@article {pmid40675338,
year = {2025},
author = {Shtilbans, A},
title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tjnut.2025.07.004},
pmid = {40675338},
issn = {1541-6100},
abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10 (CoQ10), creatine, and N-acetylcysteine (NAC) in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of such conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.},
}

@article {pmid40673975,
year = {2025},
author = {Perreault, MC and Heckman, CJ and Giorgi, A},
title = {Spinally Projecting Serotonergic Neurons in Motor Network Modulation.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00139.2025},
pmid = {40673975},
issn = {1522-1598},
support = {20153//National Science Foundation (NSF)/ ; },
abstract = {Spinally projecting serotonergic (5-HTsp) neurons represent a heterogeneous population of neurons in the brainstem whose relevance in the control of movement has largely been inferred. Numerous studies across a variety of species have suggested that 5-HTsp neurons exert a widespread influence on spinal sensorimotor networks, operating at multiple levels (primary afferents, interneurons, and motoneurons) through various serotonin receptor subtypes. However, despite the anatomical and neurochemical complexity of the 5-HTsp system, most supporting evidence has largely been derived from indirect approaches (e.g., exogenous application of 5-HT and agonists/antagonists of 5-HT receptors). Direct demonstrations of specific anatomical and functional connectivity have been limited, occasionally yielding apparent discrepant results. Consequently, as the primary provider of serotonin to the spinal cord, the exact contributions of the 5-HTsp neurons remain to be fully elucidated. For this mini-review, we sifted through the literature of the last six decades, starting after the characterization of the brainstem raphe nuclei and monoaminergic systems [1-3], to provide a clearer picture of what is currently known of the anatomy and influences of the different populations of 5-HTsp neurons on sensorimotor circuits and motor behaviors. We focused on studies reporting direct manipulation of brainstem 5-HTsp neurons, excluding those targeting 5-HT neurotransmission by exogenous application of 5-HT. This emphasis aims to highlight the urgency of resolving how 5-HTsp neuron subpopulations differentiate anatomically and functionally, so that they can be integrated as dedicated components in current models of supraspinal control of movement and motor diseases such as Parkinson's and amyotrophic lateral sclerosis. Along the way, we point out gaps in knowledge that may be filled using newly available research tools.},
}

@article {pmid40673945,
year = {2025},
author = {Shan, D and Sun, X and Tang, Y and Zhao, Y and Yan, C and Liu, F},
title = {FUS protein nuclear loss in skin biopsy: A window into the pathology and diagnosis of fused in sarcoma-associated amyotrophic lateral sclerosis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlaf077},
pmid = {40673945},
issn = {1554-6578},
support = {ZR2023MH180//Natural Science Foundation of Shandong Province/ ; 20201125//Qilu Young Scholar Program of Shandong University/ ; },
}

@article {pmid40673755,
year = {2025},
author = {Banerjee, A and Sanyal, D and Chattopadhyay, K},
title = {Investigating the Stability, Flexibility, and Phase Separation Properties of H46R and H80R Disease Mutants of SOD1: Insights into ALS Pathogenesis.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00289},
pmid = {40673755},
issn = {1520-4995},
abstract = {Human Cu, Zn superoxide dismutase (SOD1) is the primary enzyme in the cellular antioxidant defense system. Mutations in SOD1 are associated with amyotrophic lateral sclerosis (ALS), where protein misfolding and aggregation contribute to the disease pathology. Recently, SOD1 mutants have been shown to undergo phase separation, forming protein-rich droplets that can serve as precursors to the fibrillar aggregates, the pathological hallmarks of ALS. Protein phase separation is a critical process for membraneless organelle formation and the regulation of cellular activities, and its disruption is associated with neurodegeneration. In this study, we investigated two ALS-associated SOD1 mutants, H46R and H80R, and compared them to the wild-type (WT) and Apo forms to elucidate the relationship between phase separation and SOD1's biophysical properties. Using computational studies, chemical denaturation, in vitro condensate formation assays, and analyzing their dynamic behavior, we explored how these mutants influence protein phase separation propensity. Our findings demonstrate that altered secondary structures, stability, and inherent disorder in these mutants directly impact their phase separation behaviors. This study provides new insights into the role of phase separation in ALS pathogenesis and its potential as a therapeutic target.},
}

@article {pmid40673749,
year = {2025},
author = {Rong, P and Liston, E},
title = {An Explanatory Model of Speech Communication Centered on Multiscale Rhythmic Modulation: Implications for Motor Speech Assessment and Intervention for Individuals With Amyotrophic Lateral Sclerosis.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-25},
doi = {10.1044/2025_JSLHR-24-00286},
pmid = {40673749},
issn = {1558-9102},
abstract = {PURPOSE: This study proposed an explanatory model of speech communication centered on multiscale rhythmic modulation to inform motor speech assessment and management. To these ends, a fit-for-purpose, automated measurement tool was used to evaluate and/or cross-validate (a) the previously reported effect of a neuromotor disorder-amyotrophic lateral sclerosis (ALS)-and (b) the effects of two cueing strategies, commonly used in managing motor speech disorders, on rhythmic modulation of speech.

METHOD: A secondary analysis was carried out on the X-ray Microbeam database. The analyzed data included the articulatory-kinematic and acoustic recordings of a phonetically loaded sentence produced by 19 individuals with ALS and 23 neurologically healthy controls in one habitual style and two nonhabitual styles as elicited by the slow and clear speech cues, respectively. The measurement tool quantified the modulation patterns of four articulators as well as four critical-band and one wide-band envelopes at three linguistically relevant timescales (delta, theta, beta/gamma) to assess rhythm control at the prosodic, syllabic, and subsyllabic levels. To address the research aims, the disease and speaking style effects on all modulation metrics were evaluated.

RESULTS: For Aim 1, speakers with ALS showed reduced modulation depth of multiple articulators and critical-band envelopes at all timescales. For Aim 2, the slow speech cue elicited changes in articulatory modulation at multiple timescales, globally enhancing the control of all and especially syllabic and subsyllabic rhythms in speakers with ALS. Clear speech primarily elicited changes in articulatory modulation at the theta timescale, generating a more restricted effect on syllabic rhythm.

CONCLUSIONS: The findings generally aligned with our prior research, supporting the robust utility of the measurement tool for assessing rhythmic disturbances of speakers with ALS. Moreover, this tool showed promise for delineating cueing-elicited changes in rhythmic modulation of speech, which has potential implications in tailoring and evaluating the outcomes of behavioral intervention.},
}

@article {pmid40673636,
year = {2025},
author = {An, D and Wu, Y and Han, J and Fang, P and Bu, Y and Ji, G and Deng, J and Song, X},
title = {m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.},
journal = {American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics},
volume = {},
number = {},
pages = {e33048},
doi = {10.1002/ajmg.b.33048},
pmid = {40673636},
issn = {1552-485X},
support = {H2021206223//Natural Science Foundation of Hebei Province/ ; },
abstract = {We investigate the role of m6A RNA methylation in regulating transcription factor EB (TFEB) and its contribution to mitochondrial autophagy (mitophagy) dysfunction in amyotrophic lateral sclerosis (ALS). ALS cell models were used to analyse mitophagy markers and TFEB expression under METTL3 and TFEB modulation, using RT-qPCR, Western blot, MeRIP, RIP, and immunofluorescence. Elevated m6A methylation and reduced TFEB expression were observed in hSOD1-G93A models. METTL3 overexpression suppressed TFEB expression, leading to impaired mitophagy, while METTL3 knockdown alleviated these effects. MeRIP assays confirmed increased m6A modifications on TFEB mRNA, and RIP assays demonstrated direct interaction between METTL3 and TFEB mRNA. Notably, TFEB overexpression rescued mitophagy dysfunction, whereas TFEB knockdown exacerbated the impairment. METTL3-mediated m6A methylation inhibits mitophagy by downregulating TFEB expression, revealing the m6A-TFEB pathway as a promising therapeutic target for ALS.},
}

@article {pmid40672339,
year = {2025},
author = {Zeng, Y and Sianto, O and Lovchykova, A and Liu, C and Akiyama, T and Petrucelli, L and Gitler, AD},
title = {Nonsense-mediated decay masks cryptic splicing events caused by TDP-43 loss.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.09.664014},
pmid = {40672339},
issn = {2692-8205},
abstract = {In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is lost from the nucleus, leading to cryptic exon inclusion events in dozens of neuronal genes. Here, we show that many cryptic splicing events have been missed by standard RNA-sequencing analyses because they are substrates for nonsense-mediated decay. By inhibiting nonsense-mediated decay in neurons we unmask hundreds of novel cryptic splicing events caused by TDP-43 depletion, providing a new picture to TDP-43 loss of function in neurons.},
}

@article {pmid40672281,
year = {2025},
author = {Hogan, AL and Kane, M and Chiu, P and Richter, G and Maurel, C and Wu, S and Scherer, NM and Don, EK and Lee, A and Blair, I and Chung, R and Morsch, M},
title = {Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.06.663393},
pmid = {40672281},
issn = {2692-8205},
abstract = {Dysregulation of the TAR DNA-binding protein 43 (TDP-43), including intraneuronal cytoplasmic mislocalisation and aggregation is a feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE) and alzheimers disease (AD). Unravelling the causes and functional consequences of TDP-43 dysregulation is paramount to understanding disease mechanisms as well as identifying effective therapeutic targets. Here we present a comprehensive in vivo characterisation of three stable transgenic zebrafish models that express human TDP-43 variants in motor neurons. We demonstrate that overexpression of predominantly nuclear wildtype TDP-43, cytoplasm-targeted TDP-43, and an ALS-linked variant (G294V) each induce toxic gain-of-function effects, leading to impaired motor function, motor neuron loss, and muscle atrophy. Importantly, these models reveal distinct phenotypes, with the ALS-linked mutant exhibiting axonal transport deficits and neuromuscular junction disruption, while cytoplasmic mislocalised TDP-43 heightened susceptibility to oxidative stress. Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, mutant TDP-43 [G294V] . Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing.},
}

@article {pmid40672164,
year = {2025},
author = {Braspenning, SE and Ohnezeit, D and DeGulis, OA and Wilson, AC and Mohr, IJ},
title = {TDP-43 promotes efficient HSV-1 replication in human DRG-derived neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.08.662712},
pmid = {40672164},
issn = {2692-8205},
abstract = {UNLABELLED: TAR DNA-binding protein 43 (TDP-43) is a versatile nuclear RNA-binding protein that performs important functions in RNA localization, processing and stability. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) TDP-43 forms toxic, insoluble cytoplasmic aggregates that ultimately lead to neuronal loss. Although TDP-43 is expressed in every cell type, its function and subcellular localization are particularly important for neuronal homeostasis. However, it is unknown if TDP-43 has a role during herpesvirus infection. Herpes simplex virus type-1 (HSV-1), a ubiquitous neurotropic pathogen, is considered a contributing factor to neurodegenerative disorders. In this study, we tested the requirement for TDP-43 during HSV-1 infection in neuronal and non-neuronal cells. HSV-1 infection of epithelial cells and primary fibroblasts did not change overall TDP-43 abundance, nor did TDP-43 depletion detectably alter HSV-1 replication in a multicycle growth experiment. By contrast, when TDP-43 was depleted in neuronally derived, matured HD10.6 cells, HSV-1 infectious virus production was significantly reduced in both single- and multicycle growth experiments. Notably, TDP-43 depletion restricts viral lytic gene expression at the immediate-early phase. Through nanopore direct RNA-sequencing we uncovered enhanced intron retention in two essential viral genes upon TDP-43 depletion. Thus, while depletion of TDP-43 does not affect replication in epithelial cells and fibroblasts, TDP-43 is required for efficient replication in HD10.6 cells through modifying the abundance and splicing of viral mRNAs.

IMPORTANCE: Herpes simplex virus type-1 is a widespread neurotropic pathogen that can cause life-threatening infections of the brain and is increasingly linked to neurodegenerative disease. However, due to the lack of scalable in vitro human neuronal models or small animal models that recapitulate disease, little is known about virus-host interactions in neurons specifically. Using human epithelial cells, primary fibroblasts and a human neuron-derived cell line, we uncovered a cell type specific TDP-43 requirement for efficient HSV-1 virus replication. TDP-43 is a critical neuronal disease gene, and we showed it promotes virus gene expression and splicing of viral mRNAs in neuron-derived cells. This work provides valuable insights into the possible etiology of neurodegenerative disease and highlights the importance of studying virus-host interactions in relevant model systems.},
}

@article {pmid40672153,
year = {2025},
author = {Sang, X and Jiao, H and Meng, Q and Fang, X and Sundaram, KS and Zhou, J and Xu, Y and Alvarado, AIW and Nuryyev, RL and Ourenik, J and Ourednik, V and Huang, IS and Liu, X and Mei, Y and Qian, T and Ciechanover, A and Pizzo, DP and Lane, MA and Zholudeva, LV and An, J and Snyder, EY and Hu, H and Huang, Z},
title = {The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.08.663251},
pmid = {40672153},
issn = {2692-8205},
abstract = {G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1α. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1α in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1α that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1 [G93A] mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases.},
}

@article {pmid40672150,
year = {2025},
author = {Akiyama, T and Zeng, Y and Guo, C and Gautier, O and Koepke, LS and Bombosch, J and Sianto, O and Ross, JP and Hoang, PT and Zhao, LY and Spencer, C and Monje, M and Day, JW and Gitler, AD},
title = {KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.11.664426},
pmid = {40672150},
issn = {2692-8205},
abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.},
}

@article {pmid40671798,
year = {2025},
author = {Akan, T and Gelir, F and Aishwarya, R and Bhuiyan, MS and Bhuiyan, MAN},
title = {AFTG-Net: A Deep Attention-based Fusion Framework of Topological and Gradient Features for Pathological Image Analysis.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6710077/v1},
pmid = {40671798},
issn = {2693-5015},
abstract = {Skeletal muscle pathology is observed by structural disruptions in sarcomeres, increased central nuclei, and changes in myofiber cross-sectional area. In order to classify amyotrophic lateral sclerosis (ALS), diabetes, and healthy controls, pathologists examine the changes in myofiber size using Wheat Germ Agglutinin (WGA) stained histopathological images of various skeletal muscles (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus). Histological image analysis of skeletal muscle pathology is laborious and subject to inter- and intra-user variability, which can affect diagnosis accuracy and consistency. Conventional techniques like ImageJ-based tools are time-consuming and produce varying outcomes due to their manual cell counting, segmentation, and thresholding. This study introduces AFTG-Net, an attention-based machine learning framework that classifies skeletal muscle histopathological images using complementary geometric and topological descriptors. The model uses globally structural information from Topological Data Analysis (TDA) based on persistent homology and local edge and texture patterns from the Histogram of Oriented Gradients. We suggest a cross-weighted fusion approach that uses cosine similarity to adaptively balance the contributions of these heterogeneous features in order to improve their discriminative power. This integration enables the model to effectively distinguish pathological changes associated with amyotrophic lateral sclerosis (ALS) and Type I diabetes from healthy muscle tissue. We conducted comprehensive comparisons with various state-of-the-art and baseline methods, such as traditional feature-based and deep learning models. We assessed all models by analyzing WGA-stained skeletal muscle images from wild-type and disease models (G93A*SOD1 for ALS and Akita for type 1 diabetes). AFTG-Net outperformed all other models by achieving 92% classification accuracy in distinguishing healthy and diseased muscle fibers. By reducing human intervention, subjectivity, and analysis time, AFTG-Net improves scalability and diagnostic consistency, making it a valuable tool for both biomedical research and clinical practice.},
}

@article {pmid40671688,
year = {2025},
author = {Masegosa, VM and Fritz, E and Corvalan, D and Rojas, F and Garcés, P and Navarro, X and Bloms-Funke, P and van Zundert, B and Herrando-Grabulosa, M},
title = {Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00197},
pmid = {40671688},
issn = {1948-7193},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a continuous spectrum of aggressive neurodegenerative diseases affecting primarily motoneurons (MNs) and cortical frontotemporal neurons. Noncell autonomous mechanisms contribute to ALS/FTD, wherein astrocytes release toxic factor(s) detrimental to MNs. Because of the multifactorial nature of ALS, single-pathway-focused therapies have limited effectiveness in improving ALS. Therefore, novel combinatorial therapies are currently being pursued. Here, we evaluated whether the simultaneous activation of two complementary targets, the voltage-gated potassium channels 7.2/3 (Kv7.2/3) and the mitochondrial translocator protein (TSPO), by a novel synthesized compound (GRT-X) is an effective neuroprotective treatment in ALS in vitro models. We exposed primary rat ventral spinal cord neuronal cultures and rat spinal cord organotypic cultures to astrocyte-conditioned medium derived from primary mouse ALS astrocytes expressing mutant human SOD1 (SOD1[G93A]-ACM) or from human-induced pluripotent stem cell (iPSC)-derived astrocytes carrying an ALS-causing mutation in SOD1 (SOD1[D90A]-ACM) or an ALS/FTD-causing mutation in TDP-43 (TDP43[A90 V]-ACM). We report that the diverse human and mouse ALS/FTD-ACMs compromise the MN viability. Remarkably, GRT-X led to consistent protection of MNs. Moreover, ALS/FTD-ACM increases oxidative stress levels, which are prevented with GRT-X treatment. Together, we show that the complementary activation of TSPO and Kv7.2/3 may offer a novel therapeutic strategy for ALS/FTD due to its capacity to protect MNs from noncell-autonomous toxicity induced by diseased astrocytes.},
}

@article {pmid40670663,
year = {2025},
author = {Tanaka, Y and Sunamura, N and Kajitani, R and Ikeguchi, M and Kunimoto, R},
title = {Long-read RNA sequencing unveils a novel cryptic exon in MNAT1 along with its full-length transcript structure in TDP-43 proteinopathy.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1056},
pmid = {40670663},
issn = {2399-3642},
mesh = {Humans ; *Exons ; Amyotrophic Lateral Sclerosis/genetics ; *TDP-43 Proteinopathies/genetics ; *DNA-Binding Proteins/genetics/metabolism ; RNA Splicing ; Sequence Analysis, RNA ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; },
abstract = {Understanding the role of transcript isoforms is essential for elucidating disease mechanisms. TDP-43 regulates RNA splicing, and its dysfunction in neurons is a hallmark of some neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). While an association between TDP-43-dependent cryptic exons and disease pathogenesis has been suggested, an approach to investigate how cryptic exons disrupt transcript isoforms has yet to be established. In this study, we developed IsoRefiner, a novel method for identifying full-length transcript structures using long-read RNA-seq. Leveraging this method, we performed long-read RNA-seq, guided by prior short-read RNA-seq, to comprehensively determine the full-length structures of aberrant transcripts due to TDP-43 dysregulation in human iPSC-derived motor neurons. We identified a novel TDP-43-dependent cryptic exon in the MNAT1 gene, along with its full-length transcript structure. Furthermore, we confirmed the presence of the MNAT1 cryptic exon in patients with ALS and FTD. Our findings deepen understanding of TDP-43 proteinopathy and advance splicing research.},
}

