@article {pmid40943341,
year = {2025},
author = {Yang, EJ},
title = {The Emerging Role of the Brain-Gut Axis in Amyotrophic Lateral Sclerosis: Pathogenesis, Mechanisms, and Therapeutic Perspectives.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
pmid = {40943341},
issn = {1422-0067},
support = {(KIOM) KSN2224011//KIOM/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Although genetic and environmental factors are established contributors, recent research has highlighted the critical role of the gut-brain axis (GBA) in ALS pathogenesis. The GBA is a bidirectional communication network involving neural, immune, and endocrine pathways that connect the gut microbiota with the central nervous system. Dysbiosis in ALS disrupts this axis, leading to increased intestinal permeability, neuroinflammation, and excitotoxicity. Notably, reductions in butyrate-producing bacteria, alterations in microbial metabolites, and enhanced NLRP3 inflammasome activation have been observed in patients with ALS. These changes may precede motor symptoms, suggesting a potential causative role. Interventions targeting the microbiome, such as dietary modulation, have shown promise in delaying disease onset and reducing inflammation. However, the clinical evidence remains limited. Given that gut dysbiosis may precede neurological symptoms, microbiota-targeted therapies offer a novel and potentially modifiable approach to ALS treatment. Understanding the role of GBA in ALS will open new avenues for early diagnosis and intervention. Further clinical trials are required to clarify the causal links and evaluate the efficacy of microbiome-based interventions. Understanding the brain-gut-microbiota axis in ALS could lead to new diagnostic biomarkers and therapeutic strategies.},
}

@article {pmid40943213,
year = {2025},
author = {Liu, D and Yu, S and Ji, B and Peng, Q and Gao, J and Zhang, J and Guo, Y and Hu, M},
title = {Molecular Mechanisms of Herbicide Resistance in Rapeseed: Current Status and Future Prospects for Resistant Germplasm Development.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
pmid = {40943213},
issn = {1422-0067},
support = {2023ZD0404203//Science and Technology Innovation 2030 Major Program/ ; 31901503//National Natural Science Foundation of China/ ; CARS-12//Agriculture Research System of China/ ; CX (23) 1001//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; BE2021405//Jiangsu Province Key Research and Development Project/ ; },
abstract = {Rapeseed (Brassica napus) is a globally important oilseed crop whose yield and quality are frequently limited by weed competition. In recent years, there have been significant advances in our understanding of herbicide-resistance mechanisms in rapeseed and in the development of herbicide-resistant rapeseed germplasm. Here, we summarize the molecular mechanisms of resistance to three herbicides: glyphosate, glufosinate, and acetolactate synthase (ALS) inhibitors. We discuss progress in the identification of new resistance genes and the development of herbicide-resistant rapeseed germplasm, from the initial identification of natural mutants to artificial mutagenesis screening, introduction of exogenous resistance genes, and gene editing. In addition, we describe how synthetic biology and directed protein evolution will contribute to precision-breeding efforts in the near future. This is the first review to systematically integrate non-target resistance mechanisms and the potential applications of multi-omics and AI technologies for breeding of herbicide-resistant rapeseed, together with strategies for managing the risks associated with gene flow, the evolution of herbicide-resistant weeds, and the occurrence of volunteer plants resulting from deployment of herbicide-resistant rapeseed. By synthesizing current knowledge and future trends, this review provides guidance for safe, effective, and innovative approaches to the sustainable development of herbicide-resistant rapeseed.},
}

@article {pmid40943143,
year = {2025},
author = {Calcagnile, M and Alifano, P and Damiano, F and Pontieri, P and Del Giudice, L},
title = {A Perspective on the Role of Mitochondrial Biomolecular Condensates (mtBCs) in Neurodegenerative Diseases and Evolutionary Links to Bacterial BCs.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178216},
pmid = {40943143},
issn = {1422-0067},
support = {project 'NutrAge' (project nr. 7022)//CNR-DISBA/ ; FOE-2019 DBA.AD003.139//CNR/ ; },
abstract = {Biomolecular condensates (BCs), formed through liquid-liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies.},
}

@article {pmid40940798,
year = {2025},
author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X},
title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171387},
pmid = {40940798},
issn = {2073-4409},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.},
}

@article {pmid40940752,
year = {2025},
author = {Lee, JH and Chang, W and Min, SS and Song, DY and Yoo, HI},
title = {Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171342},
pmid = {40940752},
issn = {2073-4409},
support = {2023//Eulji University/ ; RS-2024-00438628//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood-brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy's dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases.},
}

@article {pmid40940730,
year = {2025},
author = {Graber, DJ and Cook, WJ and Sentman, ML and Murad-Mabaera, JM and Stommel, EW and Sentman, CL},
title = {Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171318},
pmid = {40940730},
issn = {2073-4409},
support = {NS102556,//NIH NINDS/ ; NS117895//NIH NINDS/ ; NS132666//NIH NINDS/ ; },
abstract = {Regulatory T cells (Tregs) have anti-inflammatory immunomodulatory activity and hold therapeutic potential for chronic neuroinflammatory neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). We are developing engineered human Tregs with enhanced disease-modifying activity for treating ALS. A combination of a disease-specific chimeric antigen receptor (CAR) recognizing misfolded human superoxide dismutase-1 (hSOD1) and constitutive expression of brain-derived neurotrophic factor (BDNF) was tested. The scFv region of CAR demonstrated binding to anterior horn tissues of ALS patients with and without familial ALS mutations in SOD1. Tregs transduced to express BDNF showed the ability to secrete BDNF and protect co-cultured neuronal cells from peroxidase toxicity. Co-expression of BDNF did not inhibit CAR Treg expansion, Treg markers, or CAR-mediated anti-inflammatory cytokine production. Human Tregs co-expressing CAR and BDNF were tested for activity in G93A hSOD1-NSG transgenic mice, which develop an early-onset and aggressive ALS-like disease and do not reject human cells. Human Tregs expressing CAR and BDNF delayed the onset of disease development, extended survival, and decreased spinal cord neuroinflammation. The engineered Tregs showed enhanced disease-modifying activity and hold promise as a therapy for ALS.},
}

@article {pmid40940222,
year = {2025},
author = {Poulin-Brière, A and Pozzi, S and Julien, JP},
title = {Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00737},
doi = {10.1016/j.neurot.2025.e00737},
pmid = {40940222},
issn = {1878-7479},
abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the cytoplasmic mislocalization and accumulation of TAR DNA binding protein 43 (TDP-43). We reported previously the protective effects in a transgenic mouse model expressing ALS-linked mutant TDP-43[A315T] of a monoclonal antibody, called E6, binding specifically to the RNA Recognition Motif 1 (RRM1) domain of TDP-43. Here, we tested the effects of E6 antibody in an animal model of sporadic ALS based on the intracerebroventricular (i.c.v.) infusion during 14 days of cerebrospinal fluid (CSF) from sporadic ALS patients into transgenic mice expressing human TDP-43[WT]. Either intrathecal (i.t.) or i.c.v. injection of E6 antibody conferred protective effects in this model of disease. Thus, the CSF-inoculated E6 antibody reduced motor and cognitive impairments, mitigated TDP-43 proteinopathy and prevented neurofilament (Nf) disorganization in cortical and spinal neurons. Administration of E6 antibody reduced the loss of motor neurons in the spinal cord and the denervation of neuromuscular junctions. Moreover, E6 antibody promoted a switch toward features associated with a protective phenotype of microglial activation characterized by enhanced phagocytic function and reduced secretion of pro-inflammatory cytokines. The results suggest that an immunotherapy targeting the RRM1 domain of TDP-43 may confer protection against pathogenic pathways triggered by the CSF of ALS patients.},
}

@article {pmid40939256,
year = {2025},
author = {Novo-Rigueiro, M and Crespo-De, A and Antelo-Pose, A and Novo-Veleiro, I},
title = {[Shoulder pain as a preceding symptom in amyotrophic lateral sclerosis: A retrospective descriptive and exploratory study].},
journal = {Rehabilitacion},
volume = {59},
number = {4},
pages = {100932},
doi = {10.1016/j.rh.2025.100932},
pmid = {40939256},
issn = {1578-3278},
}

@article {pmid40938412,
year = {2025},
author = {Cantré, D and König, J and Makowsky, C and Dyrba, M and Prudlo, J},
title = {Midsagittal Midbrain Area and Midbrain-to-Pons-Ratio Cannot Distinguish Overlap Syndromes Between Amyotrophic Lateral Sclerosis and Progressive Supranuclear Palsy.},
journal = {Clinical neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {40938412},
issn = {1869-1447},
abstract = {PURPOSE: When amyotrophic lateral sclerosis (ALS), a TDP-43 proteinopathy, and progressive supranuclear palsy (PSP), a tauopathy, are associated with frontotemporal dementia (ALS-FTD or PSP-FTD), clinical differentiation can be challenging. There are no established imaging biomarkers to differentiate ALS-FTD from PSP-FTD.

METHODS: We evaluated the midsagittal midbrain area (MBA) and the midbrain-to-pons-(MB/P)-ratios in T1 MPRAGE MRI of 36 PSP cases (n = 14 PSP-FTD), 77 ALS cases (n = 10 ALS-FTD), and 72 healthy controls (HC).

RESULTS: In ALS, both parameters were indistinguishable from HC. Patients with ALS-FTD had low MBA-values and MB/P-ratios not significantly different from cases of PSP. While ROC-analyses provided an excellent diagnostic accuracy of both parameters for differentiating PSP from HC (AUCMBA = 0.974) as well as PSP from ALS (AUCMBA = 0.982), midbrain morphometry provided poor diagnostic accuracy for distinguishing ALS-FTD from PSP-FTD (AUCMBA = 0,614).

CONCLUSION: The MBA and the MB/P-ratio are morphometric parameters that have proven reliable in atypical Parkinsonian syndromes. Both can distinguish between PSP and ALS in their typical clinical forms. However, they cannot differentiate between PSP-FTD and ALS-FTD.},
}

@article {pmid40938039,
year = {2025},
author = {Baroni, A and Moulton, C and Cristina, M and Sansone, L and Belli, M and Tasciotti, E},
title = {Nano- and Microplastics in the Brain: An Emerging Threat to Neural Health.},
journal = {Nanomaterials (Basel, Switzerland)},
volume = {15},
number = {17},
pages = {},
pmid = {40938039},
issn = {2079-4991},
support = {[Ricerca corrente]//Italian Ministry of Health/ ; },
abstract = {Nano- and microplastics (NMPs), with nanoplastics posing higher risks due to their smaller size and greater capacity for cellular and subcellular penetration, are being referred to as ubiquitous environmental neurotoxicants, due to their ability to pass through biological barriers, including the blood-brain barrier (BBB) and nasal olfactory epithelium, and to remain lodged in neural tissue. Upon uptake, such particles disturb neuronal homeostasis by multiple converging pathways, including oxidative stress, mitochondrial dysfunction, pathological protein aggregation, and chronic neuroinflammation, all closely involved with the molecular signatures of neurodegenerative disorders (Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis-ALS). In addition to their neurotoxicity, recent findings suggest that NMPs could disturb synaptic communication and neuroplasticity, thereby compromising the brain's capacity to recover from an injury, a trauma, or neurodegeneration, thus impacting the progression of the disease, our ability to treat it and eventually the efficacy of rehabilitation approaches. Despite these findings, our understanding remains hampered by analytical issues, the scarcity of standard detection methods, and a total lack of longitudinal studies in humans. This review combines multidisciplinary evidence on brain-plastic interactions and calls for accelerated advances in our ability to monitor bioaccumulation in humans, and to integrate neurotoxicology paradigms in the assessment of this underappreciated but growing threat to brain health.},
}

@article {pmid40935268,
year = {2025},
author = {Bonares, M and Shapiro, J and Vijayanathan, V and Abrahao, A and Zinmanc, L and Lau, C},
title = {Goal-concordant care in people with amyotrophic lateral sclerosis receiving palliative care.},
journal = {Journal of pain and symptom management},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpainsymman.2025.08.046},
pmid = {40935268},
issn = {1873-6513},
abstract = {CONTEXT: Although it is known where people with amyotrophic lateral sclerosis (ALS) are dying, less is known about whether they are dying where they want to.

OBJECTIVES: To determine the rate of dying in a preferred place and factors associated with doing so in people with ALS receiving clinic-based specialist palliative care.

METHODS: Retrospective cohort study of people with ALS receiving clinic-based specialist palliative care in Toronto, Canada between July 2022 and February 2024. Association between preferred and actual place of death was determined using a χ[2] test. Factors associated with dying in a preferred place were determined using a multivariable binary logistic regression analysis.

RESULTS: In 367 individuals, at time of consultation, median age was 67 years; 60.8% had a Palliative Performance Scale score between 50-60%, and 43.3% had non-invasive ventilation. Mortality rate up to February 2024 was 41.7%. 85.4% stated a preference to die at home, 8.7% in hospital, and 5.9% in a hospice facility; whereas, 54.9% died at home, 34% in hospital, and 11.1% in a hospice facility. Of those with known preferred and actual place of death, 70.1% died in a preferred place (χ[2]=36.2; p<0.001). Dying in a preferred place was associated with increasing age (OR=1.1; 95% CI=1.0-1.1) and having non-invasive ventilation (OR=2.5; 95% CI=1.0-6.2).

CONCLUSION: Younger age and not having non-invasive ventilation at the time of consultation may suggest a higher risk of goal-discordant end-of-life care and the need to engage in early future planning when these factors are identified.},
}

@article {pmid40935037,
year = {2025},
author = {Wang, C and Liu, L and Liu, Y and Wei, Y and Wang, M and Huang, Y and Li, K and Lu, Q},
title = {Deep eutectic solvents-assisted alkali lignin modification for pyrolytic monophenols production.},
journal = {International journal of biological macromolecules},
volume = {328},
number = {Pt 1},
pages = {147584},
doi = {10.1016/j.ijbiomac.2025.147584},
pmid = {40935037},
issn = {1879-0003},
abstract = {The efficient valorization of alkali lignin (AL) remains a significant challenge due to the multiple impurities and complex structure of AL. Lignin modification through deep eutectic solvent (DES) and subsequent fast pyrolysis offers a promising alternative for AL valorization. Thus, this study comprehensively investigated the potential of DES-pretreated ALs (DESALs) for producing pyrolytic monophenols, with particular focus on the modification process of AL during DES pretreatment, the interaction of lignin-DES, and the techno-economic feasibility of the integrated technology. Notably, under optimal experimental conditions, the ChCl/ethylene glycol (CCEG) system demonstrated the greatest potential to enhance the yields of 4-vinyl syringol (4VS) and 4-propenyl syringol (4PS) to 12.09 wt%, achieving a selectivity of 40.60 %, without using a catalyst. Moreover, multiscale simulations were performed to illustrate the enhancement effect of DESs on the production of pyrolytic monophenols. The CCEG system exhibited the lowest |HOMO-LUMO| energy gap (161.80 kcal/mol) and the highest interaction energy (-56.56 kcal/mol). The chloride ions played an integral role in forming robust hydrogen bonds between CC and EG. Further investigation indicated that the adduct and acetal structures were synthesized, and their formation pathways were subsequently modeled. Finally, the CCEG system exhibited a negligible environmental impact and high economic feasibility.},
}

@article {pmid40934740,
year = {2025},
author = {Omidbakhsh, S and Tankisi, H},
title = {Effect of reference electrode position on diagnostic accuracy of split hand index in ALS.},
journal = {Neurophysiologie clinique = Clinical neurophysiology},
volume = {55},
number = {5},
pages = {103101},
doi = {10.1016/j.neucli.2025.103101},
pmid = {40934740},
issn = {1769-7131},
}

@article {pmid40934673,
year = {2025},
author = {Misra, SR and Das, R},
title = {The imperative of careful selection and novel strategies: Comment on Mrosk et al.'s outcomes of primary chemoradiation for advanced oral cancer.},
journal = {Oral oncology},
volume = {169},
number = {},
pages = {107676},
doi = {10.1016/j.oraloncology.2025.107676},
pmid = {40934673},
issn = {1879-0593},
}

@article {pmid40934454,
year = {2025},
author = {Chen, Y and Sun, S and Bai, Z and Gao, N and Yu, W and Sun, X and Li, W and Zhao, Y and Yan, C and Lin, P and Liu, S},
title = {CSF Aβ, Tau, Axonal, Synaptic, Glial, Neural, and Inflammatory Biomarkers in Patients With Sporadic Amyotrophic Lateral Sclerosis.},
journal = {Neurology},
volume = {105},
number = {7},
pages = {e213914},
doi = {10.1212/WNL.0000000000213914},
pmid = {40934454},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with multifactorial pathophysiologic mechanisms, yet reliable CSF biomarkers for the diagnosis of ALS are lacking. The aim of this study was to systematically identify CSF protein alterations in patients with sporadic ALS and to develop an effective CSF protein panel to aid in ALS diagnosis.

