping Review as Topic ; Humans ; *Artificial Intelligence ; *Rehabilitation/education ; *Learning ; },
abstract = {Rationale Integrating artificial intelligence (AI) into education has introduced transformative possibilities, particularly through adaptive learning systems. Rehabilitation science education stands to benefit significantly from the integration of AI-driven adaptive learning systems. However, the application of these technologies remains underexplored. Understanding the current applications and outcomes of AI-driven adaptive learning in broader healthcare education can provide valuable insights into how these approaches can be effectively adapted to enhance multimodal case-based learning in Rehabilitation Science education. Methods The scoping review is based on the Joanne Briggs Institute (JBI) framework. It is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMSA-ScR). A comprehensive search strategy will be used to find relevant papers in Scopus, PubMed, CINAHL, Education Resources Information Center (ERIC), Association for Computing Machinery (ACM), ProQuest Education Journal, Web of Science, ProQuest Dissertations & Theses Global, and IEEE Digital Library. This review will include all types of studies that describe or evaluate our outcomes of interest: AI models used, learning and teaching methods, effective implementation, outcomes, and challenges of ALS's in rehabilitation health science education. Data will be extracted using a pre-piloted data extraction sheet and synthesized narratively to identify themes and patterns. Discussion This scoping review will synthesize the applications of AI models in rehabilitation science education. It will provide evidence for educators, healthcare professionals, and policymakers to incorporate AI into educational curricula effectively. The protocol is registered on Open Science Framework registries at https://osf.io/e46s3.},
}

Scoping Review as Topic
Humans
*Artificial Intelligence
*Rehabilitation/education
*Learning

@article {pmid40498248,
year = {2025},
author = {Pahwa, R and Molho, E and Lew, M and Dashtipour, K and Gil, RA and Revilla, FJ and Clinch, T and Qin, P and Isaacson, SH and , },
title = {Long-Term Safety and Efficacy of Repeated Cycles of RimabotulinumtoxinB in the Treatment of Chronic Sialorrhea: Results of the OPTIMYST Trial.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {40498248},
issn = {2193-8253},
abstract = {INTRODUCTION: Botulinum toxin injections into the salivary glands inhibit saliva production by reducing the release of acetylcholine at the parasympathetic nerve terminals within the salivary gland. The phase 3 study reported here assessed the safety, tolerability, and effectiveness of repeated cycles of rimabotulinumtoxinB (RIMA) injections in adults with troublesome sialorrhea.

METHODS: In this phase 3, open-label multicenter study, 187 adult participants with troublesome sialorrhea due to Parkinson disease (65.8%), amyotrophic lateral sclerosis (13.9%), and other etiologies (20.3%) received up to 4 cycles of RIMA treatment (3500 U every 11-15 weeks).

RESULTS: Participants (69% male, 31% female; mean age 64.1 years) had sialorrhea for a mean of 3.2 years at baseline with a mean Unstimulated Salivary Flow Rate (USFR) of 0.63 ± 0.49 g/min. During the first treatment cycle, RIMA significantly reduced the mean±standard deviation (SD) USFR from baseline to week 4 by - 0.34 ± 0.37 g/min (p < 0.0001), and efficacy was maintained through week 13 (- 0.14 ± 0.29 g/min; p < 0.0001). Reductions were maintained at subsequent injection cycles 2-4, with mean absolute USFRs at weeks 4 and 13 of each cycle similar to those of cycle 1. Most adverse events (AEs) were mild, and the most commonly reported AEs in each cycle that were considered to be treatment-related were dry mouth (≤ 15.5% participants/cycle) and dental caries (≤ 6.0% participants/cycle).

CONCLUSION: This study demonstrates that RIMA 3500 U safely reduces saliva production over repeated treatment cycles through 1 year, thereby supporting its utility in the management of troublesome sialorrhea in adults.

GOV IDENTIFIER: NCT02610868.},
}