Humans
*Exons
Amyotrophic Lateral Sclerosis/genetics
*TDP-43 Proteinopathies/genetics
*DNA-Binding Proteins/genetics/metabolism
RNA Splicing
Sequence Analysis, RNA
Induced Pluripotent Stem Cells/metabolism
Motor Neurons/metabolism

@article {pmid40669676,
year = {2025},
author = {Su, X and Tan, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H},
title = {DAPK1 induces motor neuron apoptosis in hSOD1[G93A]-linked amyotrophic lateral sclerosis via regulating the Xiap/JNK pathway.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104029},
doi = {10.1016/j.mcn.2025.104029},
pmid = {40669676},
issn = {1095-9327},
abstract = {Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1[G93A]-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.},
}

@article {pmid40669270,
year = {2025},
author = {Martinelli, I and Simonini, C and Zucchi, E and Gianferrari, G and Bedin, R and Ghezzi, A and Mandrioli, J},
title = {Predictors from systemic and neuro-inflammation in amyotrophic lateral sclerosis: A monocentric experience.},
journal = {Journal of neuroimmunology},
volume = {406},
number = {},
pages = {578683},
doi = {10.1016/j.jneuroim.2025.578683},
pmid = {40669270},
issn = {1872-8421},
abstract = {While the role of systemic and neuroinflammatory players is actually consolidated in amyotrophic lateral sclerosis (ALS) pathogenesis, a representative and reliable panel of inflammatory prognostic biomarkers is still lacking. This retrospective study on 182 ALS patients from the Modena ALS Center, investigates biomarkers of axonal injury (neurofilaments) and microglial and astrocytic activation (SerpinA1, TREM2, CHI3L1, OPN and S100B, respectively). In a subpopulation of patients, we examined blood count-derived parameters, including the Systemic-Immune-Inflammation index (SII), Systemic Inflammation Response Index (SIRI) and Aggregate Systemic Inflammation Index (AISI). All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. SerpinA1CSF was significantly lower in females [4.43 μg/ml (IQR 2.76-6.3) vs 5.61 μg/ml (IQR 3.39-9.16),p = 0.032], while SII indexes was oppositely distributed [higher in females, 540.67 (IQR 363.05-807.24) vs 384.89 (IQR 307.5-578.52),p = 0.015]. In univariate survival analysis, without overcoming neurofilaments, SIRI (HR 1.43, 95 %CI 1.03-1.966,p = 0.03), AISI (HR 1.002, 95 %CI 1.001-1.003, p = 0.002) and SII (HR 1.001, 95 %CI 1.0003-1.001,p = 0.003) impact negatively on survival, with AISI retaining its power at multivariate analysis (HR 1.002, 95 %CI 1.0004-1.001,p = 0.012). SerpinA1CSF levels influenced survival only for females (HR 1.042, 95 %CI 1.0065-1.078,p = 0.02), in a similar manner of SIRI (HR 1.483, 95 %CI 1.082-2.0334,p = 0.014) and SII (HR 1.00099, 95 %CI 1.0008-1.003,p = 0.001). Our data revealed the influence of sex on survival by SerpinA1CSF, CHI3L1CSF and systemic biomarkers in females. However, both neurofilaments and CHI3L1CSF outperform the other neuroinflammatory biomarkers at predicting rate of disease progression, so the prognostic meaning of these measure alone remains unconclusive, requiring larger collaborative studies.},
}

@article {pmid40668826,
year = {2025},
author = {Komarova, K and Gelfand, NA and Remacle, F and Levine, RD and Chakraborty, S and Jackson, TL and Kostko, O and Thiemens, MH},
title = {Photoselective isotope fractionation dynamics of N2 with cosmo and atmospheric chemistry perspectives.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {29},
pages = {e2511172122},
doi = {10.1073/pnas.2511172122},
pmid = {40668826},
issn = {1091-6490},
support = {2019722//BSF-NSF/ ; T0205.20//FNRS | Fonds pour la Formation à la Recherche/ ; DE-AC02-05CH11231//DOE office of Science/ ; 2009959//NSF-BSF/ ; },
abstract = {Stable isotope ratio measurements provide valuable insights into a broad range of natural processes, from planetary atmospheres and climate to interstellar chemistry. Nitrogen, which has two stable isotopes, exhibits varying isotope ratios across the solar system. To model these observations, the isotope fraction as a function of energy is essential. At the Advanced Light Source (ALS), we measured the photodissociation of molecular nitrogen (N2) with vacuum UV photons where a single photon is sufficiently energetic to dissociate the strong bond. The nitrogen atoms produced are scavenged with H2 to form ammonia, whose isotopic makeup is determined. Blending the experiments with dynamical computations that include the shielding of light, we examine the isotopic composition and electronic atomic states produced. The measured photodissociation of N2 at a natural isotopic composition with a frequency broad light beam exceptionally strongly favors the formation of the heavier nitrogen isotope, [15]N. Computations concur and suggest that the maximum in the quantum yield reflects significant variations in the specific electronic quantum states of the product N atoms that have quite different reactivities. Our quantum computations show that at similar energies, photodissociation of [14]N[14]N and [15]N[14]N can lead to different product channels. The computed dynamics include extensive state-selective spin-orbit and nonadiabatic couplings affecting the light absorption and dissociation pathways that proceed via the triplet manifold of states. Our results are relevant for future exploration missions, both in situ and sample-return and for other molecules such as O2 and CO.},
}

@article {pmid40543671,
year = {2025},
author = {Kim, RW and Mesinkovska, NA and Min, MS},
title = {Limitations in insurance coverage for management of alopecia, a response to Brinks et al's letter.},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.06.043},
pmid = {40543671},
issn = {1097-6787},
}

@article {pmid40667260,
year = {2025},
author = {Ghayal, NB and Crook, RJ and Jain, A and Sachdeva, G and Roemer, SF and Sekiya, H and DeTure, MA and Baker, M and Coster, W and Oskarsson, BE and Josephs, KA and Rademakers, R and van Blitterswijk, M and Dickson, DW},
title = {Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.26.661831},
pmid = {40667260},
issn = {2692-8205},
abstract = {Aggregation of TAR DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11 , as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases with FTLD-TDP, as well as FTLD-MND and MND-TDP cases subclassified neuropathologically into PLS, ALS, and PMA. All FTLD-TDP type C cases had ANXA11 proteinopathy. However, ANXA11 proteinopathy was present in over 40% of FTLD-MND and in 38 out of 40 FTLD-PLS cases (95%), of which 80% had TDP type B or an unclassifiable TDP-43 proteinopathy and 15% had TDP type C. Genetic analyses excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated novel forms of ANXA11 proteinopathy strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship of ANXA11 in TDP-43 proteinopathies, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises the molecular pathology of cases with abundant inclusions that are co-immunoreactive for both proteins and we subclassify three types of TAP based on distinct clinical and neuropathologic features.},
}

@article {pmid40667180,
year = {2025},
author = {Tam, SB and Waldeck, NJ and Wright, M and Baker, EM and Kiskinis, E and Bass, J and Kalb, RG},
title = {Cholinergic neuron circadian clock mediates RNA-binding protein function and contributes to ALS disease phenotypes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.06.652480},
pmid = {40667180},
issn = {2692-8205},
abstract = {Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) and alternative splicing provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease characterized by disrupted RBP function. Here, we reveal enrichment of genes associated with ALS and other neurodegenerative diseases in the spinal cord cholinergic neuron rhythmic transcriptome. We demonstrate that there is circadian regulation of ALS-linked RBPs and rhythmic alternative splicing of genes involved in intracellular transport (Aftph and Mvb12a), microtubule cytoskeleton organization (Limch1 and Drc3), and synaptic function (Sipa1l2) in this neuronal sub-type. Further, we show that the cholinergic neuron clock regulates sporadic ALS-associated changes in cytoskeleton and neuromuscular junction synapse gene expression. Finally, we report that cell-type-specific Bmal1 -deletion (i) increases lumbar spinal cord motor neuron loss and sciatic nerve axon degeneration, (ii) drives alternative splicing of genes encoding ALS-linked RBPs (Matr3 and Srsf7), and (iii) drives alternative splicing of genes associated with microtubule transport and postsynaptic organization. Our results establish a role for the cholinergic neuron circadian clock in RBP function and ALS disease phenotypes.},
}

@article {pmid40667053,
year = {2025},
author = {Chizari, S and Zanovello, M and Kong, S and Saigal, V and Brown, AL and Turchetti, V and Zampedri, L and Skorupinska, I and Minicuci, GM and Paron, F and Tonin, P and Marchetto, G and Li, Z and Colon-Mercado, J and Dattilo, D and Barattucci, S and Gatt, A and Qi, Y and Hanna, M and Ward, M and Petrucelli, L and Romano, M and Vattemi, G and Buratti, E and Malaspina, A and Merve, A and Machado, P and Soraru, G and Fratta, P and Jiang, N},
title = {TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.22.660773},
pmid = {40667053},
issn = {2692-8205},
abstract = {Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8+ T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8+ T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.},
}

@article {pmid40667039,
year = {2025},
author = {Sinha, IR and Ye, Y and Li, Y and Sandal, PS and Wong, PC and Sun, S and Ling, JP},
title = {Inhibition of nonsense-mediated decay in TDP-43 deficient neurons reveals novel cryptic exons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.28.661837},
pmid = {40667039},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43 kDa (TDP-43) is an essential splicing repressor whose loss of function underlies the pathophysiology of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Nuclear clearance of TDP-43 disrupts its function and leads to the inclusion of aberrant cryptic exons. These cryptic exons frequently introduce premature termination codons resulting in the degradation of affected transcripts through nonsense-mediated mRNA decay (NMD). Conventional RNA sequencing approaches thus may fail to detect cryptic exons that are efficiently degraded by NMD, precluding identification of potential therapeutic targets. We generated a comprehensive set of neuronal targets of TDP-43 in human iPSC-derived i [3] Neurons (i [3] N) by combining TDP-43 knockdown with inhibition of multiple factors essential for NMD, revealing novel cryptic targets. We then restored expression of selected NMD targets in TDP-43 deficient i [3] Ns and determined which genes improved neuronal viability. Our findings highlight the role of NMD in masking cryptic splicing events and identify novel potential therapeutic targets for TDP-43-related neurodegenerative disorders.},
}

@article {pmid40666348,
year = {2025},
author = {Johari, M and Folland, C and Saito, Y and Oud, MM and Parmar, JM and Töpf, A and Kurbatov, S and Ampleeva, M and Zakharova, EY and Chekmareva, IA and Shirokova, KS and Atiakshin, D and Gardeitchik, T and Kamsteeg, EJ and Medici, E and Kaat, LD and Bruels, CC and Stafki, SA and Estrella, EA and Littel, HR and Kunkel, LM and Kang, PB and Osei-Owusu, I and Pais, L and O'Leary, M and Austin-Tse, C and O'Donnell-Luria, A and Mangilog, B and Radio, FC and D'Amico, A and Ciolfi, A and Tartaglia, M and Perrin, A and Goethem, CV and Sole, G and Martin-Négrier, ML and Cossée, M and Genetti, CA and Valivullah, ZM and Milic, V and Kovacevic, G and Kosac, A and Moreno, CAM and Camelo, CG and Zanoteli, E and Fahey, MC and Beggs, AH and Vissing, J and Straub, V and Savarese, M and Tasca, G and Voermans, N and Laing, NG and Udd, B and Nishino, I and Ravenscroft, G},
title = {Missense variants in TUBA4A cause myo-tubulinopathies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.26.25330266},
pmid = {40666348},
abstract = {Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A -related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, affected individuals in 17 families presented with a primary axial myopathy without any identified CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness, establishing the first documented association between TUBA4A variants and multisystem proteinopathy. Our cohort exhibited diverse genotypes and associated inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A , three probands had homozygous TUBA4A variants, where the biallelic genotype was found to be associated with the disease, and the heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous TUBA4A variants were classified as "isolated-sporadic cases" where parental samples were unavailable. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were also variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies revealed a range of pathologies, including myofibre size variation, myofibre atrophy, nemaline bodies, core-like regions, internal nuclei, and endomysial fibrosis. Immunohistochemical staining showed evidence of proteinopathy, with autophagic features and TUBA4A accumulation in patient myofibres. Complementary in silico and in vitro investigations suggested that the identified TUBA4A substitutions cause significant protein abnormalities and may differentially impact microtubule dynamics. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A -related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.},
}

@article {pmid40666341,
year = {2025},
author = {Petrozziello, T and Mizerak, E and Krishnamoorthy, A and Donahue, RA and Castillo Torres, AL and Monsanto, RZB and Hammerschlag, BL and Fillingham, B and Kivisäkk, P and Timmons, J and Fox, K and Arnold, SE and Cohen, J and Klee, J and Paganoni, S and Cudkowicz, ME and Chibnik, LB and Berry, JD and Sadri-Vakili, G},
title = {Plasma tau and phosphorylated tau at T181 are altered in amyotrophic lateral sclerosis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.26.25330363},
pmid = {40666341},
abstract = {There is an unmet need for reliable biomarkers for amyotrophic lateral sclerosis (ALS). Recent studies have demonstrated that the levels of the microtubule-associated protein tau, are altered in plasma and cerebrospinal fluid (CSF) from people with ALS. Our previous findings demonstrated that while the ratio between tau and phosphorylated tau at T181 (pTau-T181) is decreased, increases in CSF tau correlated with faster disease progression in people with ALS. Here, we measured tau and pTau-T181 in plasma samples from participants with ALS and healthy controls (HC) using two methods (Quanterix Simoa and Meso Scale Discovery, MSD). Using both assays, there was an increase in pTau-T181 levels and in the pTau-T181:tau ratio in ALS compared to HC andlarger increases in pTau-T181 and pTau-T181:tau ratio at baseline correlated with faster ALS progression. Plasma total tau levels were increased in ALS compared to HC on the MSD assay and decreased on Quanterix Simoa assay. Collectively, our results suggest that plasma pTau-T181 levels are increased in ALS. Future studies should aim to clarify its role as a diagnostic or prognostic biomarker for ALS.},
}

@article {pmid40665686,
year = {2025},
author = {Lee, B and Cho, ST and Kim, R and Chung, KW and Kwon, TJ and Kim, UK and Kim, YR and Choi, BO and Park, JS},
title = {DCTN1-associated neurological disorder with symptoms similar to spinal bulbar muscular atrophy.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602251352989},
doi = {10.1177/22143602251352989},
pmid = {40665686},
issn = {2214-3602},
abstract = {BackgroundDynactin 1 (DCTN1) mutations are associated with diverse neurological disorders, including distal hereditary motor neuropathy, Perry syndrome, and amyotrophic lateral sclerosis. This study focused on a family with symptoms resembling spinal and bulbar muscular atrophy, showing severe vocal cord paralysis, to understand DCTN1-related neurological disorders in Koreans.MethodClinical examinations revealed variable phenotypes, such as proximal limb weakness, chronic hypercapnia, and gynecomastia, alongside vocal cord paralysis. Whole-exome sequencing identified a missense mutation, c.1175G > A, in DCTN1. Three more Korean families with the same mutation were analyzed to explore a potential founder effect. Microsatellite analysis indicated a shared haplotype, suggesting a common genetic origin.ResultThis study identified a missense mutation, c.1175G > A, in DCTN1 in the initial family with features resembling spinal and bulbar muscular atrophy. The mutation was also present in three other Korean families, indicating a potential founder effect. Microsatellite analysis confirmed a shared haplotype among these families. Meanwhile, the patients also manifested additional clinical features such as peripheral neuropathy and gynecomastia.ConclusionThis study highlights clinical heterogeneity in Korean patients with DCTN1-associated neurological disorders and identifies a potential founder mutation, c.1175G > A, expanding the clinical spectrum of DCTN1 mutations with clinical features of spinal bulbar muscular atrophy. Understanding such genetic and clinical diversity is crucial for accurate diagnoses and management, with implications for future research and therapeutic strategies.},
}

@article {pmid40665049,
year = {2025},
author = {Shvetcov, A and Johnson, ECB and Winchester, LM and Walker, KA and Wilkins, HM and Thompson, TG and Rothstein, JD and Krish, V and Imam, FB and , and Burns, JM and Swerdlow, RH and Slawson, C and Finney, CA},
title = {APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40665049},
issn = {1546-170X},
support = {MRF2040081//Department of Health | National Health and Medical Research Council (NHMRC)/ ; MRF2040081//Department of Health | National Health and Medical Research Council (NHMRC)/ ; K08AG08604//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG089497//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P50AG025688//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30AG072973//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21TR003589//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG07816//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U19AG068054//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35NS132179//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30AG072973//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30AG072973//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30AG072973//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG064227//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 23AARG-1023/ALZ/Alzheimer's Association/United States ; },
abstract = {The APOE ε4 genetic variant is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is increasingly being implicated in other neurodegenerative diseases. Using the Global Neurodegeneration Proteomics Consortium SomaScan dataset covering 1,346 cerebrospinal fluid (CSF) and 9,924 plasma samples, we used machine learning-based proteome profiling to identify an APOE ε4 proteomic signature shared across individuals with AD, frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and nonimpaired controls. This signature was enriched in pro-inflammatory immune and infection pathways as well as immune cells, including monocytes, T cells and natural killer cells. Analysis of the dorsolateral prefrontal cortex proteome for 262 donors from the Accelerating Medicines Partnership for AD UPenn Proteomics Study revealed a consistent APOE ε4 phenotype, independent of neurodegenerative pathology, including amyloid-β tau and gliosis for all diseases, as well as TDP-43 in ALS and FTD cases, and α-synuclein in PD and PDD cases. While systemic proteomic changes were consistent across APOE ε4 carriers, their relationship with clinical and lifestyle factors, such as hypertension and smoking, varied by disease. These findings suggest APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration, emphasizing the need to consider gene-environment interactions. Overall, our study reveals a conserved APOE ε4-associated pro-inflammatory immune signature persistent across the brain, CSF and plasma irrespective of neurodegenerative disease, highlighting a fundamental, disease-independent biological vulnerability to neurodegeneration. This work reframes APOE ε4 as a pleiotropic immune modulator rather than an AD-specific risk gene, providing a foundation for precision biomarker development and early intervention strategies across neurodegenerative diseases.},
}