METHODS: This observational study was conducted at Qilu Hospital, Cheeloo College of Medicine, Shandong University. Using proximity extension assay, single-molecule array, and ELISA, approximately 200 proteins involved in different pathogenic events, including axonal damage, neuronal damage, glial responses, synaptic dysfunction, β-amyloid (Aβ) pathology, tau pathology, and neuroinflammation, were measured in the CSF. Moreover, Xtreme gradient boosting and logistic regression models were applied to develop a CSF protein panel to distinguish patients with sporadic ALS from disease controls (DCs), and the diagnostic performance was verified in an independent cohort.

RESULTS: A total of 180 participants were included, comprising 109 patients with sporadic ALS (mean age 56.7 ± 11.9 years, 58.7% male), 30 DCs (56.9 ± 12.6 years, 56.7% male), and 41 healthy controls (HCs, 57.1 ± 12.4 years, 63.4% male). Compared with HCs, patients with ALS had significantly elevated CSF levels of neurofilament light chain, chitinase proteins including chitotriosidase (CHIT1), and 55 other proteins, whereas CSF Aβ40, Aβ42, and GAP43 levels were significantly lower. Moreover, we identified a 3-protein CSF panel (CHIT1, N-CDase, and PDGF-R-alpha) that effectively distinguished patients with ALS from DCs, achieving an area under the curve of 0.927 (95% CI 0.883-0.971) in the original cohort and 0.912 (95% CI 0.841-0.985) in the replication cohort.

DISCUSSION: Using a combined approach, we comprehensively investigated CSF protein alterations in a cohort of newly diagnosed patients with ALS and provided further in vivo evidence supporting the presence of mixed copathologies in patients with ALS. Moreover, we developed a 3-protein CSF biomarker panel that effectively distinguished patients with ALS from DCs and validated its performance in an independent cohort. However, considering the relatively small cohort and lack of multiple comparison adjustments, further validation in larger, multicenter studies is warranted.},
}

@article {pmid40934045,
year = {2025},
author = {Majzoobi, MR and Forstmeier, S},
title = {The relationship between marital reminiscence styles and psychological well-being through mediating role of marital quality.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1639240},
pmid = {40934045},
issn = {1664-1078},
abstract = {INTRODUCTION: Marital relationships are deeply shaped by the memories couples share, as reminiscence plays a pivotal role in fostering emotional connection and intimacy. Investigating how such reminiscence is related to marital quality provides valuable insights into its influence on relational dynamics. Therefore, the purpose of the present study was to examine the relationship between marital reminiscence styles (MRSs) and psychological well-being (PWB) through the mediating role of marital quality.

METHODS: This was a descriptive-correlational study. The statistical population included all married people living in Kermanshah, Iran in 2023, among whom a sample of 304 people were selected using convenience sampling method. The measures used in this study were Majzoobi and Forstmeier's (2025) marital reminiscence styles Questionnaire (MRSQ), Chonody et al.'s (2018) Relationship quality Questionnaire, and Ryff's PWB Questionnaire. Data were analyzed through Pearson's correlation coefficient and structural equations modeling (SEM) in SPSS-26 and LISREL-10 software.

RESULTS: The findings indicated that the hypothesized model had a good fit in the studied sample. MRSs were significantly associated with PWB through marital quality. As such, it was found that obsessive MRS is related negatively to marital quality, which, in turn, related positively to PWB. Moreover, narrative MRS was related positively to marital quality, which, in turn, related positively to PWB.

DISCUSSION: These results underscore the importance of fostering positive MRSs, such as narrative MRS, to enhance marital quality and PWB in marital relationships.},
}

@article {pmid40933646,
year = {2025},
author = {Ferguson, R and Subramanian, V},
title = {Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration - Implications for ALS.},
journal = {iScience},
volume = {28},
number = {9},
pages = {113338},
pmid = {40933646},
issn = {2589-0042},
abstract = {Mutations in CFAP410, a basal body protein known to be required for the formation of primary cilia, have been identified as risk modifiers in amyotrophic lateral sclerosis (ALS), a devastating late onset neurodegenerative disorder with poor prognosis. CFAP410 is also implicated in the DNA damage response and interacts with Nek1, which has been shown to be mutated in ALS. Herein, we investigated the effect of knocking in an HA epitope tag and functional mutations into the endogenous Cfap410 gene by gene editing in mouse embryonic stem cells (mESCs). We show that primary cilia in these edited mESCs, as well as in the neural progenitors and neurons differentiated from them do not exhibit any significant difference in frequency. However, ESCs, neural progenitors, and neurons with knock-in Cfap410 variants are more susceptible to DNA damage and exhibit impaired interaction with Nek1. Our findings point to DNA damage as a convergent pathway leading to ALS.},
}

@article {pmid40933539,
year = {2025},
author = {Aban, JL and Lucero-Prisno, DE and Ogaya, JB and Ong, CJN},
title = {Beyond Anaphylaxis: The Overlooked Forensic Complexity of COVID-19-Triggered Pseudoangioedema.},
journal = {Academic forensic pathology},
volume = {},
number = {},
pages = {19253621251374276},
pmid = {40933539},
issn = {1925-3621},
abstract = {Gray et al's investigation into angioedema-anaphylaxis deaths amidst the COVID-19 pandemic raises important forensic implications, particularly concerning differential diagnostics in postmortem settings (1). However, a critical avenue requiring deeper contextualization is the immunopathological intersection between SARS-CoV-2-induced mast cell activation and bradykinin-mediated pathways (2).},
}

@article {pmid40933233,
year = {2025},
author = {Kang, K and Nunes, AS and Potter, IY and Mishra, RK and Geronimo, A and Adams, JL and Isroff, C and Wang, JE and Vaziri, A and Wills, AM and Pantelyat, A},
title = {Digital speech assessments and machine learning for differentiation of neurodegenerative diseases.},
journal = {Clinical parkinsonism & related disorders},
volume = {13},
number = {},
pages = {100389},
doi = {10.1016/j.prdoa.2025.100389},
pmid = {40933233},
issn = {2590-1125},
abstract = {INTRODUCTION: Speech impairment is a prevalent symptom of neurological disorders, including Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), with mechanisms and severity varying across and within conditions. Scalable digital health tools and machine learning (ML) are essential for diagnosing and tracking neurodegenerative disease.

METHODS: A total of 92 individuals were included in this study (21 PSP, 21 PD, 18 HD, 15 ALS, and 16 healthy elderly controls (CTR)). The Rainbow Passage was collected on a digital device and analyzed to extract 12 speech features representing speech production. A set of Elastic Net ML models was trained on these speech features to differentiate between diagnostic classes. A specialized Support Vector Machine ML model was then developed to differentiate PSP from PD.

RESULTS: Elastic Net models achieved a balanced accuracy of 77% over 5 diagnostic classes (group-specific sensitivities of 76% for PSP, 67% for PD, 83% for HD, 73% for ALS, and 88% for CTR) and 83% over 4 diagnostic classes (group-specific sensitivities of 83% for PSP-PD, 83% for HD, 73% for ALS, and 94% for CTR). The PSP vs. PD classification model demonstrated a balanced accuracy of 85%, with sensitivity of 88% for PSP and 82% for PD. Key speech features differentiated clinical conditions, with Total Voiced Time being the strongest positive feature for combined PSP-PD. In HD, ALS, and CTR, Ratio Extra Words, Pauses per Second, and Intelligibility were the most strongly differentiating features, respectively. Articulatory Rate emerged as the most distinguishing feature between PD and PSP.

CONCLUSION: Our findings highlight the potential of digital health technology and ML in identifying and monitoring speech features in neurodegenerative diseases.},
}

@article {pmid40932783,
year = {2025},
author = {Strambler, MJ},
title = {Universalism is not White: Commentary on Sue et al. (2024).},
journal = {The American psychologist},
volume = {80},
number = {6},
pages = {966-967},
doi = {10.1037/amp0001489},
pmid = {40932783},
issn = {1935-990X},
abstract = {This commentary responds to Sue et al.'s (see record 2025-04512-010) claim that principles such as universalism, individualism, objectivism, and empiricism are pillars of White epistemology. Drawing on W. E. B. Du Bois's embrace of Western intellectual traditions, this commentary argues that such ideals are not inherently racialized but rather central to human flourishing. In their critique of universalism, Sue and colleagues conflated the misapplication of universalism with the intended meaning of the concept. Rather than characterizing universalism in racial terms, this commentary contends that its accurate application promotes fairness and inclusivity and aligns with civil rights and human rights movements. Defining valuable concepts like universalism through a racial lens risks alienating scholars and undermining ideas that could advance mental health and psychological research across all demographics. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid40932199,
year = {2025},
author = {Spittel, S and Grehl, T and Weydt, P and Kettemann, D and Fabian, R and Rödiger, A and Smesny, U and Steinbach, R and Ilse, B and Weyen, U and Petri, S and Lumi, R and Bjelica, B and Lingor, P and Grosskreutz, J and Göricke, BM and Pfeilschifter, W and Schmeja, W and Dorst, J and Mensch, A and Siebert, J and Norden, J and Bernsen, S and Subramanian, SK and Hildebrandt, B and Walter, B and Münch, C and Maier, A and Meyer, T},
title = {Dextromethorphan/quinidine (DMQ) for reducing bulbar symptoms in amyotrophic lateral sclerosis - assessment of treatment experience in a multicenter study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/21678421.2025.2557932},
pmid = {40932199},
issn = {2167-9223},
abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), dextromethorphan/quinidine (DMQ) has been reported to reduce bulbar symptoms, including dysarthria and dysphagia. However, data on patients' perceptions of DMQ treatment are limited.

METHODS: Data on DMQ treatment were collected from 1065 ALS patients treated at 13 ALS centers between 10-2015 and 06-2025. Patient-reported outcome measures (PROM) of 179 participants were remotely assessed via the "ALS App". PROM included the self-explanatory version of the ALS Functional Rating Scale (ALSFRS-R-SE), the Net Promoter Score (NPS); and Treatment Satisfaction Questionnaire for Medication (TSQM-9).

RESULTS: Mean disease duration was 29.3 months (SD 38.1). ALS progression before treatment was 0.82 points/month (ALSFRS-R). Mean DMQ treatment duration was 8.4 months (SD 10.8), including 35.2% (n = 374) of shorter (<3 months), 35.3% (n = 375) of longer (3-9 months), and 29.5% (n = 313) of very long DMQ treatment (>9 months). Patients' recommendation (n = 178) was positive (NPS: +23) with higher scores after very long DMQ treatment (NPS +37) compared to longer (NPS +15) and shorter treatment (NPS +7.5), respectively. TSQM-9 scores (n = 163) demonstrated high satisfaction for effectiveness 60.0 (SD 25.9), convenience 73.8 (SD 18.2), and global satisfaction 63.4 (SD 29.8).

INTERPRETATION: The positive perception in PROM underscores the value of DMQ as an individualized treatment option for bulbar symptoms in ALS. However, shortage of clinical data, online assessment, and selection biases are among the limitations of this study that need to be addressed in further investigations.},
}

@article {pmid40931867,
year = {2025},
author = {Pavey, N and Tieppo, A and Calma, AD and Hannaford, A and Grey, E and Orden, B and Ryder, J and Lee, E and Zablotska-Manos, I and Silsby, M and Menon, P and Vucic, S},
title = {Neck flexion weakness predicts respiratory dysfunction in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2025.2557939},
pmid = {40931867},
issn = {2167-9223},
abstract = {Objective: Neck flexion (NF) weakness is a frequently observed clinical feature in amyotrophic lateral sclerosis (ALS), particularly in advanced disease. The aim of the present study was to assess whether NF weakness could be a clinical biomarker for development of respiratory dysfunction. Methods: Sixty-two ALS patients were prospectively recruited at Brain and Nerve Research Center. Neck flexion strength was assessed by the Medical Research Council (MRC) score and handheld dynamometry (HHD). Respiratory function testing was assessed by spirometry, including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). Site of disease onset, disease duration, and ALSFRS-R were recorded. Results: Neck flexion weakness (MRC ≤4) was evident in 27% of ALS patients. There was a significant reduction of FVC in ALS patients with weak NF (ALSNFweakness 70.0 ± 7.2%; ALSNFnormal 86.8 ± 2.4% predicted, p = 0.038). Additionally, reduction of HHD measurements was significantly correlated with FVC (R = 0.487, p < 0.001) and FEV1 (R = 0.465, p < 0.001), and was most prominent in bulbar onset ALS (FVC: R[2] = 0.673, p = 0.002). Of relevance, the presence of NF weakness (MRC ≤ 4) was a significant predictor of reduced FVC ≤50% predicted (Chi[2] = 7.68, p = 0.006), a threshold indicating need for ventilatory support. Conclusion: Neck flexion weakness, particularly when quantified by the MRC score and HHD, serves as a marker of respiratory dysfunction in ALS patients. This simple clinical assessment may herald the development of respiratory dysfunction and requirement for respiratory ventilatory support.},
}

@article {pmid40931780,
year = {2025},
author = {Sabirin, W and Abd Latif, SA and Ahmad, F and Zainuddin, SI and Lam, CL and Soo, CI and Sabirin, S and Chuah, KH and Shahrizaila, N and Capelle, DP},
title = {An evaluation of the ALSSQOL-SF in the Malaysian context through cognitive interviewing.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/17582024.2025.2558342},
pmid = {40931780},
issn = {1758-2032},
abstract = {BACKGROUND: Quality of life is an important goal of care for people living with amyotrophic lateral sclerosis (ALS) and their carers. The ALS Specific Quality of Life instrument Short Form (ALSSQOL-SF) has been translated and validated in various cultural contexts, however its utility in the Malaysian cultural context has not yet been evaluated.

METHODS: The quality of life of 21 patients with ALS was evaluated using the ALSSOL-SF in either the English version or translated to the Malay language. A cognitive interview approach was utilized and the responses were transcribed and thematically analyzed.

RESULTS: Culture and language-related factors affecting the application of the ALSSQOL-SF were identified. Interpretations of intimacy and religiosity varied and sometimes differed significantly from the constructs underlying the ALSSQOL-SF domains.

CONCLUSION: The ALSSQOL-SF captured items from the physical domain better than those from the psycho-social and spiritual domains. Cognitive interviewing showed that patients mostly could not grasp the intended meaning of the items from the psycho-social and spiritual domains despite translation into the Malay language. There are limitations in adapting the ALSSQOL-SF for use in evaluation of QOL in Malaysian ALS patients. In the local setting a better understanding is needed about how aspects such as religion, intimacy and spiritual well-being are culturally reflected and expressed.},
}

@article {pmid40931498,
year = {2025},
author = {Alemán-Villa, KM and Armienta-Rojas, DA and Camberos-Barraza, J and Rábago-Monzón, ÁR and Camacho-Zamora, A and Osuna-Ramos, JF and Magaña-Gómez, JA and Guadrón-Llanos, AM and Calderón-Zamora, L and Norzagaray-Valenzuela, CD and Valdez-Flores, MA and Picos-Cárdenas, VJ and De la Herrán-Arita, AK},
title = {Neuroinflammation across the spectrum of neurodegenerative diseases: mechanisms and therapeutic frontiers.},
journal = {Neuroimmunomodulation},
volume = {},
number = {},
pages = {1-33},
doi = {10.1159/000548021},
pmid = {40931498},
issn = {1423-0216},
abstract = {Neuroinflammation has emerged as a central and dynamic component of the pathophysiology underlying a wide range of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Far from being a secondary consequence of neuronal damage, inflammatory processes (mediated by microglia, astrocytes, peripheral immune cells, and associated molecular mediators) actively shape disease onset, progression, and symptomatology. This review synthesizes current knowledge on the cellular and molecular mechanisms that govern neuroinflammatory responses, emphasizing both shared and disease-specific pathways. We examine how innate and adaptive immune interactions contribute to neuronal vulnerability and neurodegenerative cascades, and explore the reciprocal communication between systemic and central immune compartments. Particular attention is given to emerging therapeutic strategies aimed at modulating neuroinflammation, including immunomodulatory drugs, glial-targeted interventions, and novel delivery platforms. By integrating findings across disciplines and disease models, we outline key translational challenges and propose future directions to harness neuroinflammation as a therapeutic target in the era of precision medicine. Ultimately, a deeper understanding of neuroimmune dynamics holds promise for redefining both the diagnosis and treatment of neurodegenerative disorders.},
}

@article {pmid40931339,
year = {2025},
author = {Epplen, ASC and Rothöft, M and Stahlke, S and Theiss, C and Matschke, V},
title = {Caffeine mitigates ROS accumulation and attenuates motor neuron degeneration in the wobbler mouse model of amyotrophic lateral sclerosis.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {394},
pmid = {40931339},
issn = {1478-811X},
mesh = {Animals ; *Caffeine/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Disease Models, Animal ; *Reactive Oxygen Species/metabolism ; Mice ; Oxidative Stress/drug effects ; Male ; *Neuroprotective Agents/pharmacology ; *Nerve Degeneration/pathology/drug therapy ; NAD/metabolism ; Humans ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by oxidative stress and progressive motor neuron degeneration. This study evaluates the potential neuroprotective effects of caffeine in the Wobbler mouse, an established model of ALS.