@article {pmid40665048,
year = {2025},
author = {Imam, F and Saloner, R and Vogel, JW and Krish, V and Abdel-Azim, G and Ali, M and An, L and Anastasi, F and Bennett, D and Pichet Binette, A and Boxer, AL and Bringmann, M and Burns, JM and Cruchaga, C and Dage, JL and Farinas, A and Ferrucci, L and Finney, CA and Frasier, M and Hansson, O and Hohman, TJ and Johnson, ECB and Kivimaki, M and Korologou-Linden, R and Ruiz Laza, A and Levey, AI and Liepelt-Scarfone, I and Lu, L and Mattsson-Carlgren, N and Middleton, LT and Nho, K and Oh, HS and Petersen, RC and Reiman, EM and Robinson, O and Rothstein, JD and Saykin, AJ and Shvetcov, A and Slawson, C and Smets, B and Suárez-Calvet, M and Tijms, BM and Timmers, M and Vieira, F and Vilor-Tejedor, N and Visser, PJ and Walker, KA and Winchester, LM and Wyss-Coray, T and Yang, C and Bose, N and Lovestone, S and , },
title = {The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40665048},
issn = {1546-170X},
abstract = {More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.},
}

@article {pmid40664547,
year = {2025},
author = {Müllhaupt, G and Hechelhammer, L and Graf, N and Mordasini, L and Schmid, HP and Engeler, DS and Abt, D},
title = {Reply to Francesco Montorsi, Edoardo Pozzi, Marco Bianchi, et al's Letter to the Editor re: Gautier Müllhaupt, Lukas Hechelhammer, Nicole Graf, et al. Prostatic Artery Embolisation Versus Transurethral Resection of the Prostate for Benign Prostatic Obstruction: 5-year Outcomes of a Randomised, Open-label, Noninferiority Trial. Eur Urol Focus 2024;10:788-95.},
journal = {European urology focus},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.euf.2025.06.017},
pmid = {40664547},
issn = {2405-4569},
}

@article {pmid40664152,
year = {2025},
author = {Keivan Behjou, N and Seyedalipour, B and Hosseini Faradonbeh, SM and Hosseinkhani, S and Chaeichi, MJ},
title = {Exploring the role of ethylammonium bromide as an ionic liquid in amyloid aggregation modulation for ALS-linked hSOD1 E49K mutant.},
journal = {Bioorganic chemistry},
volume = {163},
number = {},
pages = {108740},
doi = {10.1016/j.bioorg.2025.108740},
pmid = {40664152},
issn = {1090-2120},
abstract = {Ionic liquids (ILs) offer a diverse and tunable approach to inhibiting amyloid protein formation, providing new strategies to develop anti-amyloidogenic agents for amyloid-based diseases, as explored in protein-IL research. This study explores the formation of amyloid aggregates of the E49K mutant under amyloidogenic conditions and evaluates the inhibitory potential of ethylammonium bromide (EABr) as an anti-amyloidogenic agent relevant to ALS pathology. The effect of EABr was studied using molecular dynamics simulations, FTIR spectroscopy, ANS fluorescence, ThT fluorescence, and TEM imaging. EABr promotes the formation of compact structures by reducing the exposure of contagious hydrophobic pockets in the E49K mutant aggregates, as monitored by ANS fluorescence. EABr binds with moderate affinity to the E49K mutant forms, inhibiting fibrillation by stabilizing aggregation-prone regions, as shown in fluorescence quenching. The decrease in ThT fluorescence intensity and the inhibition of fibril formation in a concentration-dependent manner highlight the interaction of EABr with the E49K mutant throughout the incubation period. TEM images during the saturation phase provide compelling evidence that EABr inhibits the formation of amyloid fibrils in the E49K mutant, thus supporting ThT analysis results. These findings demonstrate that EABr can inhibit amyloid formation of the E49K SOD1 mutant in vitro, supporting its potential as a lead compound for further pharmacological studies.},
}

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

@article {pmid40663766,
year = {2025},
author = {Matthews, AM and Whiteley, AM},
title = {UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.},
journal = {Biochemical Society transactions},
volume = {},
number = {},
pages = {},
doi = {10.1042/BST20253053},
pmid = {40663766},
issn = {1470-8752},
abstract = {Ubiquilins (UBQLNs) regulate cellular protein turnover by shuttling proteins, or 'clients', to the proteasome or autophagy pathways for degradation. Of the five different UBQLN genes in humans, UBQLN2 is the most highly expressed in the nervous system and muscle tissue and has been linked to multiple neurodegenerative diseases. In particular, point mutations of UBQLN2 cause an X-linked, dominant form of amyotrophic lateral sclerosis (ALS), ALS with frontotemporal dementia (ALS/FTD), or FTD. Failed protein degradation is a hallmark of many neurodegenerative diseases, including ALS and FTD; however, it is not clear exactly how ALS/FTD-associated UBQLN2 mutations contribute to pathogenesis. Recent studies have revealed the complexity of UBQLN2 biology and allow deeper understanding as to how UBQLN2 dysfunction may contribute to neurodegenerative disease. UBQLN2 is necessary for mitochondrial protein degradation and for regulating mitochondrial turnover, both of which are essential for motor neurons and have been implicated in the pathogenesis of ALS. Stress granule (SG) formation and regulation are also affected by UBQLN2 mutations, and their dysregulation may contribute to the toxic protein aggregation and SG changes observed in neurodegenerative disease. Finally, there are compelling links connecting UBQLN2 dysfunction with changes to downstream neuronal morphology, function, and behavior. This review will detail the emerging consensus on how UBQLN2 protects against neurodegenerative disease and will provide insights into potential therapeutic approaches.},
}

@article {pmid40661843,
year = {2025},
author = {Malmström, N and Öhlén, J and Nilsson, S and Nygren, I and Andersen, PM and Jakobsson Larsson, B and Ozanne, A},
title = {Transformed Parenthood in the Face of ALS: A Profound Struggle for Both Ill Parents and Co-parents.},
journal = {Global qualitative nursing research},
volume = {12},
number = {},
pages = {23333936251348143},
pmid = {40661843},
issn = {2333-3936},
abstract = {When a parent is diagnosed with a progressive, fatal neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS), it can have major effects on the family's health. Parenthood itself may also be affected, potentially fueling an urgent need for support from healthcare. Research focusing on this group of parents is nevertheless limited. The aim of this study was to illuminate the meaning of parenthood when a parent has ALS, from the perspective of ill parents and co-parents. An interpretive qualitative study was conducted, using data gathered from interviewing 26 parents (13 ill parents and 13 co-parents) with children living at home in Sweden. Applying a phenomenological hermeneutical analysis, structural analyses depicted the burdensome, complex impact that ALS can have on parenthood, redefining its meaning while forcing parents to face the difficult challenges it brings. The interpreted whole revealed how navigating this transformed parenthood meant a profound struggle, as the parents strived to balance their own emotional pain from grief and worry with remaining stable and supportive for their children. To promote the health of families affected by ALS, more proactive, tailored support is needed within ALS nursing, along with early integration of a palliative approach and attention to the parental perspective.},
}

@article {pmid40661641,
year = {2025},
author = {Foord, C and Prjibelski, AD and Hu, W and Michielsen, L and Vandelli, A and Narykov, O and Evans, B and Hsu, J and Belchikov, N and Jarroux, J and He, Y and Elizabeth Ross, M and Hajirasouliha, I and Tartaglia, GG and Korkin, D and Tomescu, AI and Tilgner, HU},
title = {A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.10.658877},
pmid = {40661641},
issn = {2692-8205},
abstract = {Genome-wide single-cell and spatial long-read approaches have gained traction, but mostly lack single-cell resolution - and yield limited read lengths. Here, we introduce spatial ISOform sequencing (Spl-ISO-Seq), which reveals exons and polyadenylation sites from long reads with near-single-cell resolution. Spl-ISO-Seq selects long cDNAs and doubles to triples read lengths compared to standard preparations. Adding a highly specific software tool (Spl-ISOquant) and comparing human post-mortem pre-puberty samples of the visual cortex (8-11 years) to post-puberty samples (16-19 years), we find that cortical layers harbor stronger splicing and poly(A)-site regulation than the adjacent white matter, with enrichment of multiple protein-domain types. For oligodendrocytes however, developmental splicing changes are stronger in white matter. Among cortical layers, layer 4 has the most developmental changes in alternative-exon inclusion in excitatory neurons and in poly(A) sites. We also find many repeat elements, especially ERV1 long terminal repeats downstream of developmentally-regulated layer 4 exons. Overall, alternative splicing changes are linked to synapses - specifically at the post-synapse. Age-linked splicing changes in layers 1-3 and 4 are associated with autism spectrum disorder but not with schizophrenia, amyotrophic lateral sclerosis and Alzheimer's disease. These results root developmental splicing changes during puberty and the resulting protein changes in specific layers and cell types. More generally, our new technologies enable new observations for any complex tissue.},
}

@article {pmid40661462,
year = {2025},
author = {Ye, Y and Zhang, Z and Xiao, Y and Zhu, C and Wright, N and Asbury, J and Huang, Y and Wang, W and Gomez-Isaza, L and Troncoso, JC and He, C and Sun, S},
title = {DCPS modulates TDP-43 mediated neurodegeneration through P-body regulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.13.659508},
pmid = {40661462},
issn = {2692-8205},
abstract = {The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping enzyme scavenger (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation, via disrupting the properties and function of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.},
}

@article {pmid40661327,
year = {2025},
author = {Kawakami, Y and Iguchi, Y and Li, J and Amakusa, Y and Yoshimura, T and Chikuchi, R and Yokoi, S and Iida, M and Riku, Y and Iwasaki, Y and Hirose, T and Nakagawa, S and Katsuno, M},
title = {Downregulation of NEAT1 due to loss of TDP-43 function exacerbates motor neuron degeneration in amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {4},
pages = {fcaf261},
pmid = {40661327},
issn = {2632-1297},
abstract = {TAR DNA-binding protein 43 (TDP-43) is of particular interest in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been speculated that loss of nuclear TDP-43 and its cytoplasmic aggregation contributes to neurodegeneration. Although considerable attention has been paid to RNA metabolism in TDP-43 function, TDP-43 is also known to act as a transcription factor. This study found that the expression of Nuclear-enriched abundant transcript 1 (NEAT1), a long-non-coding RNA, was substantially downregulated in motor neurons with nuclear TDP-43 loss, but upregulated in those with preserved nuclear TDP-43, in the postmortem spinal cords of patients with sporadic ALS. TDP-43 depletion induced Neat1 downregulation in Neuro2a cells, primary cortical neurons, and mouse spinal motor neurons. Furthermore, TDP-43 was found to positively regulate NEAT1 at the transcriptional level. Finally, Neat1 knockout exacerbates neurodegeneration of hSOD1[G93A] mice accompanied by increased misfolded superoxide dismutase 1 (SOD1) aggregations. Transcriptome analysis revealed that Neat1 knockout reduced protein folding-related genes, such as heat shock protein family A member 1A (Hspa1a), in the spinal cords of hSOD1[G93A] mice. Our results indicated that the loss of TDP-43 function enhances ALS neurodegeneration by losing the protective effect of NEAT1.},
}

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

@article {pmid40661236,
year = {2025},
author = {López-Royo, T and Moreno-Martínez, L and Rada, G and Macías-Redondo, S and Calvo, AC and García-Redondo, A and Manzano, R and Osta, R},
title = {LncRNA levels in the central nervous system as novel potential players and biomarkers in amyotrophic lateral sclerosis.},
journal = {Non-coding RNA research},
volume = {14},
number = {},
pages = {145-155},
pmid = {40661236},
issn = {2468-0540},
abstract = {Research in amyotrophic lateral sclerosis (ALS) faces major burdens, including the urgent need for sensitive and specific biomarkers, the identification of novel and effective therapeutic targets and a deeper understanding of the mechanisms driving the disease. In this line, long non-coding RNAs (lncRNAs) have emerged as promising candidates due to their regulatory role in a variety of important biological processes such as RNA metabolism, neuroinflammation, apoptosis or proteostasis. This study aims to elucidate the expression profile of 14 lncRNAs in both the SOD1[G93A] mouse model and ALS patients. Different stages of the disease (presymptomatic, symptomatic and terminal) and 3 regions of the central nervous system (CNS) differentially affected by ALS (spinal cord, brainstem and frontal cortex) were included in the experimental design. In SOD1[G93A] mice, all 14 lncRNAs exhibited differential expression patterns influenced by sex, age, and region, except for Malat1, Neat1, and H19, which displayed consistent expression patterns (Malat1 was decreased, while Neat1 and H19 were increased). These patterns were most prominent in the spinal cord, where lncRNAs were overall down-regulated. In contrast, in the brainstem and frontal cortex, lncRNAs were predominantly up-regulated. Notably, Gas5 expression levels in frontal cortex and spinal cord at the terminal stage correlated with the onset and progression of motor coordination and strength decline. Additionally, three lncRNAs (Gas5, Neat1 and Myoparr) were found to significantly correlate with survival. In human ALS samples, increased levels of NEAT1 and SNHG16 were observed in the brainstem, and of MEG3 and H19 in the frontal cortex, whereas MALAT1 levels were decreased in frontal cortex. In conclusion, this work supports lncRNAs as promising candidates as novel players and potential biomarkers in ALS and highlights SOD1[G93A] mice as a good model to study lncRNAs in the CNS in the context of this disease.},
}

@article {pmid40660446,
year = {2025},
author = {Singh, D},
title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.},
journal = {Current drug safety},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748863375490250626163609},
pmid = {40660446},
issn = {2212-3911},
abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.},
}

@article {pmid40660191,
year = {2025},
author = {Schmidt, R and Slotina, E and Meissner, F and Metelmann, M and Ilse, B and Vogt, V and Freytag, A},
title = {Palliative care pathways in Amyotrophic Lateral Sclerosis (ALS): a sequence analysis of health claims data.},
journal = {BMC palliative care},
volume = {24},
number = {1},
pages = {200},
pmid = {40660191},
issn = {1472-684X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; *Palliative Care/methods/statistics & numerical data/standards ; Male ; Female ; Cross-Sectional Studies ; Retrospective Studies ; Germany ; Aged ; Middle Aged ; Adult ; Insurance Claim Review/statistics & numerical data ; Aged, 80 and over ; *Critical Pathways/statistics & numerical data/standards ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease requiring palliative care. Despite the availability of palliative care services, utilization patterns among people with ALS (pALS) remain poorly understood. This study aimed to analyze palliative care utilization (i.e., primary palliative care (PPC), specialized palliative homecare (SPHC), inpatient palliative care, hospice services) in the last year of life among pALS, to identify distinct care pathways using sequence analysis, and examine their association with end-of-life care quality.

METHODS: A retrospective cross-sectional study using German health claims data (2016 - 2019). Sequence analysis with Temporal Needleman-Wunsch alignment and clustering identified pathway clusters based on type, order, and timing of palliative care services. The study included 1,295 pALS who died between 2016 and 2019 and were insured with a large German health insurance provider. Inclusion required an ALS diagnosis without concurrent cancer.

RESULTS: Of 1,295 pALS, 695 (53.7%) received palliative care. Sequence analysis identified nine distinct care pathway clusters. Quality indicators varied highly across clusters. Pathways involving SPHC, either alone, with PPC, and/or with hospice care, showed fewer emergency visits, hospital stays, and in-hospital deaths, suggesting higher end-of-life care quality.

CONCLUSIONS: Palliative care utilization varies substantially in type, order, and timing. Findings suggest that end-of-life care quality depends not only on the provision of palliative care but also on when and on how different services are combined. Future research should examine the role of interdisciplinary collaboration in palliative care pathways and explore preferences and clinical characteristics of pALS to better understand factors influencing end-of-life care quality.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/psychology
*Palliative Care/methods/statistics & numerical data/standards
Male
Female
Cross-Sectional Studies
Retrospective Studies
Germany
Aged
Middle Aged
Adult
Insurance Claim Review/statistics & numerical data
Aged, 80 and over
*Critical Pathways/statistics & numerical data/standards

@article {pmid40659932,
year = {2025},
author = {Castelnovo, V and Canu, E and Basaia, S and Spinelli, EG and Freri, F and Schito, P and Russo, T and Falzone, Y and Verde, F and Torre, S and Poletti, B and Tremolizzo, L and Appollonio, I and Ticozzi, N and Silani, V and Filippi, M and Agosta, F},
title = {Brain functional connectivity changes in amyotrophic lateral sclerosis with apathy and depression.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {509},
pmid = {40659932},
issn = {1432-1459},
support = {StG-2016_714388_NeuroTRACK//H2020 European Research Council/ ; Investment PE8 - Project Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications/psychology ; *Apathy/physiology ; Male ; Female ; Middle Aged ; *Depression/diagnostic imaging/physiopathology/etiology ; Aged ; *Brain/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging ; Connectome ; Neural Pathways/physiopathology/diagnostic imaging ; },
abstract = {BACKGROUND: Apathy and depression are the most prevalent neuropsychiatric symptoms in amyotrophic lateral sclerosis (ALS). Although insufficiently investigated, their distinction holds important clinical relevance for accurate diagnosis of ALS with behavioural impairment and for patients' prognosis and management. In the present study, we aimed to assess both apathy and depressive symptoms in patients with ALS and whether they have similar or different functional neural correlates.

METHODS: Using graph analysis and connectomics, global and lobar nodal properties and regional functional brain connectivity were assessed in ALS patients without apathy/depression (ALSn, n = 42), with apathy without depression (ALSa, n = 14), with depressive symptoms without apathy (ALSd, n = 20), and with apathy and depressive symptoms (ALSad, n = 6), and 46 healthy controls. Correlations between brain functional properties, apathy and depressive symptoms were performed in all patients.

RESULTS: Depressive symptoms were related with reduced path length within bilateral basal ganglia (BG) network, and apathy was related with increased path length, decreased nodal strength and local efficiency within left BG network. ALSa patients showed altered functional nodal properties within BG network compared to ALSn and ALSd. Compared to healthy controls and all non-apathetic patients (ALSn and ALSd), all apathetic patients (ALSa and ALSad) exhibited altered functional nodal properties within parietal, occipital and frontal networks. Non-apathetic patients, compared to apathetic patients, showed relatively preserved functional nodal properties in the BG network.

CONCLUSIONS: Our findings indicate differences in brain functional neural organization associated with apathy and depression, underscoring the importance of distinguishing these symptoms in ALS and highlighting the need for targeted interventions.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications/psychology
*Apathy/physiology
Male
Female
Middle Aged
*Depression/diagnostic imaging/physiopathology/etiology
Aged
*Brain/physiopathology/diagnostic imaging
Magnetic Resonance Imaging
Connectome
Neural Pathways/physiopathology/diagnostic imaging

@article {pmid40659544,
year = {2025},
author = {Stenvall, E and Grönlund, KÅ and Rohan, Z and Zetterström, P and Nordin, A and Forsberg, K},
title = {Pathology of three ALS patients with FUS variants, including one likely benign Q23L variant lacking FUS inclusions.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf119},
pmid = {40659544},
issn = {1460-2083},
support = {FO2023-0088//Swedish Brain Foundation/ ; FO2024-0232//Swedish Brain Foundation/ ; //Börje Salming ALS Foundation/ ; 2023.10//Ulla-Carin Lindquist Foundation/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; //Neuroförbundet Association/ ; RV-1005785//Västerbotten County Council/ ; RV-1013622//Västerbotten County Council/ ; RV-993493//Västerbotten County Council/ ; RV-996234//Västerbotten County Council/ ; RV-1014212//Västerbotten County Council/ ; RV-996140//Västerbotten County Council/ ; },
abstract = {Fused in sarcoma (FUS) is an RNA-binding protein implicated in juvenile amyotrophic lateral sclerosis (ALS). Mutations in the FUS gene, particularly those affecting the nuclear localization signal (NLS), impair nuclear import and lead to cytoplasmic accumulation of FUS inclusions in motor neurons. However, the pathological and clinical significance of FUS variants outside the NLS remains less understood. Here, we describe clinical and histopathological findings from three ALS patients carrying FUS variants: two with NLS-region variants (R495X and P525L), and one with a variant in the N-terminal region outside the NLS (Q23L). The patients carrying NLS variants presented with aggressive, juvenile-onset spinal and bulbar ALS, characterized primarily by lower motor neuron involvement and rapid disease progression. In contrast, the Q23L patient exhibited a slowly progressive disease course, with predominantly upper motor neuron signs. Neuropathological analysis revealed cytoplasmic FUS inclusions in motor neurons of patients with NLS variants, consistent with typical FUS pathology. In contrast, the Q23L patient lacked FUS inclusions and instead displayed pTDP-43 pathology in the hippocampus, neocortex (including the motor cortex), nucleus olivaris, lentiform nucleus, striatum, and some lower motor neurons. Taken together, these results suggest that Q23L is most likely a benign variant. As antisense oligonucleotides (ASOs) targeting FUS are currently being explored in clinical trials, further neuropathological investigations are needed to determine whether ASO-mediated FUS silencing would be effective for patients carrying FUS variants outside the NLS region.},
}

@article {pmid40659018,
year = {2025},
author = {Yang, EJ},
title = {Combined herbal medicine (A. bidentata, G. elata, and C. sinensis) increases anti-inflammatory and anti-oxidative effects in a mouse model of amyotrophic lateral sclerosis.},
journal = {Pharmacology},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000547388},
pmid = {40659018},
issn = {1423-0313},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons, finally leading to death by respiratory failure. However, no effective drug is available for treating patients with ALS owing to the complex pathological mechanisms. Herbal medicines are globally known for the effects of their multiple bioactive components and lack of adverse effects.

OBJECTIVE: This study investigated the effects of a combined herbal medicine formulation containing Achyranthes bidentata Blume, Gastrodia elata Blume, and Chaenomeles sinensis Koehne extracts on motor function and to analyze the underlying biological mechanisms in the gastrocnemius and tibia anterior muscles and spinal cord of hSOD1G93A mice.

METHODS: Rotarod and footprint analyses were performed to examine motor function. The biological mechanisms were examined using western blot and immunohistochemistry analyses of the muscles and spinal cord in hSOD1G93A mice.

RESULTS: Herbal medicine treatment improved motor function in hSOD1G93A mice by reducing the expression of inflammation-related proteins (glial fibrillary acidic protein and CD11b) and oxidative stress-related proteins (heme oxygenase 1 and ferritin) in the gastrocnemius and tibia anterior muscles and spinal cord. It also regulated autophagy in the muscles and spinal cord of hSOD1G93A mice.

CONCLUSIONS: Collectively, these findings suggest that the herbal medicine formulation reported herein may facilitate management of diseases with complex pathological mechanisms, such as ALS, or those with unclear pathological mechanisms.},
}

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

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

@article {pmid40655414,
year = {2025},
author = {Thiry, L and Sirois, J and Durcan, TM and Stifani, S},
title = {Derivation and Culture of Enriched Phrenic-Like Motor Neurons From Human iPSCs.},
journal = {Bio-protocol},
volume = {15},
number = {13},
pages = {e5363},
pmid = {40655414},
issn = {2331-8325},
abstract = {The fatal motor neuron (MN) disease amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of the phrenic MNs (phMNs) controlling the activity of the diaphragm, leading to death by respiratory failure. Human experimental models to study phMNs are lacking, hindering the understanding of the mechanisms of phMN degeneration in ALS. Here, we describe a protocol to derive phrenic-like MNs from human induced pluripotent stem cells (hiPSC-phMNs) within 30 days. During spinal cord development, phMNs emerge from specific MN progenitors located in the dorsalmost MN progenitor (pMN) domain at cervical levels, under the control of a ventral-to-dorsal gradient of Sonic hedgehog (SHH) signaling and a rostro-caudal gradient of retinoic acid (RA). The method presented here uses optimized concentrations of RA and the SHH agonist purmorphamine, followed by fluorescence-activated cell sorting (FACS) of the resulting MN progenitor cells (MNPCs) based on a cell-surface protein (IGDCC3) enriched in hiPSC-phMNs. The resulting cultures are highly enriched in MNs expressing typical phMN markers. This protocol enables the generation of hiPSC-phMNs and is highly reproducible using several hiPSC lines, offering a disease-relevant system to study mechanisms of respiratory MN dysfunction. While the protocol has been validated in the context of ALS research, it can be adopted to study human phrenic MNs in other research fields where these neurons are of interest. Key features • This protocol generates enriched hiPSC-derived phrenic motor neuron cultures. • The protocol can be used to develop models to study human respiratory motor neuron disease. • The protocol allows the generation of phrenic motor neuron preparations with potential for motor neuron replacement strategies. • The protocol requires experience in hiPSC culturing and FACS-based cell sorting for a successful outcome.},
}

@article {pmid40655294,
year = {2025},
author = {Rinofner-Kreidl, S},
title = {Ist das Gegebene noch zu retten? Über Chancen und Gefahren einer Politisierung der Phänomenologie.},
journal = {Husserl studies},
volume = {41},
number = {2},
pages = {267-302},
doi = {10.1007/s10743-025-09363-5},
pmid = {40655294},
issn = {0167-9848},
abstract = {Dieser Essay zielt darauf, eine Mehrdeutigkeit der Rede von "Politisierung" herauszuarbeiten, die sowohl für die Selbstkritik phänomenologischen Denkens als auch für die Kritik der Phänomenologie als eines öffentlichen Diskurses von Bedeutung ist. Die fraglichen Unterschiede betreffen das Verständnis dessen, was infolge einer Politisierung des Denkens anders konzipiert, kontextualisiert oder interpretiert wird, ob eine Politisierung intrinsisch oder extrinsisch motiviert und begründet ist und wie Art und Reichweite der daran geknüpften Ansprüche argumentiert werden können. Zwei Optionen werden erörtert: (1) eine interne Politisierung, die als phänomenologisch-methodischer Umgang mit Gegebenem und als kollektiv praktizierter Evidenzstil charakterisiert wird; (2) eine externe Politisierung, die sich als standort- und kontextabhängige weltanschauliche Idee und Praxis darstellt. Letztere versteht sich als eine politische Forderung und Erwartung, die eine thematisch einseitige bzw. verengte und / oder unreflektierte, unkritische, womöglich vorurteils- und ressentimentgeleitete phänomenologische Untersuchung korrigiert. Es wird argumentiert, dass interne Politisierung auf einer Metaebene stattfindet, auf der über Natur und Selbstbegrenzung der phänomenologischen Analyse nachgedacht wird. In konkreten Phänomenanalysen schlägt sich interne Politisierung lediglich indirekt, über deren methodische und theoretische Rahmung, nieder. Interne Politisierung ist mit autonomer Vernunftausübung verträglich. Dies gilt nicht für jede Form externer Politisierung, die als direkter Eingriff auf der gegenständlichen Ebene, im Zuge der Interpretation konkreter Phänomene, erfolgt. Zu klären ist: Wie können zulässige und eventuell unabdingbare Formen von Politisierung von unzulässigen unterschieden werden? Unter welchen Bedingungen unterliegt die Politisierung des Denkens einem Selbstwiderlegungseinwand?},
}

@article {pmid40654997,
year = {2025},
author = {Barbieri, EM and Linsenmeier, M and Whiteman, KR and Cheng, Y and Braganza, S and Copley, KE and Miranda-Castrodad, P and Lewis, B and Villafañe, K and Amado, DA and Davidson, BL and Shorter, J},
title = {Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.10.653282},
pmid = {40654997},
issn = {2692-8205},
abstract = {Cytoplasmic aggregation and concomitant dysfunction of the prion-like, RNA-binding protein TDP-43 underpin several fatal neurodegenerative diseases, including amyotrophic lateral sclerosis. To elucidate endogenous defenses, we systematically scoured the entire human Hsp70 network for buffers of TDP-43 toxicity. We identify 30 J-domain proteins (2 DNAJAs, 10 DNAJBs, 18 DNAJCs), 6 Hsp70s, and 5 nucleotide-exchange factors that mitigate TDP-43 toxicity. Specific chaperones reduce TDP-43 aggregate burden and detoxify diverse synthetic or disease-linked TDP-43 variants. Sequence-activity mapping unveiled unexpected, modular mechanisms of chaperone-mediated protection. Typically, DNAJBs collaborate with Hsp70 to suppress TDP-43 toxicity, whereas DNAJCs act independently. In human cells, specific chaperones increase TDP-43 solubility and enhance viability under proteotoxic stress. Strikingly, spliceosome-associated DNAJC8 and DNAJC17 retain TDP-43 in the nucleus and promote liquid-phase behavior. Thus, we disambiguate a diverse chaperone arsenal embedded in the human proteostasis network that counters TDP-43 toxicity and illuminate mechanistic gateways for therapeutic intervention in TDP-43 proteinopathies.},
}

@article {pmid40654973,
year = {2025},
author = {Sangwan, S and Rieder, HE and Moore, D and Khanlou, N and Novitch, B and Geisberg, M and Eisenberg, DS},
title = {A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.05.652290},
pmid = {40654973},
issn = {2692-8205},
abstract = {Antibodies offer versatility as diagnostic and therapeutic tools to target specific protein epitopes. However, the transient nature of intermediate protein conformations, such as that of amyloid oligomers, poses a challenge for antibody development. We use a structure-guided approach to generate a monoclonal antibody against oligomers of Superoxide Dismutase 1 (SOD1). Mutations in SOD1 are linked to a subset of familial Amyotrophic Lateral Sclerosis (fALS), a fatal neurodegenerative disease. Based on the corkscrew-like features of non-native SOD1 oligomers previously determined, we generate an antibody specific to SOD1 oligomers. We show that the antibody, CSAb detects SOD1 oligomers, not fibrils or native SOD1, and alleviates the cytotoxic effects of SOD1 oligomers in a cell culture model of primary motor neurons. Immunohistochemical analyses of human ALS subjects show CSAb reactivity in both neuronal and non-neuronal cells. Finally, we provide evidence that CSAb reactive SOD1 oligomers are present in non-SOD1 linked fALS and sporadic ALS subjects. Together, our study provides a new probe against SOD1 oligomers and suggests that cytotoxic SOD1 oligomers are prevalent in diverse ALS genotypes.},
}

@article {pmid40654957,
year = {2025},
author = {Sheth, U and Harrison, R and Ferber, K and Rosenbaugh, EG and Bevis, A and Khillan, R and Benatar, M and Bjorklund, NL and Di Daniel, E and Harris, GA and Kahn, OI and Liu, Y and Zetterberg, H and Mitic, LL and Graham, D and Gendron, TF},
title = {Measuring neurofilament light in human plasma and cerebrospinal fluid: a comparison of five analytical immunoassays.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.05.652212},
pmid = {40654957},
issn = {2692-8205},
abstract = {OBJECTIVES: Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays.

METHODS: To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS.

RESULTS: Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL.

CONCLUSIONS: Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, useability, footprint, and intended use, should be considered.},
}

@article {pmid40654715,
year = {2025},
author = {Van Zuiden, W and Meimoun, TD and Bar, C and Siany, A and Moshe, L and Yacovzada, NS and Weizman, E and Neumann, M and Buchman, AS and Wang, Y and Bennett, DA and Glass, JD and Trautwig, AN and Seyfried, NT and Cooper-Knock, J and Hornstein, E},
title = {TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.20.648873},
pmid = {40654715},
issn = {2692-8205},
abstract = {Loss of nuclear TDP-43 splicing activity is a common feature across neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but its relevance to Alzheimer's disease (AD) remains unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities, including aberrant splicing of amyloid precursor protein (APP). TDP-43 drives the formation of elongated APP isoforms, disrupting alternative splicing across ALS, FTLD-TDP and AD, providing a compelling mechanism for a long-standing observation of APP isoform dysregulation. We further establish a mechanistic link between TDP-43, APP splicing, and A-beta pathology. Surprisingly, the disruption to alternative APP splicing is mediated by a toxic gain of cytoplasmic TDP-43 function, rather than loss of its nuclear role. Using proximity proteomics and base editing in human iPSC-derived neurons, we show that TDP-43 pathology causes cytoplasmic co-sequestration of splicing regulators SCAF11, SRSF5, and TIAL1. Knockdown of these regulators also results in APP mis-splicing and increased A-beta burden, without affecting other TDP-43 targets such as STMN2 or UNC13A. Together, our findings suggest that TDP-43-mediated splicing dysfunction upstream of APP contributes to the pathogenesis of seemingly disparate neurodegenerative diseases, uniting AD and ALS/FTLD-TDP through a shared molecular mechanism.},
}

@article {pmid40653816,
year = {2025},
author = {Bozovic, I and Licina, E and Bjelica, B and Milicevic, O and Palibrk, A and Basta, I and Peric, S and Pavlovic, A and Stevic, Z and Mijajlovic, M},
title = {Transcranial Brain Parenchyma Sonographic Findings in Familial and Sporadic Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {32},
number = {7},
pages = {e70272},
doi = {10.1111/ene.70272},
pmid = {40653816},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; *Ultrasonography, Doppler, Transcranial/methods ; Adult ; *Brain/diagnostic imaging ; *Substantia Nigra/diagnostic imaging ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. Transcranial sonography (TCS) is a valuable tool for assessing deep brain structures. This study aimed to analyze TCS findings in both sporadic (sALS) and familial ALS (fALS) patients and compare them to healthy controls (HC).

METHODS: This cross-sectional study included 278 patients with sALS and 31 patients with genetically confirmed fALS, and 93 age- and gender- matched HC. TCS was used to assess substantia nigra (SN) and brainstem raphe (BR) echogenicity and third ventricle diameter (TVD). Functional disability was evaluated using the ALS Functional Rating Scale-Revised.

RESULTS: BR hypoechogenicity was more frequent in fALS (41.9%) and sALS (37.4%) patients, compared to HC (10.8%) (p < 0.001). Right SN hyperechogenicity was observed in 28.1% of sALS, 16.1% of fALS, and 8.6% of HC (p = 0.004). Left SN hyperechogenicity was found in 33.5% of sALS, 29.0% of fALS, and 4.3% of HC (p = 0.004). SN hyperechogenicity findings on either side were highest in sALS (48.4%) compared to fALS (31.0%) and HC (13.3%) (p < 0.001), with a borderline difference between fALS and sALS (p = 0.08). BR hypoechogenicity and SN hyperechogenicity were more common in male patients. Increased TVD correlated with older age, later disease onset, bulbar onset, and lower MMSE scores.