METHODS: Wobbler mice received caffeine supplementation (60 mg/kg/day) via drinking water, and key parameters, including muscle strength, NAD metabolism, oxidative stress, and motor neuron morphology, were assessed at critical disease stages.

RESULTS: Caffeine delayed motor performance decline, as observed in grip strength tests during the early symptomatic phase. Histological analyses revealed that significantly fewer motor neurons were lost in caffeine-treated mice at p41, despite no changes in soma morphology. Biochemical assays demonstrated that caffeine significantly reduced ROS levels and restored NAD levels to wildtype-like values, although NMNAT2 protein expression remained unaffected. The data suggest that caffeine mitigates oxidative stress through alternative pathways, potentially involving enhanced mitochondrial function and antioxidative defenses.

CONCLUSIONS: These findings highlight the potential of caffeine as a protective agent for delaying motor neuron degeneration in ALS. Future studies should explore optimal dosing strategies, combinatorial treatment approaches, and the underlying molecular mechanisms, to enable translation of these findings to human ALS patients.},
}

Animals
*Caffeine/pharmacology/therapeutic use
*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism
*Motor Neurons/drug effects/pathology/metabolism
Disease Models, Animal
*Reactive Oxygen Species/metabolism
Mice
Oxidative Stress/drug effects
Male
*Neuroprotective Agents/pharmacology
*Nerve Degeneration/pathology/drug therapy
NAD/metabolism
Humans

@article {pmid40931262,
year = {2025},
author = {Bonan, L and D'Angeli, D and Vacchiano, V and Postiglione, E and Incensi, A and Valentino, ML and Capellari, S and Donadio, V and Rizzo, G and Liguori, R},
title = {In-vivo evidence of synucleinopathy in parkinsonism due to VCP mutation.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40931262},
issn = {1435-1463},
abstract = {Multisystem proteinopathy 1 (MSP1) is a rare autosomal dominant disorder caused by mutations in the valosin-containing protein (VCP) gene typically presenting with inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Parkinsonism is a rare feature of MSP1, occurring in 3-4% of cases, with limited post-mortem evidence suggesting neuronal synucleinopathy. We report a case of VCP-related parkinsonism providing the first in vivo demonstration of phosphorylated alpha-synuclein deposition in skin biopsy, a highly sensitive and specific in vivo biomarker of synucleinopathy. A focused literature review on VCP-related parkinsonism is also presented to contextualize our findings. A 76-year-old man presented with akinetic-rigid parkinsonism, myopathy, pyramidal signs, and PDB. Genetic testing identified a pathogenic VCP mutation (c.277 C > T; p.R93C). Diagnostic workup included neuroimaging, electromyography, muscle biopsy, neuropsychological assessment, bone scintigraphy, and skin biopsy, which revealed abnormal intraneural phosphorylated α-synuclein deposits. Current evidence suggests that VCP mutations may promote alpha-synuclein aggregation in a subset of patients, leading to parkinsonism. This is the first in vivo demonstration of phosphorylated α-synuclein in a MSP1 patient, reinforcing the association between VCP mutations and synucleinopathy.},
}

@article {pmid40930972,
year = {2025},
author = {Narita, ZC},
title = {Concerns Regarding Masataka et al.'s "Revisiting the Gateway Drug Hypothesis for Cannabis: A Secondary Analysis of a Nationwide Survey Among Community Users in Japan".},
journal = {Neuropsychopharmacology reports},
volume = {45},
number = {3},
pages = {e70057},
doi = {10.1002/npr2.70057},
pmid = {40930972},
issn = {2574-173X},
mesh = {Humans ; Japan/epidemiology ; *Cannabis ; *Marijuana Use/epidemiology ; *Illicit Drugs ; Surveys and Questionnaires ; *Marijuana Abuse/epidemiology ; },
abstract = {Masataka et al.'s cannabis gateway study misrepresents the 43.8% probability of cannabis users transitioning to illegal drugs as "rare," and misuses regression via the Table 2 Fallacy. These critical issues discredit their conclusion.},
}

Humans
Japan/epidemiology
*Cannabis
*Marijuana Use/epidemiology
*Illicit Drugs
Surveys and Questionnaires
*Marijuana Abuse/epidemiology

@article {pmid40930692,
year = {2025},
author = {Wei, Y and Miao, H and Najafi, H and Kim, WJ},
title = {Precise measurement of motor neuron dysfunction in Drosophila ALS model via climbing assay and leg imaging.},
journal = {Methods in cell biology},
volume = {197},
number = {},
pages = {127-148},
doi = {10.1016/bs.mcb.2025.02.008},
pmid = {40930692},
issn = {0091-679X},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Disease Models, Animal ; *Motor Neurons/pathology/metabolism ; *Drosophila melanogaster/physiology ; *Optical Imaging/methods ; Humans ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. While there is a plethora of studies focusing on many aspects of ALS, the pathogenesis of this disease is not well understood, and effective treatments are scarce. Drosophila melanogaster is a powerful model organism for studying ALS due to its genetic tractability and its evolutionarily conserved cellular and molecular processes which are also shared between the fly and human. Here, we introduce two simple and cost-effective methodologies for assessing motor neuron dysfunction in Drosophila: (1) Fast Inexpensive Climbing Test (FICT), and (2) Economical Leg Fluorescence Imaging (ELFI). These methods are established based on using basic equipment and straightforward procedures, making them accessible and applicable in various research and educational settings. FICT provides a non-invasive and high-throughput measure of motor dysfunction, while ELFI allows for direct visualization of fluorescently labeled cells in the Drosophila leg, facilitating the study of cell-cell communications in vivo. Our approach emphasizes the importance of both neuronal and glial contributions to ALS pathogenesis, offering valuable insights for the development of novel therapeutic strategies. These methods democratize access to ALS research tools, promoting global scientific collaboration and advancing our understanding of this devastating disease.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/physiopathology
Disease Models, Animal
*Motor Neurons/pathology/metabolism
*Drosophila melanogaster/physiology
*Optical Imaging/methods
Humans

@article {pmid40930530,
year = {2025},
author = {Geng, Y and Liu, C and Miao, H and Suen, MC and Xie, Y and Zhang, B and Han, W and Wu, C and Ren, H and Chen, X and Tai, HC and Wang, Z and Zhu, G and Cai, Q},
title = {Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats.},
journal = {Nucleic acids research},
volume = {53},
number = {17},
pages = {},
doi = {10.1093/nar/gkaf879},
pmid = {40930530},
issn = {1362-4962},
support = {32301023//Natural Scientific Foundation of China/ ; 32071188//Natural Scientific Foundation of China/ ; 32471312//Natural Scientific Foundation of China/ ; 3502Z202373009//Natural Scientific Foundation of Xiamen/ ; 16101120//Hong Kong Special Administrative Region, China/ ; 161011121//Hong Kong Special Administrative Region, China/ ; AoE/M-403-16//Hong Kong Special Administrative Region, China/ ; AoE/M-401/20//Hong Kong Special Administrative Region, China/ ; //Hong Kong University of Science and Technology/ ; 3502Z20214001//Project of Xiamen Cell Therapy Research, China/ ; },
mesh = {*G-Quadruplexes ; *C9orf72 Protein/genetics/chemistry ; Humans ; Crystallography, X-Ray ; *DNA Repeat Expansion ; Models, Molecular ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; *DNA/chemistry/genetics ; Polymorphism, Genetic ; Nucleic Acid Conformation ; },
abstract = {The abnormal expansion of GGGGCC (G4C2) repeats in the noncoding region of the C9orf72 gene is a major genetic cause of two devastating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These G4C2 repeats are known to form G-quadruplex (G4) structures, which are hypothesized to contribute to disease pathogenesis. Here, we demonstrated that four DNA G4C2 repeats can fold into two structurally distinct G4 conformations: a parallel and an antiparallel topology. The high-resolution crystal structure of the parallel G4 reveals an eight-layered dimeric assembly, formed by two identical monomeric units. Each unit contains four stacked G-tetrads connected by three propeller CC loops and is stabilized through 5'-to-5' π-π interactions and coordination with a central K+ ion. Notably, the 3'-ending cytosines form a C·C+·C·C+ quadruple base pair stacking onto the adjacent G-tetrad layer. In contrast, the antiparallel G4 adopts a four-layered monomeric structure with three edgewise loops, where the C6 and C18 bases engage in stacking interaction with neighboring G-tetrad via a K+ ion. These structurally distinct G-quadruplexes provide mechanistic insights into C9orf72-associated neurodegeneration and offer potential targets for the development of structure-based therapeutic strategies for ALS and FTD.},
}

*G-Quadruplexes
*C9orf72 Protein/genetics/chemistry
Humans
Crystallography, X-Ray
*DNA Repeat Expansion
Models, Molecular
Amyotrophic Lateral Sclerosis/genetics
Frontotemporal Dementia/genetics
*DNA/chemistry/genetics
Polymorphism, Genetic
Nucleic Acid Conformation

@article {pmid40930472,
year = {2025},
author = {Roger, AL and Huston, ML and Spaulding, M and Metz, CM and Froeb, R and Wu, R and Kehoe, S and Mitchell, GS and ElMallah, MK},
title = {Therapeutic Acute Intermittent Hypoxia Modestly Improves Breathing in Pompe Disease.},
journal = {Respiratory physiology & neurobiology},
volume = {},
number = {},
pages = {104489},
doi = {10.1016/j.resp.2025.104489},
pmid = {40930472},
issn = {1878-1519},
abstract = {Pompe disease is an autosomal recessive neuromuscular disorder characterized by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for lysosomal glycogen degradation in all cells. Respiratory distress is a common symptom among patients with Pompe disease resulting from weakness of primary respiratory neuromuscular units of the diaphragm and genioglossus and the motor neurons which innervate them. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA) which slows the decline of motor function and extends life expectancy. However, ERT does not cross the blood-brain barrier and thus, is unable to treat the critical pathology present in motor neurons hindering long-term efficacy. In the present study, we sought to explore an alternative treatment for Pompe patients to improve breathing by improving the function of motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a non-invasive therapeutic modality which has had success in improving respiratory and non-respiratory motor function in patients with spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Here, we treated adult Gaa[-/-] mice with a single, week-long tAIH protocol, followed by bi-weekly tAIH for 4 months. We report three critical findings: (1) both short and long-term tAIH therapy modestly improve breathing in Gaa[-/-] mice; (2) long-term tAIH-therapy in WT mice moderately elevates breathing responses; and (3) these trending improvements to respiration in Gaa[-/-] may be related to changes in chemoreflex activation, reduced kyphosis, and improved overlap of acetylcholine receptors and phrenic motor neuron axon terminals in the diaphragm muscle.},
}

@article {pmid40928612,
year = {2025},
author = {Farhana, S},
title = {Implementation of standardized HRQoL measurement for Chinese ischemic stroke patients: comments on Wang et al.'s longitudinal multi‑center study.},
journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11136-025-04059-x},
pmid = {40928612},
issn = {1573-2649},
}

@article {pmid40928564,
year = {2025},
author = {Davidow, D and Paul, L and Jones, B and Hohlfeld, A and Rasenyalo, S and Dane, K and Shill, IJ and Hendricks, S},
title = {Player-Level Tackle Training Interventions in Tackle-Collision Sports: A Systematic Scoping Review.},
journal = {Sports medicine - open},
volume = {11},
number = {1},
pages = {103},
pmid = {40928564},
issn = {2199-1170},
abstract = {BACKGROUND: In tackle-collision sports, the tackle has the highest incidence, severity, and burden of injury. Head injuries and concussions during the tackle are a major concern within tackle-collision sports. To reduce concussion and head impact risk, evaluating optimal tackle techniques to inform tackle-related prevention strategies has been recommended. The purpose of this study was to perform a systematic scoping review of player-level tackle training intervention studies in all tackle-collision sports.

METHODS: The Arksey and O'Malley's five-stage scoping review process and Levac et al.'s framework were used, along with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) checklist. The main inclusion criteria were that the study included an intervention aimed at improving a player's tackle abilities, and the intervention had to be delivered/implemented at the player-level in a training setting.

RESULTS: Thirteen studies were included in this review, seven studies in American Football (54%), followed by a combined cohort of rugby union and rugby league players (three studies; 23%), rugby union (two studies; 15%), and one study reported on a rugby league cohort (8%). Studies focused primarily on the tackler, with the intervention incorporating a form of instruction or feedback, delivered through video or an expert coach. Other interventions included an 8-week strength and power training programme, designing practice sessions based on baseline data, and helmetless training in American Football. All interventions demonstrated a favourable change in the outcome measured-which included tackler and ball-carrier kinematics based on motion capture video, tackler proficiency scoring, tackling task analysis, head impact frequencies by xPatch head-impact sensor technology, head impact kinematics using head-impact sensors (helmet or skin patches) and football tackle kinematics with motion capture systems or video.

CONCLUSION: This review shows that a range of studies have been undertaken focusing on player-level training interventions. The quality of studies were rated as 'good', and all studies showed improvements in outcome measures. Coaches and policy makers should ensure tackle technique is profiled alongside other player characteristics, and an evidence-based approach to improving player tackling is adopted, improving both performance and reducing injury risk.

KEY POINTS: Only 13 studies tested or implemented interventions at the player level in tackle-collision sports. The focus of the studies was primarily on the tackler, with the interventions incorporating a form of instruction or feedback, which was delivered through video or an expert coach. Other interventions included an 8-week strength and power training programme, designing practice sessions based on baseline data, and helmetless training in American Football. All interventions demonstrated a favourable change in the outcome measure and provide coaches and policymakers with tackle training insights.

REGISTRATION: The systematic scoping review was prospectively registered with OSF (registration number: https://doi.org/10.17605/OSF.IO/V3KZC).},
}

@article {pmid40928424,
year = {2025},
author = {Matsubara, T and Izumi, Y and Hatanaka, Y and Takahara, M and Kondo, A and Matsukura, K and Arakawa, A and Haga, T and Miyamoto, R and Naruse, H and Morino, H and Toda, T and Murayama, S and Saito, Y},
title = {A Novel Neuropathological Subtype of Amyotrophic Lateral Sclerosis Characterised by Prominent Astroglial TDP-43 Pathology.},
journal = {Neuropathology and applied neurobiology},
volume = {51},
number = {5},
pages = {e70036},
doi = {10.1111/nan.70036},
pmid = {40928424},
issn = {1365-2990},
support = {JP21wm0425019//AMED/ ; JP24tm0524002//AMED/ ; JP22H04923//JSPS KAKENHI/ ; JP22K15740//JSPS KAKENHI/ ; JP24K18698//JSPS KAKENHI/ ; JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; //Kato Memorial Bioscience Foundation/ ; //Yukihiko Miyata Memorial Trust for ALS Research/ ; //Medical Research Grants of Takeda Science Foundation/ ; //Integrated Research Initiative for Living Well with Dementia (IRIDE) of the Tokyo Metropolitan Institute for Geriatrics and Gerontology/ ; },
}

@article {pmid40928392,
year = {2025},
author = {Silva, S and Aires, D and Souza, A and Macedo, J and Melo, L and Câmara, S and Valentim, R and Lindquist, AR and Samora, G and Ribeiro, T},
title = {What is the influence of fatigue, ALSFRS-R scores, cognitive status, and pain in individuals with Amyotrophic Lateral Sclerosis? A cross-sectional study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2557971},
pmid = {40928392},
issn = {2167-9223},
abstract = {Introduction: Fatigue remains a poorly understood symptom in individuals with ALS, and little is known about its associtation with other symptoms, including functional impairment, cognition, and pain. Objective: To identify the levels of fatigue, pain, ALSFRS-R, and cognition of a Brazilian group of individuals with ALS, in order to verify possible influences between these symptoms and fatigue. Methods: This is a cross-sectional study conducted with individuals with ALS who were recruited intentionally, using a non-probabilistic sampling method. After agreeing to participate, they were assessed using a standardized assessment form, and data regarding fatigue level, ALSFRS-R scores, cognition, and pain were collected. Data were analyzed by categorizing fatigue (with and without fatigue) and considering sociodemographic and clinical covariates, followed by comparisons, bivariate analyses, and multiple linear regression analyses. Results: Data were collected from 72 individuals with ALS. Inferential statistics indicated differences between fatigue categories concerning ALSFRS-R scores, cognition, and pain. After multiple linear regression analyses, an association between fatigue and the dependent variables was identified. Conclusion: Fatigue is associated with lower ALSFRS-R scores, poorer cognitive status, and higher levels of pain in a Brazilian cohort of ALS. Additionally, age, sex, education, and length of illness were identified as potential factors for fatigue occurrence, observed more frequently in females than in males with the condition.},
}

@article {pmid40927826,
year = {2025},
author = {Oh, YS and Jung, R and Yon, DK and Kim, MS and Shin, JH and Shin, JI and Song, TJ},
title = {The Burden of Motor Neuron Diseases in the United States, 1990-2021: A Systematic Analysis of the Global Burden of Disease Study 2021.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70023},
pmid = {40927826},
issn = {1097-4598},
support = {//Ministry of Science and ICT, South Korea/ ; //Korea Health Industry Development Institute/ ; HI22C073600//Ministry of Health & Welfare, South Korea/ ; RS-2023-00262087//Ministry of Health & Welfare, South Korea/ ; //BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF-5199990614253, Education Research Center for 4IR-Based Health Care)./ ; //Bill and Melinda Gates Foundation/ ; //Australian National Health and Medical Research Council/ ; //Queensland Department of Health, Australia/ ; //Yonsei Fellowship/ ; IITP-2024-RS-2024-00438239//Institute for Information & Communications Technology Planning & Evaluation (IITP)/ ; TJS (RS-2022-II220621//Korean government (MSIT)/ ; //Korean Health Industry Development Institute (KHIDI)/ ; //Ministry of Education (MOE, Korea)/ ; NRF-5199990614253//National Research Foundation of Korea/ ; },
abstract = {INTRODUCTION/AIMS: There is a lack of up-to-date information on the burden of motor neuron diseases (MNDs) in the United States (US). This study aimed to estimate trends in the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) for MNDs in the US from 1990 to 2021.