CONCLUSIONS: TCS is an easily applicable and sensitive diagnostic tool that offers novel insights into several brainstem structures and identify significant differences in their echogenicity between ALS patients and healthy controls, while pointing out similar but not identical patterns of echogenicity in both ALS forms.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology
Male
Female
Middle Aged
Cross-Sectional Studies
Aged
*Ultrasonography, Doppler, Transcranial/methods
Adult
*Brain/diagnostic imaging
*Substantia Nigra/diagnostic imaging

@article {pmid40653481,
year = {2025},
author = {Marabita, M and Marchioretti, C and Aravamudhan, A and Zito, S and Falconieri, A and Zuccaro, E and Andreotti, R and Gambarotto, L and Metti, S and Tonellato, M and Adami, V and Park, KH and Gunthorpe, MJ and Large, CH and Marasco, A and Vianello, S and Rosati, J and Belluzzi, E and Pozzuoli, A and Biz, C and Ruggieri, P and Basso, M and Poletti, A and Alvaro, G and Sorarù, G and Bonaldo, P and Rossetto, O and Pilati, N and Pennuto, M},
title = {Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {153},
pmid = {40653481},
issn = {2051-5960},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; *Shaw Potassium Channels/agonists/metabolism/genetics ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Mice ; Phenotype ; Muscle, Skeletal/metabolism/drug effects/pathology ; Male ; Mice, Inbred C57BL ; Female ; Superoxide Dismutase-1/genetics ; },
abstract = {Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics
*Shaw Potassium Channels/agonists/metabolism/genetics
Disease Models, Animal
Humans
Mice, Transgenic
Mice
Phenotype
Muscle, Skeletal/metabolism/drug effects/pathology
Male
Mice, Inbred C57BL
Female
Superoxide Dismutase-1/genetics

@article {pmid40655970,
year = {2023},
author = {Vardheim, EG and Toft, A and Nielsen, JE and Hasselbalch, SG and Simonsen, AH},
title = {Cerebrospinal fluid ubiquitin as a biomarker for neurodegenerative diseases: A systematic review.},
journal = {Neuroscience applied..},
volume = {2},
number = {},
pages = {102438},
pmid = {40655970},
issn = {2772-4085},
abstract = {Ubiquitin plays a vital role in neuronal proteostasis, as a major but often overlooked component of neurotoxic protein aggregates across neurodegenerative diseases. Although neuropathological changes can be present for years before clinical onset, early and accurate diagnosis remains an immense challenge in this disease category. The level of ubiquitin in cerebrospinal fluid (CSF) has been assessed as a biomarker for several disease entities. This systematic review compares current findings and evaluates the potential of CSF ubiquitin as a fluid biomarker. A systematic literature search identified studies comparing CSF ubiquitin levels between a control group and patients with one of the following diseases: Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Lewy body dementia (DLB), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). All included studies were reviewed systematically by two independent authors. 171 studies were identified. A total of 17 studies met the eligibility criteria and were included. Nine out of 13 studies found a significant increase of CSF ubiquitin in AD patients compared with control groups. Correlations between CSF ubiquitin and other established biomarkers were demonstrated in seven studies. A single study was included for both HD and DLB respectively, each showing significantly higher CSF ubiquitin in patients compared to controls. In patients with PD, FTD or ALS, CSF ubiquitin levels were generally equal to those of the control groups, with two studies showing significantly decreased concentrations in a PD and an FTD cohort. Presently, the available body of research is insufficient to assess whether CSF ubiquitin could contribute to the clinical setting, alongside established markers of neurodegeneration. The correlation of elevated CSF ubiquitin with AD is well-founded, whilst validation of reduced or unchanged levels in the other neurodegenerative diseases will determine the usefulness of the biomarker in clinical practice.},
}

@article {pmid40653468,
year = {2025},
author = {Liu, Z and Sun, L and Gao, N and Li, W and Pang, L},
title = {Reciprocal regulation of GPNMB/HIF-1α for Inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {154},
pmid = {40653468},
issn = {2051-5960},
support = {JJKH20231233KJ//Jilin Provincial Education Department/ ; Z2023LJL001//Tianhua Health Foundation of Jilin Province/ ; 82372211//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ferroptosis/physiology/drug effects ; Rats ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; *Carbon Monoxide Poisoning/metabolism/complications ; Male ; Rats, Sprague-Dawley ; *Neurons/metabolism/pathology ; *Membrane Glycoproteins/metabolism ; PC12 Cells ; *Brain Diseases/metabolism/etiology/pathology ; Oxidative Stress/physiology/drug effects ; },
abstract = {Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most common complication after acute carbon monoxide (CO) poisoning. However, the pathogenesis of DEACMP remains ambiguous. The neuroprotective role of GPNMB has been observed in amyotrophic lateral sclerosis and Parkinson's disease. GPNMB was elevated in the brain tissues of DEACMP rats, while its function in DEACMP remains unclear. In this study, a CO poisoning rat model and oxygen-glucose deprivation (OGD)-treated PC-12 cells were established as an in vivo and in vitro DEACMP model, respectively. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) ameliorated cognitive impairment, inflammation and oxidative stress of rats with DEACMP as assessed by Morris Water Maze test, ELISA assay and commercial kits of oxidative markers. Immunofluorescence, qRT-PCR or western blot showed that GPNMB was elevated in CA1 hippocampal tissues of CO-poisoned rats. Additionally, TUNEL staining, ELISA assay and western blot revealed that GPNMB rescued OGD-induced cell apoptosis, inflammation and ferroptosis in PC-12 cells. Mechanistical study showed that STAT3 was a transcriptional activator of GPNMB as detected by luciferase and ChIP assays, and co-immunoprecipitation and immunofluorescence staining revealed that GPNMB stabilized HIF-1α by direct binding. Functionally, GPNMB protected against OGD-induced impairments via inducing HIF-1α. Furthermore, GPNMB attenuated cognitive impairment, oxidative stress and neuronal ferroptosis of rats with DEACMP. In conclusion, GPNMB/HIF-1α exhibited neuroprotective effects via suppressing ferroptosis in DEACMP.},
}

Animals
*Ferroptosis/physiology/drug effects
Rats
*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
*Carbon Monoxide Poisoning/metabolism/complications
Male
Rats, Sprague-Dawley
*Neurons/metabolism/pathology
*Membrane Glycoproteins/metabolism
PC12 Cells
*Brain Diseases/metabolism/etiology/pathology
Oxidative Stress/physiology/drug effects

@article {pmid40653411,
year = {2025},
author = {Wei, Y and Zhang, Y and Yu, D},
title = {Low-dose IL-2 reinvigorates the immunoguardians of neurodegenerative diseases.},
journal = {Trends in immunology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.it.2025.07.004},
pmid = {40653411},
issn = {1471-4981},
abstract = {Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.},
}

@article {pmid40652712,
year = {2025},
author = {Brüge, A and Ponimaskin, E and Labus, J},
title = {Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.},
journal = {Pharmacological reviews},
volume = {77},
number = {5},
pages = {100071},
doi = {10.1016/j.pharmr.2025.100071},
pmid = {40652712},
issn = {1521-0081},
abstract = {More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.},
}

@article {pmid40651399,
year = {2025},
author = {Ma, Y and Wu, S and Liu, H and Ren, C and Xie, Y and Deng, G and Yao, S and Wang, X and Qin, C},
title = {Sodium lignosulfonate alkylates based-biosurfactants for efficient remediation of oily sludge.},
journal = {Journal of environmental management},
volume = {391},
number = {},
pages = {126553},
doi = {10.1016/j.jenvman.2025.126553},
pmid = {40651399},
issn = {1095-8630},
abstract = {An alkylated sodium lignosulphonate (ALS) was prepared for highly efficient thermal washing treatment of oily sludge. The ALS was characterized for their chemical structure and surface activity. Furthermore, ALS was used as a thermal cleaning agent to treat oily sludge under different conditions to obtain an optimal thermal washing process. Finally, the oily sludge before and after thermal washing were characterized to explore its structural and compositional changes. Results obtained from the Fourier Transform Infrared spectroscopy (FT-IR) and Two-dimensional Heteronuclear Single Quantum Coherence(2D-HSQC) confirmed the successful grafting of fatty acid chains(C12) onto the LS molecules. ALS was an ideal surfactant with suitable HLB value and excellent surface tension reduction, foaming and emulsification properties. The optimum thermal washing process for oily sludge was: thermal washing temperature 30 °C, ALS concentration 1.5 g/L.},
}

@article {pmid40651326,
year = {2025},
author = {Yang, S and Ma, Y and Fu, H and Wang, C and Zhang, Y},
title = {Association between allostatic load and trouble sleeping in U.S. adults.},
journal = {Journal of psychosomatic research},
volume = {196},
number = {},
pages = {112206},
doi = {10.1016/j.jpsychores.2025.112206},
pmid = {40651326},
issn = {1879-1360},
abstract = {OBJECTIVE: This study examined the association between allostatic load and trouble sleeping and assessed whether this relationship varies based on allostatic load score (ALS) criteria.

METHODS: This cross-sectional survey utilized nationally representative data from the National Health and Nutrition Examination Survey (NHANES). ALS was derived using empirical and clinical criteria based on eight biomarkers reflecting cardiovascular, metabolic, and immune function. Weighted multivariate logistic regression was employed to analyze the association between ALS and trouble sleeping, with subgroup analyses conducted to assess gender-specific differences.

RESULTS: Of 5331 participants included in this study, 1485 (29 %) reported trouble sleeping. In multivariate-adjusted logistic regression, higher ALS was associated with increased odds of trouble sleeping (empirical ALS: OR 1.13 [95 % CI 1.07-1.18]; clinical ALS: OR 1.08 [95 % CI 1.04-1.13]). Subgroup analyses confirmed the consistency of this association across genders.

CONCLUSION: This study provides robust evidence of a significant association between ALS and trouble sleeping, supported by observed OR of 1.13 (empirical) and 1.08 (clinical). The consistency of findings across both empirical and clinical ALS underscores the potential role of physiological dysregulation in sleep health, highlighting the need for integrated approaches to stress and sleep management.},
}

@article {pmid40651187,
year = {2025},
author = {Chang, J and Teo, AH and Shaw, TB and Dupuis, L and Ngo, ST and Steyn, FJ},
title = {Deciphering hypothalamic pathology in ALS: insights into non-motor symptoms and disease progression.},
journal = {EBioMedicine},
volume = {118},
number = {},
pages = {105845},
doi = {10.1016/j.ebiom.2025.105845},
pmid = {40651187},
issn = {2352-3964},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with highly heterogeneous clinical presentations. Among the non-motor features increasingly recognised as clinically relevant is the dysregulation of energy balance, with weight loss-particularly due to fat mass loss-emerging as a significant modifier of disease risk, progression, and survival. In this context, the hypothalamus-a key regulator of homeostatic and metabolic processes-has gained attention for its potential role in ALS pathophysiology. This Review synthesises emerging evidence of hypothalamic involvement in ALS, including neuronal loss, proteinopathy, and volume loss observed through histological and neuroimaging studies. We critically examine current imaging approaches and their technical limitations and explore neuroendocrine dysfunction across the hypothalamic-pituitary axes. Collectively, these findings suggest that hypothalamic dysfunction may contribute to clinically relevant metabolic, sleep, behavioural, and cognitive changes in ALS, adding to our understanding of ALS as a multisystem disease. Continued investigation of the hypothalamus may reveal novel biomarkers, inform risk stratification, and identify therapeutic opportunities to address disease heterogeneity and improve clinical outcomes.},
}

@article {pmid40650266,
year = {2025},
author = {Bashar, MA and Dash, N and Mitra, S and Dash, R},
title = {Disclosing Pathogenic Variant Effects on the Structural Dynamics of the VAPB MSP Domain Causing Familial ALS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136489},
pmid = {40650266},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Molecular Dynamics Simulation ; *Vesicular Transport Proteins/genetics/chemistry/metabolism ; Protein Domains ; Mutation ; Protein Structure, Secondary ; Protein Binding ; },
abstract = {Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) serves as a tethering factor that interacts with various proteins and recruits these proteins to the ER surface, exerting multiple functions, such as organelle membrane tethering, lipid transfer between organelles, regulation of calcium homeostasis, autophagy, and the unfolded protein response (UPR). Its interaction is often mediated by its MSP (major sperm) domain, which binds with FFAT (two phenylalanines in an acidic tract)-motif-containing proteins. However, pathogenic variations, such as P56S, P56H, and T46I, in the VAPB MSP domain lead to the familial form of amyotrophic lateral sclerosis (ALS8). Still, the underlying pathophysiology of ALS8 due to pathogenic variations in the VAPB MSP domain remains elusive. In this study, we conducted molecular dynamics (MD) simulations to understand the pathogenic-variant-derived changes in the structural dynamics of the VAPB MSP domain. We found that pathogenic variants altered the fluctuations and conformational dynamics of the VAPB protein. Analyzing the organizations of the secondary structure revealed that pathogenic variants changed the composition of secondary structure elements, especially increasing the proportion of α-helix while reducing β-sheet formation, which might affect the organelle tethering and other functions of VAPB, as well as VAPB homodimer and heterodimer formation. Taken together, these findings can be further investigated through in vivo and/or in vitro studies to not only clarify the pathophysiology of ALS8 resulting from VAPB MSP domain pathogenic variants but also develop novel therapeutics for the disease that restore the native structural organizations as well as fluctuations and motions.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
Humans
Molecular Dynamics Simulation
*Vesicular Transport Proteins/genetics/chemistry/metabolism
Protein Domains
Mutation
Protein Structure, Secondary
Protein Binding

@article {pmid40650046,
year = {2025},
author = {Cattaneo, M and Giagnorio, E and Lauria, G and Marcuzzo, S},
title = {Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136268},
pmid = {40650046},
issn = {1422-0067},
support = {//Italian Ministry of Health (RRC)/ ; T4-AN-09 prog. ZRPOS2//CALabria HUB per Ricerca Innovativa ed Avanzata- CALHUB.RIA "Creazione di Hub delle Sci-enze della Vita"/ ; prog. ZRA124//AriSLA foundation, "Bulb-Omics"/ ; PNRR-MCNT2-2023-12377336//the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS,/ ; },
mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; Animals ; DNA Repeat Expansion ; Gene Editing ; Genetic Therapy/methods ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. One of its major genetic causes is C9ORF72, where mutations lead to hexanucleotide repeat expansions in the C9ORF72 gene. These expansions drive disease progression through mechanisms, including the formation of toxic RNAs and the accumulation of damaged proteins such as dipeptide repeats (DPRs). This review highlights these pathogenic mechanisms, focusing on RNA foci formation and the accumulation of toxic DPRs, which contribute to neuronal damage. It also discusses promising targeted therapies, including small molecules and biological drugs, designed to counteract these specific molecular events. Small molecules such as G-quadruplex stabilizers, proteasome and autophagy modulators, and RNase-targeting chimeras show potential in reducing RNA foci and DPR accumulation. Furthermore, targeting enzymes involved in repeat-associated non-AUG (RAN) translation and nucleocytoplasmic transport, which are crucial for disease pathogenesis, opens new therapeutic avenues. Even some anti-viral drugs show encouraging results in preclinical studies. Biological drugs, such as antisense oligonucleotides and gene-editing technologies like CRISPR-Cas, were explored for their potential to specifically target C9ORF72 mutations and modify the disease's molecular foundations. While preclinical and early clinical data show promise, challenges remain in optimizing delivery methods, ensuring long-term safety, and improving efficacy. This review concludes by emphasizing the importance of continued research and the potential for these therapies to alter the disease trajectory and improve patient outcomes.},
}

Humans
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology
Animals
DNA Repeat Expansion
Gene Editing
Genetic Therapy/methods
Mutation
Oligonucleotides, Antisense/therapeutic use

@article {pmid40649976,
year = {2025},
author = {Jiménez-García, AM and Tortorella, ME and Nishimura, AL and Arias, N},
title = {The Differential Effects of Genetic Mutations in ALS and FTD Genes on Behavioural and Cognitive Changes: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136199},
pmid = {40649976},
issn = {1422-0067},
support = {PID2023-151715OB-IOO//Ministry of Science and Innovation/ ; PLEC2022-009464//European Union NextGeneration EU/PRTR/ ; CPP2022-009646//European Union NextGeneration EU/PRTR/ ; },
mesh = {Humans ; *Frontotemporal Dementia/genetics/psychology ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Mutation ; *Cognition ; tau Proteins/genetics ; C9orf72 Protein/genetics ; Progranulins/genetics ; Superoxide Dismutase-1/genetics ; Endosomal Sorting Complexes Required for Transport/genetics ; RNA-Binding Protein FUS/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support.},
}

Humans
*Frontotemporal Dementia/genetics/psychology
*Amyotrophic Lateral Sclerosis/genetics/psychology
*Mutation
*Cognition
tau Proteins/genetics
C9orf72 Protein/genetics
Progranulins/genetics
Superoxide Dismutase-1/genetics
Endosomal Sorting Complexes Required for Transport/genetics
RNA-Binding Protein FUS/genetics

@article {pmid40649921,
year = {2025},
author = {Neumann, S and Heumann, R},
title = {Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136138},
pmid = {40649921},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Voltage-Dependent Anion Channels/metabolism/genetics ; Animals ; Mitochondria/metabolism ; },
abstract = {The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Voltage-Dependent Anion Channels/metabolism/genetics
Animals
Mitochondria/metabolism

@article {pmid40649859,
year = {2025},
author = {Tomczak, J and Kapsa, A and Boczek, T},
title = {Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136081},
pmid = {40649859},
issn = {1422-0067},
support = {2020/39/D/NZ4/01250//National Science Center/ ; },
mesh = {Humans ; *Adenylyl Cyclases/metabolism ; Animals ; *Nerve Regeneration/drug effects ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuronal Plasticity ; },
abstract = {Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling-a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses-including gene transcription, cytoskeletal remodeling, and neurotransmitter release-to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting.},
}

Humans
*Adenylyl Cyclases/metabolism
Animals
*Nerve Regeneration/drug effects
Signal Transduction/drug effects
Cyclic AMP/metabolism
*Neurodegenerative Diseases/drug therapy/metabolism
Neuronal Plasticity

@article {pmid40648447,
year = {2025},
author = {Lovrinčević, M and Papa, I and Janeš, D and Hodak, L and Pentek, T and Đuka, A},
title = {New Possibilities of Field Data Survey in Forest Road Design.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {13},
pages = {},
doi = {10.3390/s25134192},
pmid = {40648447},
issn = {1424-8220},
support = {HRZZ-UIP-2019-04-7766//Croatian Science Foundation/ ; },
abstract = {Field data, as the basis for planning and designing forest roads, must have high spatial accuracy. Classical (using a theodolite and a level) and modern (based on total stations and GNSSs) surveying methods are used in current field data survey for forest road design. This study analyzed the spatial accuracy of classical and modern surveying methods, the accuracy of spatial data recorded using a UAV equipped with an RGB camera at different flight altitudes, and the accuracy of lidar data of the Republic of Croatia. This study was conducted on a forest area where salvage logging was carried out, which enabled the use of a GNSS receiver in RTK mode as a reference method. The highest RMSE values of the spatial coordinates were recorded for measurements obtained with the classical surveying method (0.89 m) and a total station (0.33 m). The flight altitude of the UAV did not significantly affect the spatial error of the collected data, which ranged between 0.07 and 0.09 m. The cross-terrain slope, as one of the factors that significantly affect the amount of earthworks, did not differ statistically significantly between the methods. The ALS error was strongly influenced by the cross-terrain slope. The authors conclude that the new survey methods (SfM and lidar data) provide high-accuracy data but also draw attention to challenges in their use, such as vegetation and biomass on the ground.},
}

@article {pmid40646945,
year = {2025},
author = {Davì, F and Iaconis, A and Cordaro, M and Di Paola, R and Fusco, R},
title = {Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {13},
pages = {},
doi = {10.3390/foods14132193},
pmid = {40646945},
issn = {2304-8158},
abstract = {In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.},
}

@article {pmid40644419,
year = {2025},
author = {Bertran-Recasens, B and Vidal-Notari, S and Hernández Guillamet, G and López Seguí, F and Vidal-Alaball, J and Jiménez-Balado, J and Rubio, MA},
title = {Epidemiology of amyotrophic lateral sclerosis: a population-based analysis, 2015-2020.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2527887},
pmid = {40644419},
issn = {2167-9223},
abstract = {Background: Epidemiological data on amyotrophic lateral sclerosis (ALS) in Spain have primarily been derived from small cohort studies, with limited information on survival and comorbidities. This study presents a 10-year follow-up of a large, well-phenotyped community-dwelling ALS cohort in Catalonia, Spain. Methods: This observational study utilized data from the Information System for the Development of Research in Primary Care (SIDIAP), which includes health records for 6,301,095 individuals from 2015 to 2020. We assessed ALS incidence, prevalence, comorbidities, territorial distribution, mortality, and survival times. Results: From 2015 to 2020, 1173 ALS cases were identified, with a median age at diagnosis of 68 years, and 50.4% of cases were female. Incidence and prevalence were estimated at 2.39 per 100,000 person-years and 7.98 cases per 100,000 persons. Dementia was present in 6.8% of cases before ALS diagnosis, while depression and/or anxiety affected 45.7%. Median survival from diagnosis was 2.19 years. Multivariate analysis identified older age at diagnosis (HR: 1.04, 95% CI: 1.04-1.05, p value < 0.001), alcohol abuse (HR: 1.56, 95% CI: 1.04-2.56, p value = 0.017), history of stroke (HR: 1.47, 95% CI: 1.07-2.04, p = 0.006), and dementia (HR: 1.57, 95% CI: 1.18-2.12, p value = 0.001) as independent predictors of mortality. Conclusions: ALS incidence and prevalence in Catalonia are higher than previously estimated for Spain and align closely with rates observed in other Western countries. Older age at diagnosis, alcohol abuse, stroke history, and dementia were all significantly associated with reduced survival. These findings underscore important risk factors affecting prognosis, offering valuable insights into ALS progression.},
}

@article {pmid40644388,
year = {2025},
author = {Holanda Braga, CAO and Diniz, DS},
title = {Characterizing changes in functioning in Brazilian patients with ALS using a comprehensive ICF core set.},
journal = {Disability and rehabilitation},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/09638288.2025.2532124},
pmid = {40644388},
issn = {1464-5165},
abstract = {PURPOSE: To longitudinally describe the impact of amyotrophic lateral sclerosis (ALS) using a core set based on the International Classification of Functioning, Disability and Health (ICF).

PATIENTS AND METHODS: Between May 2021 and August 2022, 42 Brazilian patients with ALS (21 men/21 women, mean age 59.92 years, 23.8% with bulbar-onset ALS and 76.2% with spinal-onset ALS) were included. Patients diagnosed at least 6 months previously were assessed using 42 ICF categories at baseline and every six months thereafter for 16 months. The Friedman test was used to compare three time points, followed by Wilcoxon post hoc analyses. The Bonferroni method was applied. P-values ≤0.05 were considered significant. Overall and subgroup (bulbar-onset/spinal-onset ALS) analyses were performed.

RESULTS: Significant changes were found in 24/42 ICF categories. The most affected Body Functions included respiratory muscle functions (b445), power of muscles of one limb (b7301), muscle power (b730) and gait pattern (b770). Early disabilities involved pain sensation (b280) and respiratory functions. Limitations in Activities and Participation included transferring oneself (d420), hand and arm use (d445), dressing (d540), washing oneself (d510) and speaking (d330).

CONCLUSION: This ICF core set may help determine key facilitators and barriers to functioning and disability in ALS, guiding rehabilitation efforts.},
}

@article {pmid40643880,
year = {2025},
author = {Wang, P and Shang, H and Li, C},
title = {Association of creatinine level with neurodegenerative disorders: a prospective cohort study and Mendelian randomization analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40643880},
issn = {1590-3478},
support = {24NSFSC0358//Sichuan Science and Technology Program/ ; },
abstract = {BACKGROUND: Multiple evidence has suggested interaction between neurodegenerative disorders (NDDs) and creatinine, a metabolite derived from the high-energy product creatine. However, findings across studies have shown inconsistency, and the effect direction remains controversial. Here, we aimed to explore the link between creatinine and the risk of NDDs.

METHODS: Utilizing data from the UK Biobank, we investigated the association between baseline serum and urine creatinine and the risk of common NDDs using Cox proportional hazards regression analysis. Furthermore, we performed genetic correlation and Mendelian randomization analyses based on summary statistics from genome-wide association studies.

RESULTS: A higher level of serum creatinine at baseline was associated with a lower risk of incident amyotrophic lateral sclerosis (ALS) (beta=-0.013, SE = 0.004, P = 1.88E-03). From the genetic perspective, a significant and negative genetic correlation was identified between serum creatinine and ALS risk (genetic correlation: -0.17, P = 0.017). Mendelian randomization analysis corroborated the primary finding, indicating that serum creatinine was associated with a reduced risk of ALS (OR: 0.92, 95% CI: 0.86-0.98, P = 0.01). Moreover, a higher level of baseline serum creatinine was associated with a reduced risk of incident Alzheimer's disease (beta=-4.89E-03, SE = 2.24E-03, P = 0.03), though the effect size was small.

CONCLUSIONS: These findings enhance our understanding of creatinine's role in the risk of NDDS, suggest the potential of targeting creatinine as a biomarker of ALS, and hold implications for designing therapeutic interventions in clinical trials.},
}

@article {pmid40643479,
year = {2025},
author = {Sgromo, C and Tosi, M and Olgasi, C and De Marchi, F and Favero, F and Venturin, G and Piola, B and Cucci, A and Corrado, L and Mazzini, L and D'Alfonso, S and Follenzi, A},
title = {Identification of Transcriptomic Differences in Induced Pluripotent Stem Cells and Neural Progenitors from Amyotrophic Lateral Sclerosis Patients Carrying Different Mutations: A Pilot Study.},
journal = {Cells},
volume = {14},
number = {13},
pages = {},
doi = {10.3390/cells14130958},
pmid = {40643479},
issn = {2073-4409},
support = {N. 68155.//The study was supported by the AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara, Italy and DIG-ALS, AriSLA Foundation. AF was supported by CSP - Compagnia San Paolo T/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; Pilot Projects ; Kruppel-Like Factor 4 ; *Mutation/genetics ; *Transcriptome/genetics ; *Neural Stem Cells/metabolism/pathology ; Female ; Middle Aged ; Male ; Cell Differentiation ; C9orf72 Protein/genetics ; Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons with a phenotypic and genetic heterogeneity and elusive molecular mechanisms. With the present pilot study, we investigated different genetic mutations (C9orf72, TARDBP, and KIF5A) associated with ALS by generating induced pluripotent stem cells (iPSCs) from peripheral blood of ALS patients and healthy donors. iPSCs showed the typical morphology, expressed stem cell markers both at RNA (OCT4, SOX2, KLF4, and c-Myc) and protein (Oct4, Sox2, SSEA3, and Tra1-60) levels. Moreover, embryoid bodies expressing the three germ-layer markers and neurospheres expressing neural progenitor markers were generated. Importantly, the transcriptomic profiles of iPSCs and neurospheres were analyzed to highlight the differences between ALS patients and healthy controls. Interestingly, the differentially expressed genes (DEGs) shared across all ALS iPSCs are linked to extracellular matrix, highlighting its importance in ALS progression. In contrast, ALS neurospheres displayed widespread deficits in neuronal pathways, although these DEGs were varied among patients, reflecting the disease's heterogeneity. Overall, we generated iPSC lines from ALS patients with diverse genetic backgrounds offering a tool for unravelling the intricate molecular landscape of ALS, paving the way for identifying key pathways implicated in pathogenesis and the disease's phenotypic variability.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
*Induced Pluripotent Stem Cells/metabolism/pathology
Pilot Projects
Kruppel-Like Factor 4
*Mutation/genetics
*Transcriptome/genetics
*Neural Stem Cells/metabolism/pathology
Female
Middle Aged
Male
Cell Differentiation
C9orf72 Protein/genetics
Aged

@article {pmid40643147,
year = {2025},
author = {Vélez-Gómez, B and Cabrera-Serrano, M and Paradas, C},
title = {Utilization of patient-reported outcome measures in amyotrophic lateral sclerosis management: a cross-sectional study of Spanish neurologists.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2523940},
pmid = {40643147},
issn = {2167-9223},
abstract = {Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that significantly impacts quality of life. Patient-Reported Outcome Measures (PROMs) offer a patient-centered approach by capturing self-reported assessments of symptoms and well-being. Despite their recognized value, PROM integration into ALS management remains inconsistent. This study evaluates the attitudes, practices, and barriers experienced by Spanish neurologists regarding PROM use in ALS care. Methods: A cross-sectional survey was distributed to Spanish neurologists specializing in neuromuscular disorders. The questionnaire assessed familiarity with and use of PROMs, as well as perceived benefits and barriers to their implementation. Statistical analysis included descriptive statistics, group comparisons, and exploratory factor analysis (EFA) to identify underlying factors influencing PROM use. Results: Among 60 neurologists surveyed, 93.3% were familiar with PROMs, yet only 18.3% used them routinely. PROM use did not vary significantly with years of experience, type of clinical setting, exclusive dedication to neuromuscular disorders, or the percentage of time spent on patient care. The only variable approaching significance was the number of ALS patients managed daily, with higher patient volumes associated with more frequent PROM use. Over 70% of non-users cited limited consultation time as a barrier; however, factor analysis indicated that time constraints were not a substantial limitation. PROMs were valued for supporting clinical decision-making, monitoring disease progression, and improving patient engagement. Conclusions: While PROMs are widely recognized for their potential in ALS care, barriers hinder their use. Targeted training, simplified tools, and culturally adapted PROMs are needed to facilitate broader adoption and improve outcomes.},
}

@article {pmid40642867,
year = {2025},
author = {Pang, C and Cao, W and Xie, J and Li, Y and Zhu, L and Yu, H and Fan, D and Deng, B},
title = {Prediagnosis Insights Into Amyotrophic Lateral Sclerosis: Clinical Symptoms and Medication Use.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {16},
number = {4},
pages = {e70003},
doi = {10.1002/jcsm.70003},
pmid = {40642867},
issn = {2190-6009},
support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology/mortality ; Female ; Male ; Aged ; Middle Aged ; Incidence ; United Kingdom/epidemiology ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) has a prolonged latency period, though its preclinical characteristics remain poorly understood. This study uses UK Biobank data to explore and compare ALS's pre-diagnostic features, including symptoms and medication use, aiming to provide insights into the disease's underlying mechanisms.

METHODS: Clinical symptoms and medications were identified from self-reports, hospital records, and death registry data. Propensity score matching was used to match ALS with Alzheimer's disease (AD) and Parkinson's disease (PD), ensuring balance in socioeconomic factors to compare symptoms 0-5 years before diagnosis. Cox regression analysis was applied to assess the associations between medication use and the risk of incident ALS and mortality after ALS diagnosis.

RESULTS: A total of 753 ALS cases were observed in 502 417 participants, with an incidence rate of 10.58 per 100 000 person-years. In the ALS cohort, the male-to-female ratio was 2.9, with a median age at onset of 64.61 years (Interquartile range (IQR): 56.80-71.31) and a median survival time post-diagnosis of 9.08 months (IQR: 3.18-18.98), while females (log-rank p = 0.038) and individuals with earlier (< 64.61 years) disease onset (log-rank p < 0.001) had longer survival periods. In the 5 years prior to diagnosis, ALS showed a higher incidence of falls compared to ad (11.3% vs. 3.2%, p < 0.001), but a lower incidence than PD (10.7% vs. 28.3%, p < 0.001). Additionally, ALS had a lower incidence of depression (4.6% vs. 25.6%, p < 0.001), anxiety (3.5% vs. 18.1%, p < 0.001), sleep disorders (1.4% vs. 7.2%, p < 0.001), hypotension (3.4% vs. 30.5%, p < 0.001), constipation (0.3% vs. 4.9%, p < 0.001), and urinary dysfunction (2.2% vs. 8.7%, p < 0.001) compared with PD. The use of calcium channel blockers may be a risk factor for incident ALS (adjusted HR 1.61, 95% CI: 1.22-2.12, p < 0.001).

CONCLUSIONS: Pre-diagnostic presentations of falls are more frequent in ALS than in AD, but less frequent than in PD. However, ALS exhibits fewer psychiatric symptoms and autonomic dysfunction compared with PD. The use of calcium channel blockers may be associated with an increased risk of developing ALS in the future.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology/mortality
Female
Male
Aged
Middle Aged
Incidence
United Kingdom/epidemiology

@article {pmid40642215,
year = {2025},
author = {Ahmed, Z and Samaddar, S and Hassieb, M and Sadek, R and Morozova, V and Begum, S},
title = {Multi-path direct current spinal stimulation extended survival in the SOD1-G93A model of amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1594169},
pmid = {40642215},
issn = {1664-2295},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the spinal cord and brain. We have developed a novel non-invasive approach, MultiPath-DCS, which utilizes direct current stimulation at multiple sites along the neural axis to provide simultaneous spinal and peripheral stimulation targeted at the affected limbs. MultiPath-DCS modulates the excitability of spinal cord neurons. This effect is significant for ALS, as motor neuron hyperexcitability is a fundamental characteristic of the disease.

METHODS: This study used a transgenic mouse model of ALS (SOD1-G93A). Anodal-MultiPath-DCS was applied with six electrodes: three on the spine (centered on T13 and with an anodal polarity), two on the sciatic nerves (one on each nerve), and one on the abdomen. Mice were divided into two groups (stimulated vs. unstimulated or sham-stimulated). The stimulated animals received stimulation for one hour a day, three times a week, for three weeks. Survival was calculated from the onset of the disease and birth until the animal's endpoint. We also performed various electrophysiological and molecular experiments to uncover the mechanism of action.

RESULTS: We demonstrated molecular changes induced by anodal MultiPath-DCS, including (a) reduced expression of mutant SOD1 protein, (b) decreased expression of elevated NKCC1, (c) reduced phosphorylated tau, (d) increased expression of HSP70, and (e) increased expression of LC3B. Additionally, we found that treatment with Anodal-MultiPath-DCS (anode on the spinal column) reduces long-term neuronal spinal excitability, slows the progression of muscle weakness, and extends the lifespan of stimulated mice. The mean survival time in the control group was 12.4 days. In comparison, the mean survival time in the stimulated group was 21.6 days using a therapeutic stimulation paradigm, representing a 74% increase in survival from disease onset. Spinal motor neuron survival showed a 54% increase in stimulated compared to non-stimulated groups.

DISCUSSION: Combined, this data provides evidence that Anodal-MultiPath-DCS reduces hyperexcitability and enhances the clearance of misfolded proteins by modulating autophagy and proteolytic systems. By decreasing spinal excitability and clearing toxic proteins from motor neurons, Anodal-MultiPath-DCS promotes survival and could serve as a disease-modifying intervention for ALS.},
}

@article {pmid40641248,
year = {2025},
author = {Yang, K and Liu, Y and Deng, W and Gong, Z and Huang, L and Li, Z and Zhang, M},
title = {Astrocytes Contribute to Motor Neuron Degeneration in ALS via the TRAIL-DR5 Signaling Pathway.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70146},
doi = {10.1111/jnc.70146},
pmid = {40641248},
issn = {1471-4159},
support = {2024AOXIANG05//Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; 82271478//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/pathology/metabolism ; Mice ; *TNF-Related Apoptosis-Inducing Ligand/metabolism ; *Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; *Signal Transduction/physiology ; *Astrocytes/metabolism/pathology ; *Nerve Degeneration/pathology/metabolism ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1 ; Disease Models, Animal ; Superoxide Dismutase/genetics ; Mice, Inbred C57BL ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. The mechanisms underlying the selective degeneration of motor neurons in ALS remain poorly understood, underscoring the need for further investigation into the factors driving this process. In this study, we utilized ALS mouse models and an in vitro NSC34 motor neuron cell line expressing the SOD1[G93A] mutation to identify a novel pathogenic mechanism wherein astrocyte-secreted Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to Death Receptor 5 (DR5)on motor neurons, leading to caspase-8 activation and subsequent neuronal death. Blocking DR5 with neutralizing antibodies significantly attenuated TRAIL-induced motor neuron death. These findings provide the first evidence that TRAIL may serve as a potential therapeutic target in ALS, offering new insights into the mechanisms of motor neuron degeneration in this disease.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics
*Motor Neurons/pathology/metabolism
Mice
*TNF-Related Apoptosis-Inducing Ligand/metabolism
*Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
*Signal Transduction/physiology
*Astrocytes/metabolism/pathology
*Nerve Degeneration/pathology/metabolism
Mice, Transgenic
Humans
Superoxide Dismutase-1
Disease Models, Animal
Superoxide Dismutase/genetics
Mice, Inbred C57BL

@article {pmid40641139,
year = {2025},
author = {Sun, Y and Wei, K and Liao, X and Wang, J and Gao, L and Pang, B},
title = {Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).},
journal = {International journal of molecular medicine},
volume = {56},
number = {3},
pages = {},
doi = {10.3892/ijmm.2025.5580},
pmid = {40641139},
issn = {1791-244X},
mesh = {*Microglia/metabolism/pathology ; Humans ; *Lipid Metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.},
}

*Microglia/metabolism/pathology
Humans
*Lipid Metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology/therapy

@article {pmid40640965,
year = {2025},
author = {Wright, K and Warren, F and Bucci, S and Dunn, BD and Jones, S and O'Mahen, H and Taylor, RS and Medina-Lara, A},
title = {A study protocol for a randomized controlled feasibility trial of behavioural therapy for interepisode bipolar symptoms (STABILISE).},
journal = {Pilot and feasibility studies},
volume = {11},
number = {1},
pages = {97},
pmid = {40640965},
issn = {2055-5784},
support = {NIHR302220//National Institute for Health and Care Research/ ; },
abstract = {BACKGROUND: In between episodes of (hypo) mania and major depression, people with bipolar disorder can experience ongoing low mood or mood instability, and these may also be present as part of cyclothymic disorder. This is a phase II evaluation of an adapted form of behavioural therapy (STABILISE) for inter-episode bipolar symptoms. The study aims to establish the feasibility and acceptability of the therapy and research procedures, including an economic component, to inform a future definitive trial.

METHODS: Patients will be randomised 1:1 to either Treatment as Usual (control arm) or Treatment as Usual plus STABILISE intervention (intervention arm). Follow up points will be at 14, 30 and 52 weeks post eligibility confirmation, with 30 weeks as the primary end point. We aim to recruit 60 individuals meeting diagnostic criteria for a Bipolar Spectrum Disorder, and reporting ongoing bipolar symptoms (low mood or mood instability) outside of a manic or severe depressive episode. Feasibility and acceptability will be examined through recruitment and retention rates, completion rates for the candidate primary outcome measures (PHQ9, ALS-SF, QoL.BD and BRQ) and feedback from participants on their experience of study participation and therapy. Proceeding to a definitive trial will be indicated if the following criteria are met: (i) trial participation is deemed, or can be made, sufficiently safe; (ii) recruitment rate indicates that larger-scale recruitment would be feasible (recruitment rate of at least two participants per month within at least one site, with mitigation plan if overall target sample size not met); (iii) for candidate primary outcome measure follow up data is available at 30 weeks from at least 75% of participants, or from between 55 and 74% with clear plan for improvement.

DISCUSSION: This study is a randomised, controlled feasibility trial that builds on an initial case series of the STABILISE approach. The findings will be used to establish whether a future, definitive trial is feasible and to refine the research procedures and therapy protocol.