METHODS: We performed a secondary analysis of MNDs in the US using estimates of prevalence, incidence, and mortality obtained from analyses of the Global Burden of Disease 2021 dataset. These data were generated using DisMod-MR 2.1, a Bayesian meta-regression tool. Estimates were analyzed by age group, sex, region, and sociodemographic index (SDI).

RESULTS: In 2021, the age-standardized prevalence rate of MNDs in the US was 8.82 (95% uncertainty interval, 7.96-9.74) per 100,000, a 12.89% (3.10-23.66) increase from 1990 (7.82 per 100,000). Age-standardized MND-related DALY and mortality rates in 2021 were 41.36 (39.47-42.94) and 1.49 (1.38-1.56) per 100,000, respectively, increases of 4.14% (0.41%-7.68%) and 18.34% (13.86%-22.70%) compared to 1990. Geographic disparities were observed, with the West North Central reporting the highest DALY rates and the Middle Atlantic showing the lowest. The burden of MNDs was consistently greater in males across all metrics, with a male-to-female ratio of approximately 1.4:1. SDI was negatively correlated with age-standardized DALYs, years of life lost, and mortality rates.

DISCUSSION: The observed burden of MNDs in the US highlights the necessity for targeted public health interventions; equitable resource distribution; and further research into environmental, genetic, and sociodemographic factors that contribute to MNDs.},
}

@article {pmid40926822,
year = {2025},
author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q},
title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.},
journal = {Alpha psychiatry},
volume = {26},
number = {4},
pages = {46108},
pmid = {40926822},
issn = {2757-8038},
abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders.

METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model.

RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029).

CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.},
}

@article {pmid40925732,
year = {2025},
author = {, },
title = {[Expert consensus on the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases].},
journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases},
volume = {48},
number = {9},
pages = {815-830},
doi = {10.3760/cma.j.cn112147-20250614-00332},
pmid = {40925732},
issn = {1001-0939},
support = {82270107//National Natural Science Fundation of China/ ; },
mesh = {Humans ; *Neuromuscular Diseases/complications ; *Sleep Apnea Syndromes/diagnosis/therapy/etiology ; Consensus ; Noninvasive Ventilation ; Sleep Apnea, Obstructive/diagnosis/therapy ; China ; },
abstract = {Neuromuscular diseases are often accompanied by various types of sleep-related breathing disorders, which can exacerbate the underlying condition and are associated with a poor prognosis. Early identification is essential, and interventions such as non-invasive ventilation, oxygen therapy, and respiratory rehabilitation should be initiated promptly to mitigate disease progression and improve outcomes. Nevertheless, the rates of missed and misdiagnosed cases remain common in clinical practice. Currently, there are no standardized guidelines for the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases in China. Therefore, based on the latest domestic and international research progress, and combined with domestic clinical diagnosis and treatment experience, the Sleep Disorder Group of Chinese Thoracic Society has brought together multidisciplinary experts to develop this expert consensus. This consensus provides a comprehensive overview of the epidemiology, clinical manifestations, diagnostic approaches, assessment strategies, and treatment of sleep-disordered breathing related to neuromuscular diseases. It formulates evidence-based recommendations to guide clinical practice, with the aim of providing standardized recommendations for their diagnosis and management.Statement 1: The neuromuscular disorders that are most frequently associated with sleep-disordered breathing include: myasthenia gravis (1A), amyotrophic lateral sclerosis (2B), post-polio syndrome (2B), myotonic dystrophy (2B), peripheral neuropathies (2C), and metabolic myopathies, among other neuromuscular conditions.Statement 2: Patients with neuromuscular disorders frequently develop multiple types of sleep-disordered breathing concurrently or sequentially, with obstructive sleep apnea (OSA) being the most prevalent manifestation. Distinct clinical manifestations of OSA are observed across different neuromuscular disease subtypes (1A).Statement 3: Neuromuscular disorders predispose to central sleep apnea (CSA), with clinical manifestations varying significantly across disease subtypes, stages of progression, and severity levels (1A).Recommendation 1: In patients with neuromuscular disorders exhibiting progressive hypercapnia or worsening hypoxemia, clinicians should investigate potential comorbid nocturnal alveolar hypoventilation and/or sleep-associated hypoxemia (1A).Recommendation 2: When sleep-disordered breathing is suspected, patients with neuromuscular disorders should be evaluated for symptoms of sleep-disordered breathing. Meanwhile, sleep monitoring, non-invasive CO2 monitoring, and related examinations should be actively performed according to the actual situation (1A). A polysomnography should be performed when there is a high clinical suspicion of sleep-disordered breathing but a negative result on a portable sleep monitor (1A).Recommendation 3: (1) Noninvasive positive pressure ventilation (NPPV) titration under polysomnography is the standard method to determine the effective treatment parameters for neuromuscular diseases with sleep-disordered breathing (1A). (2) Positive airway pressure titration in OSA patients with neuromuscular diseases should follow American Academy of Sleep Medicine (AASM) guidelines (1A). (3) For neuromuscular disorders with CSA or Cheyne-Stokes respiration, bi-level positive airway pressure (BPAP) with ST pattern is recommended (1A); When BPAP is not tolerated or accompanied by severe Cheyne-Stokes respiratory and heart failure in patients, adaptive support ventilation (ASV) should be used (2B). (4) Patients with neuromuscular disease and sleep-related alveolar hypoventilation should be treated with BPAP or variable assurance pressure support (VAPS) (1A). (5) BPAP with alternate frequency is preferred for neuromuscular disorders with "pseudo-central events" (1A).Recommendation 4: Oxygen therapy alone is not recommended for neuromuscular disease patients combined with sleep-disordered breathing (2D). Oxygen therapy with monitoring of CO2 level is recommended when non-invasive ventilation therapy cannot effectively correct hypoxemia (2C). Diaphragmatic pacing should not be routinely used in amyotrophic lateral sclerosis patients with respiratory failure (2B). Transvenous phrenic nerve stimulation is not currently applied to CSA caused by neuromuscular disorders (2D). Respiratory rehabilitation may improve respiratory muscle strength in a subset of patients with neuromuscular disorders (2B). Protiline can be used for REM-associated alveolar hypoventilation, and daytime sleepiness could be addressed with methylphenidate and modafinil (2C).Recommendation 5: Neuromuscular disease combined with sleep-disordered breathing is a chronic disease requiring patient-centered, individualized education and long-term follow-up management (1A).},
}

Humans
*Neuromuscular Diseases/complications
*Sleep Apnea Syndromes/diagnosis/therapy/etiology
Consensus
Noninvasive Ventilation
Sleep Apnea, Obstructive/diagnosis/therapy
China

@article {pmid40924345,
year = {2025},
author = {Kutlubaev, MA and Pervushina, EV and Kiernan, MC},
title = {The nature of fatigue in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {40924345},
issn = {2240-2993},
abstract = {OBJECTIVES: Patients diagnosed with amyotrophic lateral sclerosis (ALS) typically describe symptoms of fatigue. Despite this frequency, the underlying mechanisms of fatigue are poorly understood, and are likely multifactorial. To help clarify mechanisms, the present systematic review was undertaken to determine the risk factors related to fatigue in ALS.

METHODS: A systematic review was conducted using PubMed and Google Scholar databases using key words. From a total of 40,014 articles, 18 articles were included in the final review, following PRISMA guidelines. Meta-regression and subgroup analyses were conducted to study the relationship between fatigue in ALS and different covariates.

RESULTS: Eighteen studies were included in the analysis. A number of factors were investigated, including age, sex, disease severity and duration, site of disease onset, neurophysiological parameters, and respiratory symptoms, depression and anxiety, sleep disorders, and pain. Combined analyses established that participants with ALS who reported fatigue had more severe disease, as confirmed by lower functional rating scores, than those who did not report fatigue. The remaining factors including depression, anxiety and pain, were not found to be related to the onset of fatigue in ALS. Overall, fatigue worsened quality of life in patients diagnosed with ALS.

DISCUSSION: Fatigue in ALS appears to be particularly associated with progressive neurological deficit and disability, linked to both central and peripheral neuromuscular mechanisms.},
}

@article {pmid40923926,
year = {2025},
author = {Arnold, L and Tomsitz, D and Buchillon, R and Leding, J and Senner, S and Frey, S and Janjic, N and French, LE and Heinzerling, L},
title = {Successful treatment of localized Merkel cell carcinoma with avelumab in a patient with amyotrophic lateral sclerosis.},
journal = {Immunotherapy},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/1750743X.2025.2554566},
pmid = {40923926},
issn = {1750-7448},
abstract = {Currently, the first-line treatment of non-metastatic Merkel cell carcinoma (MCC) is complete resection. In case of unresectable or metastatic MCC, immune checkpoint inhibitor (ICI) therapy with avelumab (or in the US also pembrolizumab or retifanlimab) is indicated. We report on a patient with a primary, non-metastatic MCC on the left eyelid and amyotrophic lateral sclerosis (ALS). Due to ALS, the patient's communication was limited to eye movement and blinking. Complete resection or definitive radiotherapy of the tumor while preserving the function of the eye muscles was not possible. No prior data was available for patients with ALS under ICI therapy. In agreement with the patient and his family, a monotherapy with avelumab, a programmed death ligand 1 (PD-L1) inhibitor, was initiated. This led to a complete remission of the tumor with a progression-free survival of over 24 months and importantly no deterioration of the ALS.},
}

@article {pmid40923569,
year = {2025},
author = {Stikvoort García, DJL and Goedee, HS and van den Berg, LH and Sleutjes, BTHM},
title = {Nerve Excitability in Asymptomatic Carriers and Amyotrophic Lateral Sclerosis Patients With C9orf72.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70187},
pmid = {40923569},
issn = {2328-9503},
support = {//Stichting ALS Nederland/ ; },
abstract = {OBJECTIVE: We investigated the effects of C9orf72 mutation carriership on peripheral nerve excitability in asymptomatic individuals from families with a history of C9orf72 amyotrophic lateral sclerosis (ALS) and patients.

METHODS: We included 47 asymptomatic individuals from families with a history of C9orf72 ALS, of whom 23 were carriers (C9[+]) and 24 were noncarriers (C9[-]). In addition, 11 C9[+] and 110 C9[-] ALS patients and 50 healthy controls participated. Nerve excitability tests were conducted on the median nerve. We obtained standard excitability measurements as well as composites of these measurements that reflect various passive and active membrane properties. Data of C9[+] and C9[-] asymptomatic individuals were compared, followed by a kinship-adjusted comparison in asymptomatic individuals from the same families. We then compared C9[+] to C9[-] ALS patients.

RESULTS: In the subset of asymptomatic individuals from the same families, C9[+] individuals had lower values than C9[-] individuals on one of the composite excitability measurements (t = -2.15, p = 0.034), corresponding to a hypoexcitable profile consistent with smaller Na[+]-window currents. C9[+] ALS patients had a hyperexcitable profile with larger refractoriness at 2 ms and relative refractory periods than C9[-] ALS patients (t = 4.58, p < 0.001; t = 3.43, p = 0.002, respectively), which is in line with slower recovery of the Na[+]-channels from inactivation.

INTERPRETATION: Asymptomatic individuals and ALS patients carrying the C9orf72 mutation exhibit a unique electrophysiological phenotype, implicating altered Na[+]-channel characteristics compared to asymptomatic noncarriers and sporadic ALS patients. Monitoring hypoexcitable to hyperexcitable profile transitions in individuals carrying the C9orf72 mutation may be valuable as an early indicator of phenoconversion.},
}

@article {pmid40922888,
year = {2025},
author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF},
title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e89629},
pmid = {40922888},
issn = {2168-8184},
abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.},
}

@article {pmid40922457,
year = {2025},
author = {Eroglu, E and Harmanci, N},
title = {Emerging Molecular Targets in Neurodegenerative Disorders: New Avenues for Therapeutic Intervention.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {137},
number = {4},
pages = {e70107},
doi = {10.1111/bcpt.70107},
pmid = {40922457},
issn = {1742-7843},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism/genetics ; Animals ; *Molecular Targeted Therapy ; Autophagy/drug effects ; Drug Development ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and frontotemporal dementia represent a significant global health burden with limited therapeutic options. Current treatments are primarily symptomatic and fail to modify disease progression, emphasizing the urgent need for novel, mechanism-based interventions. Recent advances in molecular neuroscience have identified several non-classical pathogenic pathways, including neuroinflammation, mitochondrial dysfunction, impaired autophagy and proteostasis, synaptic degeneration and non-coding RNA dysregulation. In this focused review, we highlight emerging molecular targets such as TREM2, NLRP3, mTOR, TFEB, PINK1 and SIRT3, which offer promising avenues for therapeutic intervention. We also address challenges in target validation and translational drug development, while proposing future research directions that may facilitate the design of more effective treatments. A deeper understanding of these molecular mechanisms is essential for developing disease-modifying strategies to combat neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/drug therapy/physiopathology/metabolism/genetics
Animals
*Molecular Targeted Therapy
Autophagy/drug effects
Drug Development

@article {pmid40920400,
year = {2025},
author = {Urso, D and Giannoni-Luza, S and Brayne, C and Ray, N and Logroscino, G},
title = {Incidence and Prevalence of Frontotemporal Dementia: A Systematic Review and Meta-Analysis.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {40920400},
issn = {2168-6157},
abstract = {IMPORTANCE: Comprehensive incidence and prevalence rates of frontotemporal dementia are currently not available.

OBJECTIVE: To estimate the incidence and prevalence of frontotemporal dementia and its clinical variants in the overall population and age subgroups.

We systematically searched PubMed, EMBASE, and Scopus between January 1, 1990, and October 22, 2024, for population-based studies estimating the incidence and/or prevalence of FTD.

DATA EXTRACTION AND SYNTHESIS: Studies and data were screened and extracted independently by 2 investigators in accordance with PRISMA guidelines. Incident and prevalent cases together with the population at risk were pooled using random-effects meta-analysis. Differences in heterogeneity by FTD variants and populations at risk were estimated.

MAIN OUTCOMES AND MEASURES: Prevalent and incident cases as numerator were based on well-defined clinical criteria. Denominators were derived either from census population data or from author-defined populations at risk.

RESULTS: From 1854 screened articles, 32 eligible population-based studies were identified. Sixteen were on prevalence and 22 on incidence reporting FTD measures, including those with estimates for the whole population and for specific age subgroups. Pooled crude incidence for FTD was 2.28 (95% CI, 1.55-3.36) per 100 000 person-years and prevalence, 9.17 (95% CI, 3.59-23.42) per 100 000 people. The behavioral-variant FTD pooled crude incidence was 1.20 (95% CI, 0.67-2.16) per 100 000 person-years and prevalence, 9.74 (95% CI, 2.90-32.73) per 100 000 people. The primary progressive aphasia variant pooled crude incidence was 0.52 (95% CI, 0.35-0.79) per 100 000 person-years and prevalence, 3.67 (95% CI, 3.05-4.43). FTD incidence among individuals younger than 65 years was 1.84 (95% CI, 0.79-4.30) per 100 000 person-years and prevalence, 7.47 (95% CI, 4.13-13.49) per 100 000 people. The denominator based on census data showed less heterogeneity than the population at risk defined by the authors (I2: for incidence, 91.6% vs 97.6%, respectively, and for prevalence, 98.8% vs 99.2%, respectively).

CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, estimates indicate that FTD is comparable in frequency to dementia with Lewy bodies and occurs at higher rates than progressive supranuclear palsy, corticobasal syndrome, and amyotrophic lateral sclerosis. These results provide a foundation for future research and public health strategy, especially for underrepresented populations, to better comprehend the global burden of FTD. Our findings provide robust pooled estimates of the incidence and prevalence of FTD and its subtypes, offering a foundation for future research and public health planning.},
}

@article {pmid40920272,
year = {2025},
author = {Ku, JB and Pak, RJ and Ku, SS and Holland, RD and Kim, HS},
title = {Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review.},
journal = {Tissue engineering and regenerative medicine},
volume = {},
number = {},
pages = {},
pmid = {40920272},
issn = {2212-5469},
abstract = {BACKGROUND: Neurotraumatic conditions, such as spinal cord injury, brain injury, and neurodegenerative conditions, such as amyotrophic lateral sclerosis, pose a challenge to the field of rehabilitation for its complexity and nuances in management. For decades, the use of cell therapy in treatment of neurorehabilitation conditions have been explored to complement the current, mainstay treatment options; however, a consensus for standardization of the cell therapy and its efficacy has not been reached in the medical community. This study aims to provide a comparative review on the very topic of cell therapy use in neurorehabilitation conditions in an attempt to bridge the gap in knowledge.

METHODS: Studies were searched from the PubMed database published from 2014 to 2024 employing the terms including but not exclusive to "spinal cord injury," "brain injury," "amyotrophic lateral sclerosis," "regenerative medicine," "cell therapy," and "stem cell." Following the PRISMA 2020 statement, the studies were screened, included, and excluded. Thirty three studies were identified and selected for this review.

RESULTS: Countless researchers investigated the efficacy of various stem cell products for the treatment of numerous neurotraumatic conditions, such as spinal cord injury, traumatic brain injury, and neurodegenerative conditions such as amyotrophic lateral sclerosis. The recent decade of studies suggest that in neurotraumatic conditions, bone-marrow-derived and neural stem cells can be effective, and in neurodegenerative conditions, such as ALS, mesenchymal and neural stem cells can be efficacious.

CONCLUSION: Emerging data from the latest research is encouraging to the patients suffering from neurotraumatic and neurodegenerative conditions, which present themselves as a need for further studies with improved standardization in study design, including cell source specification, differentiation and culture method, and outcome measures to ensure a wide applicability.},
}

@article {pmid40919318,
year = {2025},
author = {Harrison, D and Billinton, A and Bock, MG and Clarke, NP and Digby, Z and Gabel, CA and Lindsay, N and Reader, V and Scanlon, J and Smolak, P and Thornton, P and Wescott, H and Watt, AP},
title = {Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {40919318},
issn = {2632-8682},
abstract = {Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.},
}

@article {pmid40917547,
year = {2025},
author = {Tai, XY and Toniolo, S and Llewellyn, DJ and van Duijn, CM and Husain, M and Manohar, SG},
title = {Detection of cognitive deficits years prior to clinical diagnosis across neurological conditions.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf307},
pmid = {40917547},
issn = {2632-1297},
abstract = {Understanding the cognitive trajectory of a neurological disease can provide important insight on underlying mechanisms and disease progression. Cognitive impairment is now well established as beginning many years before the diagnosis of Alzheimer's disease, but pre-diagnostic profiles are unclear for other neurological conditions that may be associated with cognitive impairment. We analysed data from the prospective UK Biobank cohort with study baseline assessment performed between 2006 and 2010 and participants followed until 2021. We examined data from 497 252 participants, aged between 38 and 72 years at baseline, with an imaging sub-sample of 42 468 participants. Using time-to-diagnosis and time-from-diagnosis data in relation to time of assessment, we compared a continuous measure of executive function and magnetic resonance imaging brain measures of total grey matter (GM) and hippocampal volume in individuals with ischaemic stroke, focal epilepsy, Parkinson's disease, multiple sclerosis, motor neurone disease (amyotrophic lateral sclerosis) and migraine. Of the 497 252 participants [226 206 (45.5%) men, mean (SD) age, 57.5(8.1) years], 12 755 had ischaemic stroke, 6758 had a diagnosis of focal epilepsy, 3315 had Parkinson's disease, 2315 had multiple sclerosis, 559 had motor neurone disease and 18 254 had migraine either at study baseline or diagnosed during the follow-up period. Apart from motor neurone disease, all conditions had lower pre-diagnosis executive function compared to controls (assessment performed median 7.4 years before diagnosis). At a group level, focal epilepsy and multiple sclerosis showed a gradual worsening in executive function up to 15 years prior to diagnosis, while ischaemic stroke was characterised by a modest decline for a few years followed by a substantial reduction at the time of diagnosis. By contrast, participants with migraine showed a mild reduction in pre-diagnosis cognition compared to controls which improved following clinical diagnosis. Pre-diagnosis MRI GM volume was lower than controls for stroke, Parkinson's disease and multiple sclerosis (scans performed median 1.7 years before diagnosis), while other conditions had lower volumes post-diagnosis. These cognitive trajectory models reveal disease-specific temporal patterns at a group level, including a long cognitive prodrome associated with focal epilepsy and multiple sclerosis. The findings may help to prioritise risk management of individual diseases and inform clinical decision-making.},
}

@article {pmid40917070,
year = {2025},
author = {Xie, J and Xu, J and Tian, Z and Liang, J and Tang, H},
title = {Extended Insights Into Advancing Multi-Omics and Prognostic Methods for Cancer Prognosis Forecasting.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {8},
pages = {44091},
doi = {10.31083/FBL44091},
pmid = {40917070},
issn = {2768-6698},
mesh = {Humans ; *Adenocarcinoma of Lung/genetics/pathology ; *Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic ; Genomics/methods ; *Lung Neoplasms/genetics/pathology/therapy/diagnosis ; Multiomics ; Prognosis ; },
abstract = {Zhang et al.'s recent article utilizes comprehensive single-cell data to identify differences in tumor cell populations, highlighting the CKS1B+ malignant cell subcluster as a potential target for immunotherapy. It develops a prognostic and immunotherapeutic signature (PIS) based on this subcluster, demonstrating good performance in predicting lung adenocarcinoma (LUAD) prognosis. The study also validates the role of PSMB7 in LUAD progression. However, there are areas for improvement. There is a lack of clarity regarding the relationship between the CKS1B+ malignant cell subcluster and the PIS, particularly in terms of why PSMB7 was selected for functional studies. The sequencing data are retrospectively obtained from public databases and lack prospective clinical validation. It is suggested to collect LUAD patient tissues for RT-qPCR and RNA-seq analysis and seek external multi-center validations. Additionally, integrating emerging multi-omics methods is recommended to further validate the findings. Despite these limitations, the study represents progress in understanding LUAD and treatment strategies, and continuous evaluation and refinement of multi-omics and machine learning methods are expected for future research and clinical practice.},
}

Humans
*Adenocarcinoma of Lung/genetics/pathology
*Biomarkers, Tumor/genetics
Gene Expression Regulation, Neoplastic
Genomics/methods
*Lung Neoplasms/genetics/pathology/therapy/diagnosis
Multiomics
Prognosis

@article {pmid40916891,
year = {2025},
author = {Ludolph, A},
title = {Progress in ALS research 2025.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {566-567},
doi = {10.1097/WCO.0000000000001410},
pmid = {40916891},
issn = {1473-6551},
}

@article {pmid40916690,
year = {2025},
author = {Sharma, S and Gupta, M and Sharma, S},
title = {Exploring Thiophene-Based Pharmacophores as Emerging Therapeutics for Neurodegenerative Disorders.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/10408347.2025.2554239},
pmid = {40916690},
issn = {1547-6510},
abstract = {Neurodegenerative disorders (NDD) i.e., dementia of the Alzheimer's type, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a rising worldwide epidemic driven by aging populations and characterized by progressive neuronal impairment. In the face of symptomatic therapies, disease-modifying treatments are beyond reach, for many years, at least, owing to the multifactorial origin, including protein aggregation, oxidative stress, neuroinflammation, and neurotransmitter dysregulation. Here, we point out thiophene, a five-membered heterocyclic sulfur-containing scaffold, as an underinvestigated but highly versatile pharmacophore with great potential in therapeutics of NDD. Here, we provide a systematic review of thiophene derivatives identified between 2006 and 2024, highlighting that these compounds are capable of modulating the aggregation of amyloid-β, inhibiting acetylcholinesterase, alleviating oxidative stress, inhibiting the toxicity of α-synuclein, and restoring neurotransmitter homeostasis. Specific emphasis is placed on their structural malleability, blood-brain barrier penetrability, and multi-targeting, which collectively present advantages over traditional heterocyclic templates. Progress in the areas of structure-activity relationship (SAR)-motivated design, synthetic methods, molecular docking, and preclinical assessment is reviewed, leading to the establishment of lead thiophene scaffolds with micro or nanomolar-range activity. This review also provides future directions, such as the requirement of pharmacokinetic improvement, target verification, and translational research to bridge preclinical discoveries with clinical utility. This article collectively places thiophene derivatives as an innovative chemical platform for the design of next-generation drugs for neurodegenerative diseases.},
}

@article {pmid40916417,
year = {2025},
author = {Liu, Y and Li, J and Liu, Y},
title = {HIV-Associated Lymphomas: Updates from Pathogenesis to Treatment Strategies.},
journal = {Current HIV research},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570162X367092250901062629},
pmid = {40916417},
issn = {1873-4251},
abstract = {HIV-associated lymphoma (HAL) is an aggressive malignancy directly linked to HIV infection and accounts for more than 30% of cancer-related deaths in people living with HIV (PLWH). HAL subtypes, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), primary effusion lymphoma (PEL), and plasmablastic lymphoma (PBL), exhibit five to ten times higher incidence rates and distinct molecular profiles compared to HIV-negative lympho-mas. Pathogenesis involves HIV-driven CD4+ T-cell depletion, chronic B-cell activation, and on-cogenic viral coinfection. First-line therapy combines antiretroviral therapy (ART) with chemo-therapy, achieving complete remission rates of 60-70% for DLBCL using R-EPOCH and 50-60% for BL with CODOX-M/IVAC. Relapsed/refractory cases show durable responses to CD19-CAR-T therapy; however, only 10% of HAL patients are enrolled in pivotal immunotherapy tri-als. Severe immunosuppression necessitates PET-CT-guided de-escalation and nanoparticle-based drug delivery systems to minimize toxicity. Emerging strategies include PD-1 inhibitors and broad-spectrum antivirals targeting HIV reservoirs, underscoring the need for precision med-icine that integrates tumor genomics and viral dynamics.},
}

@article {pmid40916343,
year = {2025},
author = {Wu, J and Guo, J and Wu, J and Song, J and Xu, J and Lin, Y and Huang, C and Shi, C and Li, J and Li, C and Chen, Y and Wang, W and Gao, J and Zhou, Q and Zhang, Y and Li, S and Li, XJ and Zhang, CY and Chen, X and Yan, S},
title = {In vivo self-assembled siRNAs ameliorate neurological pathology in TDP-43-associated neurodegenerative disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf330},
pmid = {40916343},
issn = {1460-2156},
abstract = {Abnormal accumulation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Small interfering RNAs (siRNAs) targeting TDP-43 offer potential therapeutic strategies for these diseases. However, efficient and safe delivery of siRNAs to the central nervous system (CNS) remains a critical challenge. Here, we present a synthetic biology-based approach that leverages endogenous small RNA processing machinery to self-assemble siRNA-encapsulating small extracellular vesicles (sEVs) and utilizes the host's natural circulatory system to transport siRNAs. Specifically, we engineered liver cells to express and package TDP-43-targeting siRNAs into rabies virus glycoprotein (RVG)-tagged sEVs, which are released into circulation and cross the blood-brain barrier to deliver siRNAs to the CNS. In a mouse model of TDP-43 pathology induced by stereotactic injection of mutant TDP-43 (M337V) virus, treatment with in vivo self-assembled TDP-43 siRNAs (IVSA-siR-TDP43) effectively reduced TDP-43 accumulation, leading to significant improvements in motor function and neuropathology. Additionally, an adeno-associated virus (AAV)-based delivery system was utilized to produce IVSA-siR-TDP43, demonstrating sustained therapeutic effects in TDP-43-associated neurodegeneration. These findings highlight a novel, effective, and minimally invasive gene therapy platform for addressing TDP-43 pathology in ALS and FTLD, offering a promising avenue for future clinical applications.},
}

@article {pmid40915850,
year = {2025},
author = {Zhan, Y and Cao, Z and Qi, J and Luo, Y and Hu, L and Bai, L and Pan, L},
title = {Fenoxaprop-P-ethyl resistance in Alopecurus aequalis: Involvement of GSTF13 in addition to Ile-1781-Leu mutation.},
journal = {Pesticide biochemistry and physiology},
volume = {214},
number = {},
pages = {106614},
doi = {10.1016/j.pestbp.2025.106614},
pmid = {40915850},
issn = {1095-9939},
mesh = {*Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Oxazoles/pharmacology ; *Propionates/pharmacology ; *Plant Proteins/genetics/metabolism ; *Poaceae/genetics/drug effects ; Mutation ; Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors ; Acetolactate Synthase/genetics/antagonists & inhibitors ; *Glutathione Transferase/genetics/metabolism ; },
abstract = {Shortawn foxtail (Alopecurus aequalis Sobol.) is a challenging weed species to manage in wheat production systems globally. In prior research, we identified a field population of A. aequalis (Aa-R) that had developed resistance to the widely used acetolactate synthase (ALS)-inhibiting herbicide mesosulfuron-methyl. In this study, we found that the Aa-R population also exhibited significant resistance to the acetyl-CoA carboxylase (ACCase)-inhibiting herbicide fenoxaprop-P-ethyl and showed broad-spectrum resistance to other three ACCase-inhibiting herbicides, haloxyfop-P-methyl, clodinafop-propargyl, clethodim, and pinoxaden. Sequence analysis of the ACCase gene revealed the presence of a known resistance mutation (Ile-1781-Leu) in the Aa-R population. Pretreatment with the GST inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) decreased the resistance to fenoxaprop-P-ethyl in the Aa-R population. We amplified an upregulated GST gene in the Aa-R population, designated AaGSTF13. Transgenic rice calli and seedlings overexpressing AaGSTF13 exhibited resistance specifically to fenoxaprop-P-ethyl, and might enhance reactive oxygen species (ROS) scavenging capacity. Further transcriptome analyses suggested that the expressions of genes associated with ROS scavenging was upregulated in transgenic plants. Our results indicate that AaGSTF13 enhances detoxification metabolism and could potentially enhances ROS scavenging in transgenic rice, which might contribute to enhanced herbicide resistance. These findings suggest that AaGSTF13 represents a promising candidate gene for the genetic improvement of new rice varieties under herbicide stress conditions.},
}

*Herbicides/pharmacology
*Herbicide Resistance/genetics
*Oxazoles/pharmacology
*Propionates/pharmacology
*Plant Proteins/genetics/metabolism
*Poaceae/genetics/drug effects
Mutation
Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors
Acetolactate Synthase/genetics/antagonists & inhibitors
*Glutathione Transferase/genetics/metabolism

@article {pmid40915735,
year = {2025},
author = {Mazivila, SJ and Soares, JX and Santos, JLM},
title = {Multi-way calibration strategies involving excitation-emission data measurements from drug-modulated fluorescence in CdTe quantum dots and AgInS2 nanocrystals.},
journal = {Analytica chimica acta},
volume = {1373},
number = {},
pages = {344547},
doi = {10.1016/j.aca.2025.344547},
pmid = {40915735},
issn = {1873-4324},
abstract = {BACKGROUND: When using semiconductor quantum dots (QDs) for single-analyte sensing, recognition is commonly achieved through interactions with capping ligands attached to the QDs surface. These ligands form an organic layer that provides stability in solution and assures selectivity by binding the target analyte via surface functional groups. However, a common analytical challenge arises in the subsequent stage of the QD-based sensing scheme. Specifically, in a system combining CdTe and AgInS2 QDs, the CdTe QD core can effectively dock sodium-2-mercaptoethane sulfonate (MES) ligands, which act as recognition elements for amlodipine. In contrast, the AgInS2 QD core, may not properly anchor d-penicillamine (PCM) ligands, which bind selectively to olmesartan. This disparity in ligand-QDs affinity may lead to inconsistent excitation-emission fluorescence matrix (EEFM) signals. Such inconsistencies arise when the contribution of the four components present in the system 'CdTe QD-MES-amlodipine & AgInS2 QD-PCM-olmesartan' deviates from low-rank subspace estimated across different excitation/emission modes.

RESULTS: Upon analyzing a fixed-dosage form sample of amlodipine and olmesartan medoxomil, we demonstrate that the complexity of the mixture signal in EEFM measurements - whether from individual or combined single-analyte QD-based sensing scheme - can be experimentally assessed by determining the low-rank subspace of the analytical signals. Specifically, we evaluated whether the number of fluorescently responsive constituents across different excitation and emission modes matches the four components present in the system 'CdTe QD-MES-amlodipine & AgInS2 QD-PCM-olmesartan' - a prerequisite for the joint calibration of both analytes. If this condition is not met the analytes must be individually calibrated. Thus, a mixture of single-analyte QD-based sensing scheme, involving different concentrations of amlodipine and olmesartan medoxomil, was used to generate a set of EEFM measurements. A rank-two model was found optimal for emission wavelengths, while a rank-three model was calculated for excitation wavelengths. These results reveal an evident rank-deficient as at least four-components are present in the QD-sensing photoluminescence modulation process.