TRIAL REGISTRATION: ISRCTN18207465. Registered 13th March 2024, https://www.isrctn.com/ISRCTN18207465 .},
}

@article {pmid40640916,
year = {2025},
author = {Lemarchant, S and Engelhardt, B and Cicchetti, F and Bix, GJ and Janus, A and Godfrin, Y and Blasco, H and Campbell, M and de Rus Jacquet, A},
title = {Restoring brain barriers: an innovative approach for treating neurological disorders.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {72},
pmid = {40640916},
issn = {2045-8118},
abstract = {The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.},
}

@article {pmid40640892,
year = {2025},
author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH},
title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {82},
pmid = {40640892},
issn = {1750-1326},
support = {RS-2024-00348451//Korea Dementia Research Center/ ; },
abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.},
}

@article {pmid40640855,
year = {2025},
author = {Soliman, SS and Talib, NFA and Elghobashy, MR and Rahman, MAA},
title = {Sustainable analysis of COVID-19 Co-packaged paxlovid: exploring advanced sampling techniques and multivariate processing tools.},
journal = {BMC chemistry},
volume = {19},
number = {1},
pages = {206},
pmid = {40640855},
issn = {2661-801X},
abstract = {The drawbacks of random sampling not only hinder the development of more reliable and efficient methods but also weaken their accuracy, predictive abilities, and validity across several domains. During the current study, a pioneering statistical technique namely, Latin Hypercube Sampling (LHS) was integrated with different multivariate chemometric models namely; Partial Least Squares (PLS), Genetic Algorithm‑Partial Least Squares (GA-PLS), Artificial Neural Networks (ANN), and Multivariate Curve Resolution‑Alternating Least Squares (MCR-ALS). This integration aimed to achieve full data coverage and thereby enhance the predictive powers of these models. Being of clinical significance, Paxlovid[®], a newly co-packaged antiCOVID-19 drug containing ritonavir (RNV)-boosted nirmatrelvir (NMV), was utilized as a study subject to demonstrate the powerful potentials of LHS in enhancing models' robustness and predictive accuracy. The LHS technique was able to provide well-interpreted and informative samples by capturing essential variabilities across the input space without any increase in sample numbers. It was compared and outperformed the random sampling Monte Carlo technique. A comprehensive comparison between the developed models was held where the RMSEP was relatively reduced by 14.1%, 8.9%, 53.1%, and 34.6% for RNV and NMV, respectively using the ANN and MCR-ALS models. Various preprocessing techniques were employed to improve signal quality for PLS construction, yielding superior results (RMSEC of 0.19 for both RNV and NMV) compared to the original, unprocessed spectral data (RMSEC of 0.21 for both RNV and NMV). The Principal Component Analysis score plot was constructed, confirming the consistency of the dataset and the absence of systematic errors, enhancing confidence in the models' robustness. A new hybrid variable selection strategy (GA-ICOMP-PLS) was developed to enhance the robustness and parsimony of the GA-PLS model. Prediction error values of 0.15 and 0.14 were successfully achieved for RNV and NMV, respectively, indicating strong predictive power and generalization. Consistent with sustainability and eco-friendly goals, the current study pioneers the usage of green-blue-white alternatives to conventional analytical methods. A comprehensive assessment was conducted using the "Sample Preparation Metric of Sustainability", the "Analytical Greenness metric for Sample Preparation" and the "Analytical Greenness metric" alongside two solvent sustainability evaluation tools. These evaluations yielded promising results, with green quadrant classification and high scores of 5.89, 0.67, and 0.82 for each metric, respectively, as well as satisfactory t- and F-test values. Moreover, the models achieved outstanding results on the RGB12 metric and Blueness Applicability Grade Index, scoring 96.8% and 82.5, respectively, highlighting their broad applicability, high efficiency, and alignment with eco-friendly analytical practices.},
}

@article {pmid40640528,
year = {2025},
author = {McGuigan, A and Blair, HA},
title = {Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {40640528},
issn = {1179-1934},
abstract = {Tofersen (QALSODY[®]) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.},
}

@article {pmid40640025,
year = {2025},
author = {Kim, S and Yang, M and Ku, B and Cha, E and Seo, W and Son, I and Kang, H and Kim, D and Song, B and Yang, CS and Kim, S},
title = {Corrigendum to "Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial" [J. Ethnopharmacol. 320 (2023) 116670].},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120239},
doi = {10.1016/j.jep.2025.120239},
pmid = {40640025},
issn = {1872-7573},
}

@article {pmid40639550,
year = {2025},
author = {Mondal, M and Chouksey, A and Gurjar, V and Tiwari, R and Srivasatava, RK and Mishra, PK},
title = {Micro(nano)plastics in the brain: Epigenetic perturbations in progression to neurodegenerative diseases.},
journal = {Neurotoxicology and teratology},
volume = {},
number = {},
pages = {107521},
doi = {10.1016/j.ntt.2025.107521},
pmid = {40639550},
issn = {1872-9738},
abstract = {As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.},
}

@article {pmid40637865,
year = {2025},
author = {Coleman, A and Touzé, A and Farag, M and Pengo, M and Murphy, MJ and Hassan, Y and Thackeray, O and Fayer, K and Field, S and Nakajima, M and Broom, EL and Hobbs, NZ and Huxford, B and Donkor, N and Camboe, E and Dey, KC and Zirra, A and Ahmed, A and Gameiro Costa, AR and Sorrell, H and Zampedri, L and Lombardi, V and Wade, C and Mangion, S and Fneich, B and Heslegrave, A and Zetterberg, H and Scahill, R and Noyce, A and Malaspina, A and Chataway, J and Tabrizi, SJ and Byrne, LM},
title = {Evaluating finger-prick blood collection for remote quantification of neurofilament light in neurological diseases.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {501},
pmid = {40637865},
issn = {1432-1459},
support = {MR/W026686/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Adult ; Aged ; *Blood Specimen Collection/methods/standards ; *Nervous System Diseases/blood/diagnosis ; Cohort Studies ; Parkinson Disease/blood ; Amyotrophic Lateral Sclerosis/blood ; Huntington Disease/blood/diagnosis ; Multiple Sclerosis/blood ; },
abstract = {Promising blood-based biomarkers of neuropathology have emerged with potential for therapeutic development and disease monitoring. However, these tools will require specialist tertiary services for integration into clinical management. Remote sampling for biomarker assessment could reduce burden of in-person clinical visits for such tests as well as increasing the sampling frequency and patient geographical outreach. Here, we evaluated a finger-prick blood collection approach for remote quantification of neurofilament light (NfL), a candidate blood-based biomarker evident in various neurological disorders, and other exploratory markers of neuronal injury and neuroinflammation (GFAP, tau). Matched samples from venepuncture and finger-prick were collected and processed into plasma and/or serum to directly compare analyte levels from a multi-disease discovery cohort (n = 54 healthy controls; n = 57 Huntington's disease (HD); n = 34 multiple sclerosis; n = 7 amyotrophic lateral sclerosis; n = 11 Parkinson's disease), and a HD confirmatory cohort (n = 57 healthy controls; n = 64 HD). Two delayed processing conditions were compared, three- and seven-day delay, simulating ambient shipment. Capillary NfL and GFAP concentrations were equivalent to those in venous serum and plasma in the multi-disease discovery cohort and HD confirmatory cohort. Only NfL remained stable after a seven-day processing delay in both venous and capillary serum samples. Using NfL concentrations from capillary blood, we replicated previously published disease group differences measured in venous blood. This data supports our finger-prick approach for remote collection and quantification of NfL. With the widespread applications for NfL across the spectrum of neurological disorders, this has the potential to transform disease monitoring, prognosis, and therapeutic development within clinical practice and research.},
}

Humans
*Neurofilament Proteins/blood
Male
Female
Middle Aged
Biomarkers/blood
Adult
Aged
*Blood Specimen Collection/methods/standards
*Nervous System Diseases/blood/diagnosis
Cohort Studies
Parkinson Disease/blood
Amyotrophic Lateral Sclerosis/blood
Huntington Disease/blood/diagnosis
Multiple Sclerosis/blood

@article {pmid40635530,
year = {2025},
author = {Manicardi, A and Mora, G and Araujo, ALS and Gaines, TA and Lozano-Juste, J and Torra, J},
title = {Analysis of multiple-herbicide resistant Amaranthus palmeri populations from Spain points to an introduction of the eccDNA from America.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.70034},
pmid = {40635530},
issn = {1526-4998},
support = {PRTR-C17.I1//European Union NextGenerationEU, AGROALNEXT, GVA/ ; 801586//H2020 Marie Skłodowska-Curie Actions/ ; PID2020-113229RB-C42//Spanish State Research Agency and the European Regional Development Fund, EU (ERDF)/ ; PID2021-128826OAI00//Spanish MCIN/AEI/ ; RYC2020-029097-I//Spanish MCIN/AEI/ ; RYC2018-023866-I//Spanish MCIN/AEI/ ; CISEJI/2022/26//Generalitat Valenciana, Plan GenT/ ; RED2022-134285-T(PalmerNET)//Spanish Ministry of Science and Innovation/ ; },
abstract = {BACKGROUND: The herbicide-resistant invasive weed species Amaranthus palmeri threatens agricultural production and native plant ecology in Spain, as well as in other European countries. Understanding whether herbicide resistance alleles evolve in situ or are introduced via gene flow remains unclear. To address this, we characterized multiple resistance to acetolactate synthase (ALS)-- and 5-enolpyruvylshikimate-3phosphate synthase (EPSPS)-inhibiting herbicides in two Spanish A. palmeri populations at the plant level. Additionally, we analyzed the extra-chromosomal circular DNA (eccDNA) to determine whether glyphosate resistance resulted from local selection pressure or was introduced by gene flow.

RESULTS: Both populations exhibit individuals that survived both herbicide MoA, with multiple resistance mechanisms to ALS- and EPSPS-inhibiting herbicides. Eight different ALS allele mutations were identified in resistant plants, including Pro-197-Ile, reported only in one species previously. Glyphosate resistance in the two populations is to the result of gene duplication mediated by eccDNA. Spanish and North American eccDNAs showed complete identity, with no single nucleotide polymorphisms (SNPs) found between the partial analyzed sequences of noncoding regions.

CONCLUSION: We confirm for the first time in Europe resistance to ALS and EPSPS inhibitors at both the population and individual levels in two Spanish A. palmeri populations. The absence of SNPs in the eccDNA from Spanish populations compared to the reference American sequence and the presence of target-site mutations in the ALS gene occurred without selective pressure from ALS herbicides, suggests that the origin of resistance traits may have evolved elsewhere and been introduced from the place of origin to Spain. However, it is important to note that the limited number of populations studied and the partial sequencing of eccDNA do not provide definitive confirmation of the exact origins of resistance mechanisms. This work raises concerns about the arrival of this and potentially other new herbicide-resistant A. palmeri populations in Europe posing challenges for management. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid40633900,
year = {2025},
author = {Singh, N and Mishra, D and Gomes, J},
title = {Deleterious Sequestosome 1 mutations G262R and P438L in amyotrophic lateral sclerosis cause autophagy and oxidative stress imbalance.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.07.011},
pmid = {40633900},
issn = {1873-7544},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease (NDD) prevalent across the world. It is known that mutations in ALS associated genes can cause imbalances between cellular processes such as apoptosis, necroptosis, autophagy and proteasomal degradation that remove dysfunctional and aggregating proteins. Two rare missense variants namely G262R (G > A) and P438L (C > T) in Sequestosome 1 (SQSTM1), were identified by our group in a cohort of Indian ALS patients. SQSTM1 codes for p62, which is an autophagy adaptor protein involved in several signaling pathways. In this study, we investigated how these SQSTM1 mutations affect autophagy and the oxidative stress response pathway in SH-SY5Y cells through quantitative RT-PCR, immunoblotting and confocal microscopy. In addition, we examined how changes in the downstream signaling pathways alters nuclear-cytoplasmic localization of TDP-43 protein, a marker protein usually found in cytoplasmic inclusions in ALS patient tissues. We observed up-regulation of autophagy marker proteins LC3-II and ubiquitin, and down-regulation of oxidative stress marker protein Nrf2. Along with LC3-II, p-OPTN and ATG5, proteins that are also associated with autophagy were up-regulated. We also observed an increase in cytoplasmic localization of TDP-43 protein in cells expressing these p62 mutant proteins. Overall, our study provides evidence that the G262R (G > A) and P438L (C > T) mutations are deleterious through mechanisms that increase cytoplasmic localization of TDP-43, and adversely affect the autophagy and oxidative stress response pathway.},
}

@article {pmid40633079,
year = {2025},
author = {Al-Akeedi, JM and Khudiar, HH and Al Muhtaser, STM and Al-Fahham, AA},
title = {Genotypes of Candida albicans and its cooperative interaction with Streptococci isolated from throat infections.},
journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego},
volume = {53},
number = {3},
pages = {378-383},
doi = {10.36740/Merkur202503112},
pmid = {40633079},
issn = {1426-9686},
mesh = {*Candida albicans/genetics/isolation & purification/physiology ; Humans ; Genotype ; Biofilms/growth & development ; *Streptococcus/isolation & purification/genetics/physiology ; *Streptococcal Infections/microbiology ; *Pharyngitis/microbiology ; },
abstract = {OBJECTIVE: Aim: This study was aimed to detect and determine genotypes of Candida albicans and its cooperative interaction with streptococci isolated from throat infections.

PATIENTS AND METHODS: Materials and Methods: This survey was carried out during November 2023 and March 2024 to collect a total of 80 throat swab samples from patients in in Al-Sadr Medical City in Najaf during. Candida was isolated from culturing throat swab samples on Sabouraud agar, and Blood agar. Each isolate (Candida & Streptococci) enhanced in monoculture using enrichment media; Potato Dextrose broth. Molecular assay included detecting three of biofilm forming genes; Als1, Als2, Als3.

RESULTS: Results: Twelve out of fifteen Candida isolates showed increase in number after mixing with Streptococci and incubation. In contrast, three isolates showed no change or decrease after mixing in co-culture media. Five Candida isolates (out of 15 isolates) were positive in gel electrophoresis to three biofilm genes classified as first genotype (CALSG1). Four Candida isolates were negative in gel electrophoresis to three biofilm genes, classified as second genotype (CALSG2). Other Candida isolates were positive to one or two of three biofilm genes, classified with genotypes (CALSG3, CALSG4, CALSG5 and CALSG6).

CONCLUSION: Conclusions: Candida albicans has biofilm formation genes (Als), which attract other organisms, like streptococci resulting in synergistic interaction. Despite the presence of some Als genes, it's not necessary to found strong biofilm results as Als genes may not be translated to form biofilm.},
}

*Candida albicans/genetics/isolation & purification/physiology
Humans
Genotype
Biofilms/growth & development
*Streptococcus/isolation & purification/genetics/physiology
*Streptococcal Infections/microbiology
*Pharyngitis/microbiology

@article {pmid40632651,
year = {2025},
author = {Dos Santos, M and Bezprozvannaya, S and McAnally, JR and Cai, C and Liu, N and Olson, EN},
title = {A mechanistic basis of fast myofiber vulnerability to neuromuscular diseases.},
journal = {Cell reports},
volume = {44},
number = {7},
pages = {115959},
doi = {10.1016/j.celrep.2025.115959},
pmid = {40632651},
issn = {2211-1247},
abstract = {Neuromuscular diseases such as amyotrophic lateral sclerosis and sarcopenia cause muscle atrophy, which preferentially affects fast-twitch glycolytic myofibers. The mechanisms underlying the susceptibility of fast myofibers to disease remain unclear. To investigate this, we analyzed the transcriptional profiles of myonuclei from denervated muscle fibers. We found that the fast muscle gene program and the transcription factor Maf were repressed upon denervation. Overexpression of Maf in mice prevented loss of muscle mass caused by denervation by repressing atrophic genes and restoring fast gene expression. Similar repression of fast genes and Maf was observed in muscles from mice and humans with amyotrophic lateral sclerosis. Notably, Maf overexpression in human skeletal muscle cells in vitro prevented muscle atrophy and activated the expression of fast muscle genes. Our findings highlight a key role for Maf in maintaining muscle mass and could offer a promising therapeutic strategy to preserve muscle function during disease, aging, and injury.},
}

@article {pmid40632556,
year = {2025},
author = {Shaked, R and Katz, M and Cohen-Dvashi, H and Diskin, R},
title = {The prefusion structure of the HERV-K (HML-2) Env spike complex.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {28},
pages = {e2505505122},
doi = {10.1073/pnas.2505505122},
pmid = {40632556},
issn = {1091-6490},
support = {209/20//Israel Science Foundation (ISF)/ ; },
mesh = {*Endogenous Retroviruses/chemistry/metabolism/genetics ; Cryoelectron Microscopy ; Humans ; Models, Molecular ; *Gene Products, env/chemistry/metabolism ; },
abstract = {The human endogenous retrovirus K (HERV-K) is a retrovirus that got assimilated into the human genome in ancient times and has been inherited in our germline ever since. It enters cells using a class-I spike protein (Env) that mediates receptor recognition and membrane fusion. On top of having a biological role during development, HERV-K is activated in amyotrophic lateral sclerosis, various cancers, and other pathological conditions. Antibodies that target the HERV-K spike complex have therapeutic value, flagging the spike as a novel drug target. Here, we use cryo-EM to determine the trimeric structure of the HERV-K spike. The spike presents a distinct structure, which substantially differs from other class-I fusogens. Nevertheless, some general architectural features suggest a common origin with other retroviruses. The ability to structurally characterize the HERV-K spike may facilitate the development of antibody-based therapies.},
}

*Endogenous Retroviruses/chemistry/metabolism/genetics
Cryoelectron Microscopy
Humans
Models, Molecular
*Gene Products, env/chemistry/metabolism

@article {pmid40631777,
year = {2025},
author = {LaBarge, B and Lorenz, FJ and Gniady, JP},
title = {Association of Laryngeal Dystonia With Common Neurologic Disorders.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.32407},
pmid = {40631777},
issn = {1531-4995},
support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; },
abstract = {OBJECTIVE: Laryngeal dystonia is a heterogenous disorder consisting of involuntary spasms of laryngeal muscles. There are multiple forms including adductor, abductor, and mixed phenotypes. The disorder is thought to be multifactorial, with various reported associations with family history of dystonia or movement disorders. The relationship between laryngeal dystonia and various neurologic disorders is not well defined in the literature.

METHODS: We utilized the TriNetX de-identified electronic medical record database system spanning 2010-2023 to assess the prevalence of laryngeal dystonia with common neurologic disorders, compared to an age-sex matched control population. We included patients with the laryngeal spasm J38.5 ICD-10 code and 64617 CPT code, in order to categorize laryngeal dystonia patients undergoing chemodenervation.