SIGNIFICANCE: The unfolded partial least-squares (U-PLS) model was successfully applied for the determination of amlodipine-net analyte signal (NAS) from binary CdTe QDs fluorescence modulation. In contrast, the olmesartan- NAS from ternary AgInS2 QDs fluorescence modulation did not allow a combined calibration. Consequently, the analytes must be individually calibrated based on their respective individual mixture signals using either PARAllel FACtor (PARAFAC) analysis or multivariate curve resolution - alternating least-squares (MCR-ALS) model according to the data structure.},
}

@article {pmid40914817,
year = {2025},
author = {Alves, I and Aiello, EN and Lopes, D and Gromicho, M and Simão, S and Moreschi, A and De Luca, G and Curti, B and Silani, V and Ticozzi, N and Poletti, B and de Carvalho, M},
title = {Reliable change indices for the cognitive section of Portuguese version of the Edinburgh Cognitive and Behavioural ALS screen (ECAS).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2025.2555216},
pmid = {40914817},
issn = {2167-9223},
abstract = {This study aimed to derive standardized regression-based (SRB) reliable change indices (RCIs) for the cognitive section of the Portuguese Edinburgh Cognitive and Behavioral ALS Screen (ECAS-C). Forty-nine MND patients undergoing the ECAS were followed-up (T1) at 7.2 ± 2 months (range = 5-12). RCIs were derived via an SRB approach by accounting for demographic, motor-functional and test-related variables. Practice effects were detected as to Total and Memory measures; all ECAS-C measures proved to be reliable at retest. Baseline ECAS-C measures predicted their follow-up performances. SRB RCIs herewith delivered will help assess MND patients' cognition over time, although they would benefit from further validation in independent cohorts.},
}

@article {pmid40914405,
year = {2025},
author = {Wang, J and Li, X and Yang, F and Guo, P and Ren, C and Duan, Z and Bi, M and Kong, Y and Zhang, Y and Lu, J},
title = {Exploration of endoplasmic reticulum stress-related gene markers in amyotrophic lateral sclerosis: a comprehensive analysis of bioinformatics and machine learning.},
journal = {Analytical biochemistry},
volume = {},
number = {},
pages = {115969},
doi = {10.1016/j.ab.2025.115969},
pmid = {40914405},
issn = {1096-0309},
abstract = {This study aimed to investigate potential biomarkers related to Endoplasmic reticulum (ER) stress in Amyotrophic lateral sclerosis (ALS) through a comprehensive bioinformatic approach. The gene expression profiles of ALS patients and healthy controls were downloaded from the Gene Expression Omnibus (GEO) database. ER stress-related genes were collected from the MSigDB databases and document literature. The "limma" R package was employed to detect the differentially expressed ER stress-related genes (DE-ERSGs). Three methods of machine learning were applied to select the hub DE-ERSGs. ROC curves were conducted to evaluate model performance. An external dataset was chosen to evaluate the diagnostic capability of hub genes. The CIBERSORT algorithm was used to evaluate the immune cell infiltration characteristics. Additionally, we constructed a systematic ceRNA regulatory network using Cytoscape software and predicted the possible drug candidates using the Enrichr platform. Molecular docking analysis was used to further validate the binding ability of the candidate drug molecules to the hub genes. Six hub DE-ERSGs (ABCA1, CKAP4, TOR1AIP1, MMP9, EDC4, and ALPP) were identified, and the related models performed well. These hub genes were concentrated in multiple pathways and related to various immune cells. Drugs such as nitroglycerin, diazepam, FENRETINIDE, and edaravone exhibited good binding affinity to the hub genes, indicating that they may be promising drugs for the management of ALS. This study revealed the essential role of ER stress in the pathogenesis of ALS from an integrative perspective, providing guidance for the development of new therapeutic targets and diagnostic strategies.},
}

@article {pmid40913874,
year = {2025},
author = {Peethambaran, ST and Ashokan, A and Subhose, V},
title = {A case report on Ayurvedic management of progressive bulbar palsy-A rare amyotrophic lateral sclerosis phenotype.},
journal = {Journal of Ayurveda and integrative medicine},
volume = {16},
number = {5},
pages = {101176},
doi = {10.1016/j.jaim.2025.101176},
pmid = {40913874},
issn = {0975-9476},
abstract = {This case report is the description of a devastating illness, Progressive Bulbar Palsy (PBP) of a sixty-seven years old male patient. He presented with complaints of slurred speech, hearing impairment, generalised weakness of limbs, weakened grip to hold objects in hand, difficulty to walk with normal speed, frequent dizzy feeling while walking, severe fatigue, increased anger, heaviness of head, depression, anxiety, decreased memory and headache for 1 year. When he consulted conventional medicine, in Magnetic Resonance Imaging (MRI) of brain, only 'Partial empty sella' and age related mild cerebral atrophy was detected and the patient was diagnosed PBP clinically. They prescribed Riluzole 50 mg tablet twice a day and Fluoxetine 10mg capsules at night time for 3 months, but obtained no relief for symptoms and consulted this Out Patient Department (OPD). In Ayurvedic parlance, PBP resembles conditions like Kaphavruta vata. In this patient, Pittavritavata symptoms like bhrama (∼dizziness) was also present in increased severity. Diagnosis was done with the aid of Gold Coast diagnostic criteria. Internal and external medications with properties alleviating avarana (∼occlusion) of vata by kapha and pitta, shodhana (∼expelling the aggravated doshas and cleanses the body internally), rejuvenating (Rasayana) properties, for overall strengthening of nervous system and musculoskeletal system, enhancing balance and coordination, improving speech and memory were used. The assessment was done before and after the treatment by 'Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The score before and after the treatment was 35 and 45 respectively out of 48. The treatment helped to increase the quality of life exceptionally as symptomatic relief was obtained. As it is a devastating disorder with poor prognosis and most probably will lead to death, it is advisable to repeat the treatments in regular intervals, depending on the recurrence of symptoms, if any.},
}

@article {pmid40913365,
year = {2025},
author = {Zhang, J and Kaiser, E and Marcelis, LFM and Vialet-Chabrand, S},
title = {DynG: a dynamic scaling factor for thermographic stomatal conductance estimation under changing environmental conditions.},
journal = {The New phytologist},
volume = {},
number = {},
pages = {},
doi = {10.1111/nph.70555},
pmid = {40913365},
issn = {1469-8137},
support = {202006300044//China Scholarship Council/ ; 19652//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; },
abstract = {Thermal imaging is a key plant phenotyping and monitoring technique but faces major bottlenecks in accurately and efficiently inferring stomatal conductance (gsw) from leaf temperature. The conductance index (Ig) was previously proposed to estimate gsw from thermography by linking temperature differences between real and artificial leaves (ALs) based on the leaf energy balance. However, Ig is highly sensitive to environmental fluctuations, hampering interpretation and reducing reproducibility. We developed a simple and novel correction factor (named DynG) for Ig that accounts for environmental fluctuations when scaling Ig to gsw. This was achieved by capturing temperature variations in a set of ALs with a range of known constant pore conductances. This approach provided the Ig-conductance relationship, using ALs as a reference, to infer gsw of real leaves from their measured Ig. In fluctuating environments, gsw estimated using DynG showed greater accuracy and stability than gsw calculated from Ig alone, and was in good agreement with gsw determined using lysimetric and gas exchange methods. DynG's power was further showcased in distinguishing gsw of Arabidopsis genotypes differing in stomatal traits (Col-0, epf1epf2, and EPF2OE). We conclude that Ig corrected with DynG can reliably estimate gsw in fluctuating environments without complex modeling, opening new avenues for gsw phenotyping and monitoring.},
}

@article {pmid40912729,
year = {2025},
author = {LaBarbera, V and Dai, X and Sachs, G},
title = {Co-occurrence of ipsilateral partial Horner's syndrome in a patient with monomelic amyotrophy.},
journal = {BMJ case reports},
volume = {18},
number = {9},
pages = {},
doi = {10.1136/bcr-2025-265315},
pmid = {40912729},
issn = {1757-790X},
mesh = {Humans ; *Horner Syndrome/complications/diagnosis ; *Spinal Muscular Atrophies of Childhood/complications/diagnosis ; Male ; Female ; Diagnosis, Differential ; Middle Aged ; },
abstract = {Monomelic amyotrophy (MMA) is a lower motor neuron predominant disorder affecting an upper limb, which can mimic amyotrophic lateral sclerosis (ALS). It often presents with unilateral, distal upper limb weakness and atrophy, whose trajectory is one of an initial period of progression followed by a prolonged plateau, as opposed to the typically relentless progression as is seen in ALS. This case report describes a novel observation of a patient with MMA with an unexplained ipsilateral partial Horner's syndrome (miosis and ptosis). Horner's syndrome is known to result from sympathetic dysfunction from lesions from the hypothalamus to the cervical/upper thoracic spine and can be seen with brachial plexopathies, but has never been, to our knowledge, described in MMA. This finding is of interest because it may facilitate earlier diagnosis of MMA in isolated upper extremity, lower motor neuron-predominant syndromes, as Horner's syndrome is not known to complicate ALS.},
}

Humans
*Horner Syndrome/complications/diagnosis
*Spinal Muscular Atrophies of Childhood/complications/diagnosis
Male
Female
Diagnosis, Differential
Middle Aged

@article {pmid40912409,
year = {2025},
author = {Bordoni, M and Scarian, E and Jacchetti, E and Viola, C and Diamanti, L and Dragoni, F and Di Gerlando, R and Rizzo, B and Raimondi, MT and Gagliardi, S and Pansarasa, O},
title = {HDAC6 and TDP-43 promote autophagy impairment in amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107079},
doi = {10.1016/j.nbd.2025.107079},
pmid = {40912409},
issn = {1095-953X},
abstract = {TDP-43 is known to bind the mRNA of histone deacetylase 6 (HDAC6), influencing its RNA translation. Many studies suggest that HDAC6 participates in the regulation of autophagy, which we found impaired in sporadic ALS (sALS) patients. Aim of this work is to evaluate the interaction between TDP-43 and HDAC6 mRNA and to evaluate the effect of the up- and down-regulation of HDAC6 on autophagy in SH-SY5Y cells. Protein level of HDAC6 and TDP-43 binding with HDAC6 mRNA by RNA immunoprecipitation were studied on sALS peripheral blood mononuclear cells (PBMCs). Initially, we observed increased level of HDAC6 protein and increased binding of its mRNA with TDP-43 in sALS PBMCs. We observed that TDP-43 transfection and aggregation in SH-SY5Y cells leads to overexpression of HDAC6. Our results indicate that the autophagy pathway is sensitive to both extremes of α-tubulin acetylation. Indeed, a marked reduction due to HDAC6 overexpression, as well as an excessive increase following HDAC6 downregulation, both result in autophagic dysfunction. This work supports the hypothesis that dysregulation of HDAC6 is a key factor in the disruption of the autophagy pathway previously detected in sALS PBMCs. Our work suggests for the first time that TDP-43 influences autophagy by binding and modulating HDAC6 mRNA. This new pathway suggests that in ALS the aggregation of TDP-43 leads to the overexpression of HDAC6 which impairs autophagy pathway. Thus, our work suggest that in sALS HDAC6 should be tuned and these findings could be exploited in the future as possible therapeutic target.},
}

@article {pmid40912321,
year = {2025},
author = {Durpoix, A and Blay, M and Moog, C and Rolling, J and Weiner, L and Lalanne, L and Weibel, S},
title = {Clarifying conceptualization of emotional dysregulation: Differences with emotional lability during 4-month DBT skills training - A naturalistic study.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120199},
doi = {10.1016/j.jad.2025.120199},
pmid = {40912321},
issn = {1573-2517},
abstract = {INTRODUCTION: Emotion dysregulation is common in many different psychiatric disorders and it can be effectively treated with the well-established Dialectical Behavioral Therapy (DBT). Despite its clinical relevance and increasing scientific interest, emotional dysregulation (ED) is sometimes conflated with emotional lability (EL). However, these constructs differ: ED involves top-down neurobiological processes, while EL involves bottom-up processes. As psychotherapy essentially influences top-down processes compared to pharmacotherapy, this study aimed to investigate whether ED is more sensitive to DBT than EL.

METHOD: Our naturalistic study involved the 39 participants (sex ratio = 9 m/30w, mean age = 33.23) who completed questionnaires assessing ED (DERS-36) and EL (ALS-18) before then after transdiagnostic DBT skills training (DBT-ST). The diagnoses of participants included BPD (64 %), BD (23 %), ADHD (23 %), addiction (17 %) or eating disorder (17 %). DBT was performed in a transdiagnostic group over 4 months.

RESULT: After DBT-ST, ED improved significantly with a medium effect size (d = 0.73), while EL showed no significant change (d = 0.13). The percentages of improvement on DERS were significantly higher than on ALS (p < 0.002, d = 0.50). The correlation between these both measures decreased during therapy from r = 0.37 to r = 0.32.

DISCUSSION: Our findings indicate that ED improved more than EL after DBT and that their correlation diminished during therapy. These results suggest that ED is a different process from EL and that ED is more sensitive to treatments like DBT Skills Training. To confirm these findings, further studies are needed ideally with larger sample size, long-term follow-up and a controlled design.},
}

@article {pmid40912271,
year = {2025},
author = {Heyne, S and Kuzmanova, A and Esser, P and Mehnert-Theuerkauf, A and Metelmann, M},
title = {[Psychosocial support needs and requirements for psychosocial care programs for caregivers of patients with ALS - A qualitative analysis from the "potentiALS" project].},
journal = {Psychotherapie, Psychosomatik, medizinische Psychologie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2679-1065},
pmid = {40912271},
issn = {1439-1058},
abstract = {ALS is a terminal illness that places significant burden on caregivers due to the intensive care demands. Little research exists on the specific design of psychological support programs for caregivers of ALS patients. This study aims to identify psychosocial needs of caregivers, specific therapeutic topics and structural requirements for tailored support programs.The study is based on a subset of qualitative data from a participatory mixed-methods observational study. Semi-structured, one-hour interviews were conducted with caregivers of ALS patients, either online or in person. The transcripts were analyzed using Mayring's qualitative content analysis.Four caregivers participated in the study. They reported a high need for psychological support, especially immediately following the diagnosis. Key themes included emotional relief through dialogue with psychologists, strategies for emotion regulation, and fostering self-care. Practical needs highlighted the importance of clear guidelines for caregiving organization, assistance with medical devices, and the development of supportive programs to help manage life and plan for the future during challenging circumstances. Participants emphasized that support programs should be flexible, easily accessible, and personalized. Individual sessions with the option of in-person or online formats were preferred. Caregivers highlighted the necessity of continuous support throughout the disease trajectory, particularly during critical phases.The results of our study highlight the psychosocial challenges faced by caregivers of ALS patients. The findings emphasize the need for comprehensive support systems that address both the emotional and practical needs of caregivers.},
}

@article {pmid40911608,
year = {2025},
author = {Li, Z and Qiao, Q and Han, Z and Liu, X and Wang, Y and Tang, H and Deng, L},
title = {Terrestrial laser scanning in forestry: Accuracy and efficiency in measuring individual tree parameters.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0331126},
doi = {10.1371/journal.pone.0331126},
pmid = {40911608},
issn = {1932-6203},
mesh = {*Trees/anatomy & histology/growth & development ; *Forestry/methods ; Forests ; *Lasers ; Populus ; },
abstract = {With the growing global emphasis on forest resource monitoring, evaluating the accuracy of retrieving key individual tree parameters-such as tree position, tree height, and diameter at breast height (DBH)-using Terrestrial Laser Scanning (TLS) has become an important research focus. TLS has been widely applied in forest surveys due to its significant advantages in data acquisition efficiency and measurement precision. However, studies on the accuracy of extracting forest parameters from single-station, single-scan TLS data remain limited, underscoring the need for systematic evaluation and validation. This paper analyzes the accuracy and effectiveness of TLS in extracting structural parameters (tree height and DBH) and its position using Poplar and Styphnolobium as examples by using TLS, Airborne laser Scanning (ALS), and combining with field measurements. Results show that tree height estimates from single-scan TLS is limited in accuracy: the RMSE of 11.61 m in the Populus plot and 2.13 m in the Styphnolobium plot. Within a 50 m radius, single-scan TLS achieves a tree detection rate of 55.96-64.26% and a DBH RMSE of 1.60 cm (RRMSE: 9.03%). In addition, the point root mean square error of individual tree measurements remains at 0.11 m. These findings highlight the potential of TLS as an effective tool for forest inventory and provide a basis for evaluating the reliability of TLS-based plot measurements.},
}