RESULTS: The patient cohort consisted of approximately 4000 patients. 75% were female, 71% were white, and the mean age was 61 years. The laryngeal dystonia population had an elevated relative risk of Parkinson's disease (RR = 2.7, 1.8-3.9, 95% CI). In contrast, the relative risk of Alzheimer's disease was decreased in the laryngeal dystonia population (RR = 0.28, 0.16-0.48, 95% CI). There were no differences between the laryngeal dystonia and control populations for multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, migraine, muscular dystrophy, or cerebral palsy.

CONCLUSION: Laryngeal dystonia patients have a significantly greater association with Parkinson's disease and less association with Alzheimer's disease compared to the control population. There were no meaningful associations with the remainder of the neurologic conditions included in the study.},
}

@article {pmid40631187,
year = {2025},
author = {Scheutzow, AN and Thanthirige, S and Siffer, G and Sorkin, AD and Wohlever, ML},
title = {E3 ligase recruitment by UBQLN2 protects substrates from proteasomal degradation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.04.602059},
pmid = {40631187},
issn = {2692-8205},
abstract = {Ubiquilins are a family of proteins critical to cellular proteostasis that are also linked to several neurodegenerative diseases, with specific mutations in UBQLN2 causing dominant, X-linked ALS. Despite an initial characterization as proteasomal shuttle factors, Ubiquilins have paradoxically been reported to stabilize numerous substrates. The basis of this triage decision remains enigmatic. Many other fundamental aspects of Ubiquilin function are unclear at the mechanistic level, such as the physiological significance of Ubiquilin phase separation, the unique role of each Ubiquilin paralog, and the mechanistic defects of ALS mutants. To address these questions, we utilized a library of triple knockout (TKO) rescue cell lines with physiological expression of single Ubiquilin paralogs or disease mutants in an isogenic background. Our findings reveal that UBQLN2 has a unique ability to protect substrates from degradation and that substrate stabilization correlates with the recruitment of multiple E3 ligases, including SCF [bxo7] . We propose that E3 ligase recruitment promotes UBQLN2 phase separation, which protects substrates from proteasomal degradation. Consistent with this model, we demonstrate that ALS mutants, which were previously shown to have altered phase separation properties, also show a defect in substrate stabilization. Finally, we show that substrate stabilization appears to be a general feature of proteins that interact with the UBQLN2 Sti1 domains as amyloid precursor protein (APP) is also protected from proteasomal degradation by the formation of biomolecular condensates. This proposal unifies many existing observations in the field and presents a new paradigm for understanding Ubiquilin function in neurodegenerative disease.},
}

@article {pmid40630909,
year = {2025},
author = {Peller, J and Trevisan, MA and Bujia, G and Aguirre, F and Shalom, DE and Taitz, A and Henze, S and Bastola, S and Osik, J and Shewcraft, RA and Jiang, P and Schwartz, J and Heiman-Patterson, T and Sherman, ME and Wipperman, MF and Levy, O and Shou, G and Sillay, KA and Ostrow, LW and Fraenkel, E and Berry, JD and Navar Bingham, I and Roitberg, EG},
title = {Reliable monitoring of respiratory function with home spirometry in people living with amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1588992},
pmid = {40630909},
issn = {1664-2295},
abstract = {INTRODUCTION: Monitoring respiratory function is essential for assessing the progression of Amyotrophic Lateral Sclerosis (ALS) and planning interventions. Remote pulmonary function testing offers a promising alternative to in-clinic visits by reducing participant burden and enabling more frequent and accessible measurements.

METHODS: To evaluate the feasibility and reliability of home-based spirometry in ALS, we built on the Radcliff Study, a fully remote, longitudinal, exploratory study conducted at home by 67 people with ALS (pALS). After an initial training period, participants managed their coaching autonomously, performing spirometry independently or requesting assistance from trained personnel.

RESULTS: We demonstrate that combining flexible coaching with a predefined automatic quality control protocol yields consistent and reliable spirometry results for tracking respiratory function over time. This approach reveals that home-measured Slow Vital Capacity (SVC) and Forced Vital Capacity (FVC) evolve similarly and follow a linear trajectory throughout the study period (7.7 ± 4.0 months), in both slow and fast progressor subpopulations.

DISCUSSION: The observed linearity in respiratory trajectories supports the potential for early and accurate estimation of progression, reinforcing the feasibility of less frequent monitoring without compromising assessment precision and reducing the burden on both pALS and the healthcare system. Furthermore, our results align with reported in-clinic pulmonary tests, validating remote monitoring as a means to promote more equitable and accessible clinical trial designs.},
}

@article {pmid40629851,
year = {2025},
author = {Lawless, MJ and Chan, N and Patel, K and Wang, M and Colter, DC},
title = {Qualification of a electrochemiluminescence assay for the detection of human urinary neurotrophin receptor p75.},
journal = {Bioanalysis},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17576180.2025.2529147},
pmid = {40629851},
issn = {1757-6199},
abstract = {The extracellular domain of the neurotrophin receptor p75 has been shown to be a prominent biomarker for both disease diagnosis and progression for amyotrophic lateral sclerosis. This urinary analyte may serve as a valuable fluid biomarker which greatly increases the ease of sample collection in both healthy volunteers and patients. In this paper, the method development and validation for an electrochemiluminescence assay is described. This assay completely uses commercially available reagents and can be performed using common lab equipment found in most bioanalytical labs. This method shows good accuracy and precision, high sensitivity as well as good parallelism illustrating the ability of the method to detect and report on urinary concentrations of neurotrophin receptor p75. The assay can quantitate as low as 78 pg/mL of neurotrophin receptor p75 and > 98% of healthy urine samples tested fell within the dynamic range of the assay.},
}

@article {pmid40629698,
year = {2025},
author = {Murdock, BJ and Park, J and Jang, DG and Zhao, B and Teener, SJ and Webber-Davis, IF and Zhao, L and Feldman, EL and Goutman, SA},
title = {In Vitro Modeling of Natural Killer Cell Cytotoxicity to Inform Personalized ALS Therapeutics.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70127},
pmid = {40629698},
issn = {2328-9503},
support = {//Sinai Medical Staff Foundation/ ; //Coleman Discovery Fund/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //NeuroNetwork for Emerging Therapies at the University of Michigan/ ; R01TS000339/ACL/ACL HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; AL200064//U.S. Department of Defense/ ; 20-IIA-431//ALS Association/ ; //Hiller and Novak Families/ ; //Peter R. Clark Fund for ALS Research/ ; //Scott L. Pranger/ ; },
abstract = {OBJECTIVE: Natural killer (NK) cells might contribute to motor neuron death in amyotrophic lateral sclerosis (ALS) through direct cytotoxicity, a process that could be inhibited with the FDA-approved JAK/STAT pathway inhibitor, tofacitinib. This study aimed to verify that tofacitinib can suppress NK cell cytotoxicity, investigate if immune cell profiles can predict responsiveness to tofacitinib, and assess the role of NK cell cytotoxicity in ALS progression.

METHODS: Primary NK cells were isolated from peripheral blood samples of ALS participants and healthy controls. NK cells were then co-cultured with target cancer cells, with or without tofacitinib, to assess their cytotoxic activity. Flow cytometry was used to generate immune profiles for each participant, based on 154 immune markers, to explore correlations with NK cell cytotoxicity and response to tofacitinib. The potential association between NK cell cytotoxicity and disease severity, as measured by the revised ALS Functional Rating Scale, was also assessed. All analyses were stratified by age and sex.

RESULTS: Tofacitinib effectively reduced the cytotoxicity of primary NK cells isolated from the blood of ALS participants (n = 80) and healthy controls (n = 71), with immune cell profiles correlating with the response to tofacitinib. However, NK cell cytotoxicity was lower in ALS participants compared to healthy controls and showed no association with ALS progression.

INTERPRETATION: These findings confirm that tofacitinib suppresses NK cell cytotoxicity, and that immune profiling may help identify treatment responder groups. However, further research is needed to fully understand the role and timing of NK cell activity in ALS pathogenesis.},
}

@article {pmid40629595,
year = {2025},
author = {Liu, G and Liu, N and Xu, Y and Su, F},
title = {Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: A bibliometric analysis.},
journal = {Medicine},
volume = {104},
number = {27},
pages = {e43180},
doi = {10.1097/MD.0000000000043180},
pmid = {40629595},
issn = {1536-5964},
support = {202134068//Jinan City 2021 Science and Technology Innovation Development Program/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Lobar Degeneration/genetics ; *Bibliometrics ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Mutation ; },
abstract = {OBJECTIVE: This study analyzes the research hotspots and future directions of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis.

METHODS: Relevant literature was searched using the Web of Science database and analyzed using econometric tools such as CiteSpace and VOSviewer.

RESULTS: A total of 145 articles were included in this study, involving 317 research institutions in 31 countries and regions. Acta Neuropathologica is a prominent journal in terms of issuance and influence, and countries such as the United States and Japan, as well as institutions such as the University of Pennsylvania, occupy an important position in the research. The keywords cover various aspects such as disease characteristics and gene mutations; highly-cited literature focuses on TDP-43 protein and C9orf72 gene mutations. Research hotspots include TDP-43 protein disease-driven pathomechanisms, RNA-related studies, clinical manifestations of the disease and genetic studies, etc. In recent years, research focus has shifted to RNA, C9orf72 gene and so on.

CONCLUSION: To our knowledge, this study is the first econometric evaluation of the FTLD-ALS literature, and although there are limitations such as relying on the number of documents and citation relationships, and a single source of data, it provides a valuable reference for research in this field and helps to promote subsequent research.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Frontotemporal Lobar Degeneration/genetics
*Bibliometrics
C9orf72 Protein/genetics
DNA-Binding Proteins/genetics
Mutation

@article {pmid40629407,
year = {2025},
author = {Choi, Y and Chung, WS},
title = {Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {81},
pmid = {40629407},
issn = {1750-1326},
support = {2020M3E5D9079912//Ministry of Science and ICT, South Korea/ ; 2021R1A2C3005704//Ministry of Science and ICT, South Korea/ ; 2022M3E5E8081188//Ministry of Science and ICT, South Korea/ ; IBS-R025-A1//Institute for Basic Science/ ; },
abstract = {Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.},
}

@article {pmid40629298,
year = {2025},
author = {Douglas, A and McPhee, M and Fisher, F and Cheng, C and Henders, A and Ziser, L and Stout, JC and Kiernan, MC and Osborne, R and Mathers, S},
title = {Using cluster analysis to identify the health literacy strengths and challenges of people living with motor neurone disease in Australia.},
journal = {BMC health services research},
volume = {25},
number = {1},
pages = {942},
pmid = {40629298},
issn = {1472-6963},
abstract = {BACKGROUND: There is growing appreciation of the role health literacy plays in population health and health care design. Health literacy encompasses an individual's capacity to manage their health and the responsiveness of the health system. Our aim was to identify the health literacy strengths and challenges in an Australian cohort living with motor neurone disease (MND), including both people living with the disease and their carers.

METHODS: This study used the Health Literacy Questionnaire and eHealth Literacy Questionnaire for health literacy assessment. Using a secure online platform, an anonymous survey was disseminated which included demographic data and clinical measurements. Descriptive statistical analysis and cluster analysis were employed to describe the sample and to identify different health literacy patterns in subgroups of people living with MND and their carers.

RESULTS: A total of 227 people participated (171 people living with MND and 56 carers). Cluster analysis generated fifteen cluster profiles for the cohort living with MND and seven cluster profiles for carers. The variability and potential significance of patterns of health literacy strengths and challenges within the MND community are described. There was extensive diversity within the sampled population, with a mix of sociodemographic backgrounds across each cluster profile.

CONCLUSIONS: The health literacy cluster profiles created from this study provide insight into the full spectrum of where the challenges and strengths exist for individuals and subgroups of people managing this fatal disease. The results from this study pave the way for generating system wide interventions that address health literacy diversity, to create more enabling health care environments for all those affected by MND.},
}

@article {pmid40629037,
year = {2025},
author = {Wood, H},
title = {Brain-computer interface restores naturalistic speech to a man with ALS.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40629037},
issn = {1759-4766},
}

@article {pmid40627876,
year = {2025},
author = {Zeinab, EM and Lynn, K and Mohammad, M and Houssein, HA},
title = {Meckel's diverticulum in patient with early-onset ALS: A case report.},
journal = {International journal of surgery case reports},
volume = {133},
number = {},
pages = {111585},
doi = {10.1016/j.ijscr.2025.111585},
pmid = {40627876},
issn = {2210-2612},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease primarily affecting the neuromuscular system. Gastrointestinal manifestations are typically functional in nature, while mechanical obstructions are rarely reported. Meckel's diverticulum (MD), a congenital gastrointestinal anomaly, is often asymptomatic but can cause obstruction in rare adult cases.

CASE REPORT: We present the case of a 30-year-old male with early-onset ALS who presented with signs of intestinal obstruction, including severe abdominal pain, vomiting, and obstipation. Imaging revealed a closed-loop small bowel obstruction. Emergency laparotomy identified a torsed Meckel's diverticulum as the underlying cause. Surgical resection was performed, and the postoperative course was managed with tracheostomy and PEG placement due to progressive ALS-related respiratory and swallowing impairment. The patient was successfully stabilized and discharged with ongoing multidisciplinary support. The patient was discharged three weeks later in a stable condition and remains alive under multidisciplinary follow-up.

DISCUSSION: This case highlights the diagnostic challenge of distinguishing mechanical from functional gastrointestinal symptoms in patients with advanced ALS. While neurodegenerative progression often explains GI complaints in ALS, this case emphasizes the need to consider alternative etiologies, including surgical emergencies like MD-related obstruction.

CONCLUSION: Mechanical small bowel obstruction due to Meckel's diverticulum in ALS is exceedingly rare. Timely diagnosis and intervention, supported by multidisciplinary perioperative care, are critical for favorable outcomes in this high-risk population. Despite significant ALS-related comorbidities, the patient's outcome was favorable with stable discharge and ongoing respiratory and nutritional support.},
}

@article {pmid40626770,
year = {2025},
author = {Devrim, İ and Ergun, D and Kaçar, P and Çelebi, MY and Özer, A and Koyun, E and Koç, Y and Yıldız, ÖD and Akgül, E and Ayhan, FY and Bayram, N},
title = {The Comparison of Flushing With Prefilled Saline Syringes Versus Manually Prepared Saline Syringes on Colonization of Peripheral Intravenous Catheters in Children.},
journal = {Journal of infusion nursing : the official publication of the Infusion Nurses Society},
volume = {48},
number = {4},
pages = {247-252},
pmid = {40626770},
issn = {1539-0667},
mesh = {Humans ; *Syringes ; Child ; *Saline Solution/administration & dosage ; *Catheterization, Peripheral/adverse effects ; Turkey ; *Catheter-Related Infections/prevention & control ; *Catheters, Indwelling/microbiology ; Infusions, Intravenous ; Child, Preschool ; },
abstract = {We appreciate the study performed and described by Devrim et al, who practice at Dr. Behçet Uz Children's Diseases and Surgery Training and Research Hospital in Izmir, Turkey. This study aimed to compare the colonization rates of short-term PIVC tips between patients' catheters flushed with manually prepared saline syringes and single-use prefilled saline syringes. The practice of manually preparing saline syringes for use in flushing intravenous catheters is uncommon in many health care organizations. While many health care organizations have permanently exchanged manual flush syringe preparation for prefilled single-use saline syringes, we are respectful of professionals and organizations who serve in areas where practice is different. As noted, we appreciate Devrim et al's study and described findings. The conclusion of this study affirms and further substantiates the INS Infusion Therapy Standards of Practice described in Standard 38. Flushing and Locking. Practice Recommendation - A. Use single-dose systems (eg, single-dose vials and syringes or prefilled labeled syringes) for all VAD flushing and locking. Additional recommendations are listed in A.2. and A.3. Use commercially manufactured prefilled flush syringes (when available) to reduce the risk of catheter-associated bloodstream infection (CABSI) and device failure, save time for syringe preparation, and aid optimal flushing technique and objectives. 3. Do not use IV solution containers (eg, bags or bottles) as a source for obtaining flush solutions (see Standard 56, Compounding and Preparation of Parenteral Solutions and Medications).},
}

Humans
*Syringes
Child
*Saline Solution/administration & dosage
*Catheterization, Peripheral/adverse effects
Turkey
*Catheter-Related Infections/prevention & control
*Catheters, Indwelling/microbiology
Infusions, Intravenous
Child, Preschool

@article {pmid40626296,
year = {2025},
author = {Li, D and Wang, P and Zhang, M and Zhang, X and Yao, H and Liu, X},
title = {Advances in examination methods for adolescent idiopathic scoliosis.},
journal = {Pediatric discovery..},
volume = {3},
number = {1},
pages = {e2518},
pmid = {40626296},
issn = {2835-5598},
abstract = {The purpose of this article is to provide an overview of techniques for evaluating patients with adolescent idiopathic scoliosis (AIS). It encompasses the history, clinical examinations, and diagnostic imaging methods for AIS. These methods include digital radiological examination, EOS® imaging, nuclear medicine, ultrasound, body surface topography techniques such as the Moiré pattern technique, raster stereophotography, and DIERS formetric 4D as well as computed tomography and magnetic resonance imaging (MRI). Traditionally, full-spine standing X-rays have been the standard for diagnosing AIS. High-quality clinical assessments may continue as a reference for assessing other spinal deformities. However, the new diagnostic imaging methods aim to reduce radiation exposure while maintaining image quality and practicality. Emerging technologies demonstrate strong reliability and effectiveness in diagnostic imaging of AlS. These techniques may be beneficial for diagnosing and monitoring AIS and its progression without requiring high levels of radiation exposure. The article is a search and summary of the PubMed electronic database to understand the current and future status of AIS imaging technology, which can not only help to introduce other researchers to the field but also serve as a valuable source for healthcare professionals to study existing methods, develop new ones, or select evaluation strategies.},
}

@article {pmid40625857,
year = {2025},
author = {Khorrami, F and Gupta, N and Zhou, X and Liang, Y and Yucel, YH},
title = {A Novel Retinal Nerve Fiber Layer Biomarker of Amyotrophic Lateral Sclerosis (ALS) Identified Using Longitudinal in vivo Ocular Imaging.},
journal = {Eye and brain},
volume = {17},
number = {},
pages = {69-79},
pmid = {40625857},
issn = {1179-2744},
abstract = {PURPOSE: Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age.

METHODS: Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20 weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20 weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex.

RESULTS: IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20 weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1±2.3 vs 0.5±0.8; (mean±SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21±0.04 log number puncta/week vs 0.16±0.04, respectively; p=0.037).

CONCLUSION: Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans.},
}