*Trees/anatomy & histology/growth & development
*Forestry/methods
Forests
*Lasers
Populus

@article {pmid40911406,
year = {2025},
author = {Vieira, RGS and Lima, ÍNDF and Pondofe, KM and Maciel, ACMG and Dourado-Júnior, MET and Otto-Yáñez, M and Vilaró, J and Torres-Castro, R and Uribe, RV and da Fonsêca, JDM and Lo Mauro, A and Resqueti, VR and Aliverti, A and Fregonezi, GAF},
title = {Acute Effects of Mechanical Insufflation-Exsufflation on Cough Peak Flow, Chest Wall Volumes, and Breathing Pattern of Patients With Amyotrophic Lateral Sclerosis.},
journal = {Respiratory care},
volume = {},
number = {},
pages = {},
doi = {10.1177/19433654251367414},
pmid = {40911406},
issn = {1943-3654},
abstract = {Background: Mechanical insufflation-exsufflation (MI-E) consists of increasing expiratory air flow, thereby promoting an increase in cough peak flow (CPF) and secretion clearance. Respiratory impairment, characterized by reduced lung volumes and ineffective cough, is the major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis (ALS). This study aimed to assess the acute effects of MI-E on CPF and chest wall compartmental and operational volumes in patients with ALS. Methods: Ten ALS subjects (6 males) were studied by optoelectronic plethysmography (OEP) to assess the immediate effects of MI-E on CPF, chest wall volume variations and their distribution in the chest wall compartments, breathing pattern, and shortening velocity of the respiratory muscles before, during, and after the application of MI-E. Results: No differences were observed in the CPF analysis between time points (pre, MI-E, post). A significant increase in CPF (P = .01) was obtained immediately after the application of MI-E in subjects with spinal-onset ALS (n = 7). No significant differences in total and compartmental lung volumes and chest wall operational volumes were observed between pre MI-E (quiet breathing), during MI-E (after coughs 1, 2, and 3), and post MI-E time points. Conclusions: The application of the MI-E technique may increase CPF in individuals with spinal ALS. However, no significant changes in total thoracic volumes, total and compartmental chest wall volumes, or changes in breathing patterns in the participants in our sample after the application of the technique were observed.},
}

@article {pmid40911048,
year = {2025},
author = {Massey, C and Hobson, E and McDermott, C and Griffiths, AW},
title = {Living with cough and secretion issues: the experiences of people with amyotrophic lateral sclerosis and their caregivers.},
journal = {Disability and rehabilitation},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/09638288.2025.2555973},
pmid = {40911048},
issn = {1464-5165},
abstract = {PURPOSE: To explore the experiences of people living with amyotrophic lateral sclerosis (ALS) and their caregivers managing cough and secretion problems.

METHODS: A qualitative study was completed with 15 individuals participating in 10 interviews; 10 people living with ALS and five informal caregivers. Interview methods were adapted to ensure inclusivity of participants who had physical, respiratory and communication impairments. Data was analysed inductively using reflexive thematic analysis.

RESULTS: Our analysis identified the challenges of living day to day with cough and secretion problems. Care coordination and the presence of informal caregivers were important in ensuring that cough and secretion interventions could be implemented successfully. Participants felt access to cough and secretion knowledge and skills specific to ALS was key to supporting care and supported them to acquire information which influenced decision-making around their care.

CONCLUSION: Cough and secretion care in ALS is multifaceted and multifactorial. Future development of clinical interventions in this area are needed to support the complex web of professionals, treatments and knowledge to optimise care.},
}

@article {pmid40910745,
year = {2025},
author = {Simoni, D and Gotkine, M and Ben-Dov, IZ and Lerner, B},
title = {Identifying diagnostic markers in the health records of prediagnostic amyotrophic lateral sclerosis patients.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2539898},
pmid = {40910745},
issn = {2167-9223},
abstract = {Objective: Amyotrophic lateral sclerosis (ALS) has a poorly understood preclinical phase, particularly concerning diagnostic blood markers. Our objective was to determine whether distinct patterns in routinely collected clinical and laboratory markers exist during the preclinical phase and could be incorporated to facilitate early diagnosis. Methods: We conducted a longitudinal, retrospective, case-control study with health records of prediagnostic ALS patients (PDALS) from health maintenance organizations covering approximately 40% of the Israeli population. We included PDALS with at least 10 clinical visits and a minimal observation period of 36 months prior to the diagnosis date to measure differences between PDALS and controls and analyzed data from 1,810 adult individuals; 362 PDALS and 1,448 age- and sex-matched controls. Results: Significant differences were found in PDALS many months before the diagnosis date. These included biochemical parameters such as urea, creatinine, CK, calcium, iron, and liver enzymes, hematological values, and BMI. Some differences were detectable over 10 years prior to the diagnosis date. Conclusions: This study highlights the potential for early detection of ALS based on blood markers in the years preceding clinical diagnosis. These findings could significantly expedite diagnosis, identify individuals at risk for ALS, and uncover unrecognized disease mechanisms.},
}

@article {pmid40910231,
year = {2025},
author = {He, M and Zeng, S and Tang, Z and Qin, L and Yan, W and Wang, C and Zhang, H and Chen, Z and Long, Z},
title = {A Decade of Research on C9orf72 in Frontotemporal Dementia (2014-2024): A Bibliometric Analysis of Global Trends and Hotspots.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X388118250808030811},
pmid = {40910231},
issn = {1875-6190},
abstract = {INTRODUCTION: Frontotemporal dementia (FTD) is the third most frequent dementia and the leading dementia subtype in individuals under 65. The discovery of C9orf72 (chromosome 9 open reading frame 72) GGGGCC abnormal expansion is a major genetic cause of both FTD and amyotrophic lateral sclerosis (ALS), linking these diseases along a clinicopathological spectrum. This study aimed to depict the research landscape of C9orf72 in FTD over the past decade, track emerging research hotspots, and provide insights into under-researched areas.

METHOD: Based on the Web of Science database, a bibliometric analysis was conducted to explore publication trends, key contributors, funding sources, journal categories, co-authorship networks, and keyword co-occurrence, clustering, and bursts.

RESULTS: A total of 1,220 articles were identified, with sustained output of over 100 articles annually. The majority of contributions and funding support came from North America and Europe. Hot research themes included hexanucleotide repeats, nucleocytoplasmic transport, disease mechanisms, and therapeutic targets.

DISCUSSION: North America and Europe were highly productive, supported by higher regional prevalence, genetic burden, and robust funding. Ploy-GR in cerebrospinal fluid has emerged as a diagnostic biomarker. Pathogenic mechanisms remain complex, involving both gain- and loss-of-function effects. Metformin and antisense oligonucleotides were considered as potential therapeutics. Further research is needed in underrepresented populations and on the translational potential of emerging molecular targets.

CONCLUSION: This study offers a comprehensive overview of current trends and future directions over the past decade in C9orf72-related FTD research, allowing researchers-particularly those new to the area-to quickly understand the current landscape.},
}

@article {pmid40909873,
year = {2025},
author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J},
title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.},
journal = {FASEB bioAdvances},
volume = {7},
number = {8},
pages = {e70041},
pmid = {40909873},
issn = {2573-9832},
abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.},
}

@article {pmid40909834,
year = {2025},
author = {Homann, J and Korologou-Linden, R and Viallon, V and Morgan, S and Dobricic, V and Deecke, L and Schessner, JP and Smith-Byrne, K and Birtles, D and Zhao, Y and Wuu, J and Artaud, F and Hajizadah, F and Huerta, JM and Ohlei, O and Lebedev, M and Kolijn, PM and Guevara, M and Jimenez-Zabala, A and Sánchez, MJ and Trobajo-Sanmartín, C and Colorado-Yohar, SM and Alonso-Martín, S and Petrova, D and Sieri, S and Berger, K and Peters, S and Wareham, N and Kaaks, R and Travis, RC and Vermeulen, RCH and , and Tzoulaki, I and Elbaz, A and Mann, M and Sacerdote, C and Masala, G and Katzke, V and Benatar, M and Bertram, L and Middleton, L and Riboli, E and Gunter, MJ and Ferrari, P and Robinson, O and Lill, CM},
title = {Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.20.25334061},
pmid = {40909834},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form.

METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM).

FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance.

INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.

FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.},
}

@article {pmid40909710,
year = {2025},
author = {Gautier, O and Blum, JA and Nguyen, TP and Klemm, S and Yamakawa, M and Sinnott-Armstrong, N and Zeng, Y and Davis, CO and Bombosch, J and Nakayama, L and Guttenplan, KA and Chen, D and Kathira, A and Zhao, L and Rexach, JE and Greenleaf, WJ and Gitler, AD},
title = {An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.21.671404},
pmid = {40909710},
issn = {2692-8205},
abstract = {To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.},
}

@article {pmid40909641,
year = {2025},
author = {Dhawka, L and Evangelista, BA and Arooji, OK and Iannone, MA and Pellegrino, K and Traub, R and Li, X and Bedlack, R and Meeker, RB and Cohen, TJ and Stanley, N},
title = {Peripheral immune patterns enable robust cross-platform prediction of ALS onset and progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.26.672381},
pmid = {40909641},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) progression rates vary dramatically between patients, yet the basis of this heterogeneity remains elusive, with no prognostic biomarkers existing to guide clinical decisions or stratify patients for therapeutic trials. Here, we identify a network of coordinated immune cell types, which exhibit differential disruption across progression groups. Using mass cytometry (CyTOF) to profile 2.2 million immune cells from 35 ALS patients stratified by progression rate and 9 healthy controls, we find that the extent of immune dysfunction cannot be reflected by examining differences in individual cell type frequencies. In contrast, analyses of correlation patterns between cell types revealed distinct immune organization patterns, where coordination complexity varied with disease progression. Across all progression groups, we observed striking immune reorganization in natural killer (NK) cells and a major shift from B cell/basophil coordination hubs in healthy controls to neutrophil/T cell-dominated patterns in ALS. Having established coordinated immune patterns, we developed machine learning models to further improve our ability to stratify between disease and non-disease cohorts, achieving superior performance compared to models using cell frequencies alone. Central and effector memory (CM/EM) CD4+ T cell interactions emerged as top discriminative features for disease status, while plasmacytoid dendritic cell (pDC) relationships, especially their ratio with regulatory T cells (T-regs), distinguished progression rates, supporting T-reg-based therapeutic approaches. These findings reframe ALS as a disease of immune coordination breakdown, pointing towards cell-type specific therapeutics and biomarkers that may extend beyond ALS to other neurodegenerative diseases characterized by immune dysfunction.},
}

@article {pmid40908789,
year = {2025},
author = {Carletta, O and Perfetto, C and Rifai, OM and Manganelli, F and Waldron, FM and Maniatis, T and Gregory, JM and Gerbino, V},
title = {Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf324},
pmid = {40908789},
issn = {1460-2156},
abstract = {Innate immune signaling pathways are hyperactivated in the central nervous system (CNS) of patients with Amyotrophic Lateral Sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1, and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial. Here, we systematically profile Type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n=18), genetic ALS caused by (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n=11), and (ii) a SOD1 mutation (SOD1-ALS; n=5), alongside age- and sex-matched individuals who died of a non-neurological cause (n=12). Using this deeply phenotyped cohort we have implemented targeted transcriptomic analysis and immunohistochemistry to interrogate the nature and extent of the activation of the Type-I IFN response in patients. We determined disease and genotype specific IFN signatures that correlate with clinical phenotype. Correlation analysis linked six ISGs with aggressive disease progression, as indicated by negative correlation with age at death in ALS patients. Notably, significant upregulation of ISGs was observed in C9-ALS patients, with higher ISG expression correlating with shorter disease duration. Noting that our genotype and disease specific signatures correlated with metrics of disease progression, we explored the therapeutic potential of targeting this pathway in a mouse model of ALS. Treatment with an IFN pathway inhibitor reduced IFN response markers, delayed disease progression, including motor decline, and extended survival in ALS mice. We conclude that upregulation of gene expression in the Type-I IFN pathway represents a key pathological feature of ALS and that inhibiting this pathway may provide a promising therapeutic approach for treating ALS.},
}

@article {pmid40908745,
year = {2025},
author = {Pask, S and Okwuosa, C and Mohamed, A and Price, R and Young, J and Curtis, T and Henderson, S and Winter-Luke, I and Sunny, A and Chambers, RL and Greenley, S and Johansson, T and Bone, AE and Barclay, S and Higginson, IJ and Sleeman, KE and Murtagh, FE},
title = {Models, components and outcomes of palliative and end-of-life care provided to adults living at home: A systematic umbrella review of reviews.},
journal = {Palliative medicine},
volume = {},
number = {},
pages = {2692163251362567},
doi = {10.1177/02692163251362567},
pmid = {40908745},
issn = {1477-030X},
abstract = {BACKGROUND: There is growing demand for home-based palliative care because of patient preference, and increased number of deaths. Optimal models for community-based palliative and end-of-life care are unknown.

AIM: To identify, synthesise and describe review-level evidence to better understand models of palliative and end-of-life care for adults living at home, and examine components of these models and their association with outcomes.

DESIGN: Systematic umbrella review, using key concepts established a priori from Firth et al. and Brereton et al.''s model descriptions. Quality assessment used AMSTAR-2 or equivalent.

DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Database, Epistemonikos (inception - 2024), supplemented by CareSearch, PROSPERO and citation searches.

RESULTS: From 6683 initial papers, n = 66 reviews were included. Seven models of care were identified; by setting (in-home, outpatient); type of professionals (specialist, integrated, non-specialist); or mode (telehealth, education/training). Components included: holistic person-centred assessment, skilled professionals, access to medicines/care/equipment, patient/family support, advance care planning, integration of services, virtual/remote technology and education. We categorised outcomes into: (i) patient outcomes, (ii) family/informal caregiver outcomes, (iii) professional outcomes and iv) service utilisation/cost outcomes. The 'in-home palliative care' model was most researched with good evidence of positive benefit. Specialist and integrated models of care were next most researched, with evidence of improved patient and service utilisation outcomes. Cost-effectiveness evidence was lacking.

CONCLUSION: This meta-level evidence supports provision of in-home palliative care, with most review level evidence showing positive effect on patient outcomes. There was also evidence to support specialist palliative care and integration of primary palliative care with specialist support.},
}

@article {pmid40908710,
year = {2025},
author = {Giove, E and Ferraro, PM and Lungu, M and Pasquinelli, L and Truffelli, R and Trinchero, C and Rebagliati, B and Caponnetto, C and Vignolo, M and Rao, F},
title = {Effects of Dog-Assisted Occupational Therapy on Upper Limb Functions in ALS and Other Neuromuscular Disorders: A Randomized Controlled Pilot Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70012},
pmid = {40908710},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: The beneficial effects of animal-assisted therapy (AAT) on balance, walking endurance, and mood symptoms in amyotrophic lateral sclerosis (ALS) have been previously demonstrated. In this study, we aimed at expanding upon these findings by further evaluating its effects on upper limb (UL) functions and mood symptoms both in ALS and other neuromuscular disorders (NMDs).

METHODS: Sixty-eight patients participated in a regular 2-week occupational therapy program once a day. For three days a week, in place of the traditional treatment, the AAT group (N = 34) performed a session in interaction with the therapy dog. Outcome measures included hand grip strength, manual dexterity, and mood symptoms. Differences between baseline and post-treatment values were assessed using the Wilcoxon Signed-Rank Test, and one-way analysis of covariance was used to examine between-group differences in post-treatment values, adjusting for baseline measurements.

RESULTS: Both groups improved in hand grip strength (p = 0.004-0.03), whereas mood symptoms improved exclusively in the AAT group (p = 0.0003-0.03). Post-treatment values were significantly better in the AAT group (p = 0.01-0.03). When ALS patients were analyzed separately, the improvement of hand grip strength and mood symptoms was observed only in the AAT group (p = 0.001-0.04), which accordingly showed better post-treatment values (p = 0.0007-0.05).

DISCUSSION: Our findings indicate that AAT has greater beneficial effects than traditional treatments on UL strength and mood symptoms. These findings have the potential to facilitate more effective rehabilitation strategies both in ALS and other NMDs.},
}

@article {pmid40908696,
year = {2025},
author = {Paul, S and Tiwari, P and Dubey, S},
title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665391103250825102319},
pmid = {40908696},
issn = {1875-5305},
abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management.

METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes.

RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects.

DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity.

CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.},
}

@article {pmid40908144,
year = {2025},
author = {Kim, SK and Gelfand, VI},
title = {PolyQ-expansion of Ataxin-2 disrupts microtubule stability and impairs axon outgrowth.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0682-25.2025},
pmid = {40908144},
issn = {1529-2401},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by mislocalization and aggregation of proteins in motor neurons. Ataxin-2 (ATXN2), an RNA-binding protein harboring 22-polyglutamine (polyQ) repeats, is a risk factor for ALS, when its polyQ repeats are expanded to 27-33 repeats. However, the physiological function of ATXN2 beyond its role in RNA regulation, and how polyQ expansion in ATXN2 increases risk for ALS, remain unclear. We previously demonstrated that Drosophila Atx2 functions as a regulator of microtubule (MT) dynamics in motor neurons. Here, we uncover the molecular mechanism underlying Atx2-mediated MT regulation and how polyQ expansion disrupts its function, using a mixed-sex population of Drosophila as a model system. Specifically, we show that Atx2 requires its RNA-binding Lsm domain to regulate MTs. Notably, the LSM domains of human ATXN2 rescue MT phenotype in Drosophila, demonstrating an evolutionarily conserved role of ATXN2 in MT regulation. Importantly, we find that polyQ-expanded ATXN2 forms cytoplasmic aggregates and leads to excessive MT destabilization. Additionally, polyQ expansion severely impairs axon outgrowth. Finally, we identify Uncoordinated-76 (UNC-76/FEZ1) as a downstream effector of Atx2 in MT regulation and neuronal development.Significance Statement ALS is a progressive neurodegenerative disease with no effective treatment. Although polyglutamine (polyQ) expansion in the RNA-binding protein ATXN2 is a known risk factor for ALS, its mechanistic role in ALS pathogenesis has remained unclear. We demonstrate that ATXN2 regulates MT dynamics via its RNA-binding domain, and this role is evolutionarily conserved between Drosophila and humans. We further identify UNC-76/FEZ1 as a downstream effector of ATXN2 in regulating MT dynamics and neuronal development. Importantly, this study reveals how polyQ expansion in ATXN2 disrupts MT stability and axon growth, proposing a mechanism that may contribute to increased ALS risk.},
}

@article {pmid40908143,
year = {2025},
author = {Rodemer, W and Ra, I and Gujral, J and Jia, E and Juul, H and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Rekulak, S and Porta, S and Jensen, FE and Talos, DM and Lee, VM},
title = {Network dysfunction precedes neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2297-24.2025},
pmid = {40908143},
issn = {1529-2401},
abstract = {Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence indicates that TDP-43 pathology induces neuronal hyperexcitability, which may contribute to excitotoxic neuronal death. To characterize TDP-43 mediated network excitability changes in a disease-relevant model, we performed in vivo continuous electroencephalography monitoring and ex vivo acute hippocampal slice electrophysiology in rNLS8 mice (males and females), which express human TDP-43 with a defective nuclear localization signal (hTDP-43ΔNLS). Surprisingly, we identified the presence of seizures in approximately 64% of rNLS8 mice beginning around 2.5 weeks after transgene induction (off-DOX). More broadly, we observed longitudinal changes in cortical EEG patterns and circuit hyperexcitability preceding neurodegeneration of vulnerable hippocampal subfields. Consistent with previous reports, we have observed broad dysregulation of AMPA subunit expression in mice expressing hTDP-43ΔNLS. These changes were most pronounced in the hippocampus, where we hypothesized they promote hyperexcitability and ultimately, excitotoxic cell death. Interestingly, hippocampal injection of AAV encoding inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on the elevated zero maze but did not reduce neurodegeneration. Moreover, therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complex relationship between TDP-43 -mediated neuronal hyperexcitability and neurodegeneration. Although targeting hyperexcitability may ameliorate some behavioral deficits, our study suggests it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.Significance Statement Cytoplasmic aggregates of TDP-43 are the predominant pathology in over 90% of ALS and 50% of frontotemporal lobar degeneration cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. In this study, we identified hippocampal network hyperexcitability and generalized seizures that preceded neurodegeneration in the inducible rNLS8 mouse model. Local suppression of hippocampal hyperexcitability with chemogenetics (hM4Di) improved behavioral function but did not reduce neuron loss. Systemic anti-seizure medications had no beneficial effects. These results highlight the complexity of TDP-43 induced excitability changes but ultimately suggest that directly targeting hyperexcitability may not be therapeutically effective.},
}

@article {pmid40907612,
year = {2025},
author = {Kumar, AP and Puthussery, DT},
title = {Regulation of PPAR-γ coactivator-1α and its implication in mitochondrial function and neurodegenerative diseases.},
journal = {Ageing research reviews},
volume = {112},
number = {},
pages = {102887},
doi = {10.1016/j.arr.2025.102887},
pmid = {40907612},
issn = {1872-9649},
abstract = {Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data supporting PGC1-α-mediated regulation by transcriptional and post-translational modification. We summarize the mechanisms involved in PGC1-α regulation by phosphorylation (AMPK, p38 MAPK, Akt, and GSK3β), acetylation (GCN5, p300, and SRCC), and ubiquitination (E3-ubiquitin ligase). Moreover, the review focuses on the multidomain structure of PGC1-α, its expression in the brain, and the importance of PGC1-α-mediated mitochondrial functions. Mitochondrial dysfunction and impaired energy metabolism are key characteristics of neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and multiple sclerosis. It is associated with reduced PGC1-α expression or activity, resulting in an imbalance in the maintenance of mitochondrial dynamics. In this backdrop, we additionally provide a comprehensive overview of the implication of PGC1-α in the pathogenesis of neurodegenerative disease. Overall, PGC1-α acts as a potential target for therapies to reduce mitochondrial dysfunction associated with neurodegenerative diseases and aid in neuroprotection.},
}

@article {pmid40906916,
year = {2025},
author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT},
title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00376},
pmid = {40906916},
issn = {1948-7193},
abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.},
}

@article {pmid40906311,
year = {2025},
author = {Oubari, H and Berkane, Y and Jeljeli, M and Lellouch, AG and Smadja, DM},
title = {Engineering the Future of Stem Cells in Vascular Reconstruction: A Leap Towards Functional Endothelialized Tissue-Engineered Vascular Conduits.},
journal = {Stem cell reviews and reports},
volume = {},
number = {},
pages = {},
pmid = {40906311},
issn = {2629-3277},
abstract = {The transition from reconstructive to regenerative strategies in vascular surgery has intensified the need for grafts that are biocompatible, growth-capable, and resistant to thrombosis. Addressing this challenge, Park et al. introduce a groundbreaking method for engineering fully biological, endothelialized tissue-engineered vascular conduits (TEVCs) using decellularized human umbilical arteries (dHUAs) coated with human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). These constructs undergo shear stress training in bioreactors, mimicking physiological blood flow to enhance endothelial functionality and anti-thrombotic properties. Upon implantation in animal models, the grafts showed long-term patency, resistance to thrombosis, and progressive replacement of hiPSC-ECs by host endothelial cells, highlighting their regenerative and integrative potential. The study emphasizes the pivotal role of hemodynamic conditioning and key regulators such as KLF2 in promoting endothelial quiescence and vascular homeostasis. It further explores alternative strategies like endothelial colony-forming cells (ECFCs) and microfluidic systems for flow-induced maturation. Clinically, this approach offers a promising, scalable avenue for patient-specific, immune-compatible vascular grafts applicable in congenital heart disease, dialysis access, vascular grafts and coronary bypass. While challenges such as long-term durability and mechanical reinforcement remain, this research marks a transformative step toward functional, off-the-shelf vascular grafts. Park et al.'s work bridges biomimicry with regenerative medicine, paving the way for next-generation vascular therapies rooted in endothelial mechanobiology and personalized bioengineering.},
}

@article {pmid40906043,
year = {2025},
author = {García-Toledo, I and Godoy-Corchuelo, JM and Fernández-Beltrán, LC and Ali, Z and Guindo-Arroyo, A and Jiménez-Coca, I and Jiménez-Rodríguez, J and Javaloyes-García, K and Viñuela, M and Gómez-Pinedo, U and Saiz-Aúz, L and Rábano, A and Área-Gómez, E and Cunningham, TJ and Corrochano, S},
title = {TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {23},
pmid = {40906043},
issn = {1432-0533},
support = {PIPF-2022/SAL-GL-24282//Consejería de educación, ciencia y universidades, Comunidad de Madrid/ ; PDI2020-1153-70RB-100//Ministerio de Ciencia e Innovación/ ; PID2023-147947OB-I00//Ministerio de Ciencia e Innovación/ ; CT58/21-CT59/21//Unversidad Complutense de Madrid/ ; },
mesh = {*Cholesterol/metabolism ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Myelin Sheath/metabolism/pathology ; Mice ; Humans ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; Male ; Brain/metabolism/pathology ; Mice, Transgenic ; Female ; Mice, Inbred C57BL ; Lipid Metabolism ; Frontal Lobe/metabolism/pathology ; Disease Models, Animal ; },
abstract = {TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the Tardbp[M323K/M323K] knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.},
}

*Cholesterol/metabolism
Animals
*DNA-Binding Proteins/metabolism/genetics
*Myelin Sheath/metabolism/pathology
Mice
Humans
*TDP-43 Proteinopathies/metabolism/pathology/genetics
Male
Brain/metabolism/pathology
Mice, Transgenic
Female
Mice, Inbred C57BL
Lipid Metabolism
Frontal Lobe/metabolism/pathology
Disease Models, Animal

@article {pmid40906007,
year = {2025},
author = {Howard-Williams, EL and Ossman, P and Fuller, J},
title = {Respiratory-Onset Amyotrophic Lateral Sclerosis (ALS): A Rare Initial Presentation.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
pmid = {40906007},
issn = {1525-1497},
}

@article {pmid40905788,
year = {2025},
author = {Willemse, SW and Demaegd, KC and Van Eijk, RPA and Van Damme, P and Harrington, E and Harms, MB and Shneider, NA and Van Rheenen, W and Veldink, JH and Van Den Berg, LH and Van Es, MA},
title = {A VAPB (P56S) mutation in a Dutch patient with familial motor neuron disease: a case report.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/21678421.2025.2555218},
pmid = {40905788},
issn = {2167-9223},
abstract = {The c.166C > T p.(Pro56Ser) or P56S mutation in the VAPB gene was initially identified as a cause of motor neuron disease in Brazil in a large extended pedigree comprising >1,500 individuals including more than 200 cases. This VAPB mutation gives rise to three phenotypes: late-onset spinal muscular atrophy, classical ALS with bulbar involvement, pyramidal signs and rapid disease progression, and atypical ALS with slow progression. Nearly all known cases originate from a single founder, with most cases outside of Brazil being related to this pedigree. However, there is one report of an independent German family with the same mutation on a different haplotype, indicating a second founder event. Here, we report the first Dutch patient with a P56S mutation in VAPB and motor neuron disease. Documenting rare genetic causes of MND and their natural history are of increasing importance in light of emerging gene-specific therapies.},
}

@article {pmid40905723,
year = {2025},
author = {Peng, C and Maiuri, T and Truant, R},
title = {Tipping the PARylation scale: Dysregulation of PAR signaling in Huntington and neurodegenerative diseases.},
journal = {Journal of Huntington's disease},
volume = {},
number = {},
pages = {18796397251372667},
doi = {10.1177/18796397251372667},
pmid = {40905723},
issn = {1879-6400},
abstract = {Poly(ADP-ribosyl)ation (PARylation), a crucial post-translational modification, is catalyzed by ADP-ribosyltransferases (ARTs) and has significant implications in various cellular processes, including DNA damage response, cell signaling, and immune processes. Aberrant PAR signaling is implicated in numerous neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, and cerebellar ataxia, where increased PAR levels and PARP1 activity are commonly observed. However, Huntington disease exhibits a unique characteristic: reduced PAR levels and impaired PARP1 activity even in prodromal phase. This finding challenges the prevailing understanding of PAR's role in neurodegeneration and suggests that dysregulation of PAR signaling, whether through overactivation or suppression, can lead to neuronal dysfunction. Herein, we discuss how this balance may impact neurodegenerative diseases, and possible connections between PAR signaling and emerging modifiers of disease onset identified by HD genome-wide association studies (GWAS).},
}

@article {pmid40905633,
year = {2025},
author = {Verdés, S and Navarro, X and Bosch, A},
title = {Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.},
journal = {Human gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.1177/10430342251372898},
pmid = {40905633},
issn = {1557-7422},
abstract = {Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting. As a result, gene therapy strategies must often address multiple pathological mechanisms simultaneously. So far, current gene therapy strategies aim to either suppress toxic gene expression or promote neuroprotection, predominantly via viral-mediated delivery systems. This review will provide an overview of emerging preclinical and clinical gene therapy approaches for ALS, focusing on two main strategies: gene silencing and neuroprotection. Gene silencing techniques, including antisense oligonucleotides (ASOs), viral-mediated RNA interference, and gene editing, have demonstrated efficacy in reducing mutant gene expression, particularly in SOD1 and C9orf72 models, although clinical translation has so far yielded limited success. The recent Food and Drug Administration's approval of the ASO therapy Qalsody for SOD1-ALS underscores the clinical potential of these approaches. Neuroprotective strategies aim to enhance motor neuron survival through delivery of trophic factors, often targeting both central and peripheral tissues to harness retrograde transport mechanisms. We will discuss the advantages and limitations of various delivery vectors, targeting specificity, timing of intervention, and translational challenges, alongside current clinical trial data. This review aims to synthesize how these approaches may converge to address the multifaceted nature of ALS and guide the development of next-generation therapeutics.},
}

@article {pmid40905501,
year = {2025},
author = {Huang, Y and Wan, Y and Chen, J and Qin, M and Wang, J and Liang, H},
title = {Knowledge mapping of biomarkers in amyotrophic lateral sclerosis: a comprehensive bibliometric and visual analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17582024.2025.2554525},
pmid = {40905501},
issn = {1758-2032},
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, and there is currently an urgent need to identify valuable biomarkers to accelerate diagnosis, optimize treatment and prognosis.

METHODS: To conduct a bibliometric analysis of publications related to "ALS biomarker" over the past 20 years, utilizing the subject search feature of the Web of Science Core Collection along with CiteSpace, VOSviewer, and Bibliometrix.

RESULTS: This review presents a 20-year bibliometric analysis of ALS biomarker research (2004-2024), analyzing 2535 publications showing rising trends. The United States led contributions, with Turner, Martin R as the most productive/cited author. Key research hotspots included cerebrospinal fluid, tdp-43, clinical trial, and neuroinflammation. Topics such as neurofilament light chain, machine learning, and exosomes could potentially represent the cutting edge of future research.

CONCLUSION: In summary, this study uses bibliometric analysis of ALS biomarker research to provide a forward-looking perspective on its future limitations and potential.},
}

@article {pmid40904817,
year = {2025},
author = {Kuo, T and Reynolds, T and Chen, L and Park, C and Rascati, K and Godley, P},
title = {Racial and ethnic disparities in ALS: a longitudinal electronic health records study.},
journal = {Therapeutic advances in neurological disorders},
volume = {18},
number = {},
pages = {17562864251365001},
pmid = {40904817},
issn = {1756-2856},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options and significant variability in care. Racial and ethnic disparities in ALS management and outcomes have been reported, but findings remain inconsistent.

OBJECTIVES: This study aimed to evaluate racial and ethnic disparities in ALS care, specifically differences in healthcare utilization, treatment patterns, and survival, within a large healthcare system.

DESIGN: This retrospective cohort study analyzed electronic health records from a large healthcare system in Texas for patients diagnosed with ALS between 2013 and 2023, examining racial and ethnic differences in treatment and outcomes.

METHODS: Patients were identified using International Classification of Diseases (ICD) codes. Baseline characteristics, including race/ethnicity and socioeconomic factors, were collected. Primary outcomes included the use of noninvasive ventilation (NIV), tracheostomy, gastrostomy, mobility aids, and ALS medications; secondary outcomes included time to diagnosis and survival. Racial and ethnic disparities were assessed using generalized linear regression and Cox proportional hazards models, adjusting for demographic and socioeconomic factors.

RESULTS: A total of 636 patients were included (74.5% Non-Hispanic White, 5.3% Non-Hispanic Black, 7.4% Hispanic, and 12.7% Other). Non-Hispanic Black patients had significantly higher tracheostomy rates than Non-Hispanic White patients (35.3% vs 8.7%; adjusted odds ratio (OR), 6.20; 95% confidence interval (CI), 2.43-15.84). Hispanic patients had lower odds of receiving riluzole (42.6% vs 61.8%; adjusted OR, 0.36; 95% CI, 0.18-0.71) and higher rates of emergency department visits (adjusted OR, 2.00; 95% CI, 1.09-3.65) and hospitalizations (adjusted OR, 2.57; 95% CI, 1.37-4.81). No significant racial or ethnic differences were observed in time to diagnosis or survival after adjustment.

CONCLUSION: Significant racial and ethnic disparities exist in ALS care, particularly in tracheostomy utilization, medication prescribing, and healthcare access. These findings underscore the need for targeted interventions to promote equitable ALS management, including provider education and improved healthcare accessibility.},
}

@article {pmid40904199,
year = {2025},
author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME},
title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70577},
doi = {10.1111/cns.70577},
pmid = {40904199},
issn = {1755-5949},
mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; },
abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.

RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.

CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.},
}

Humans
*Exosomes/transplantation/metabolism
*Neurodegenerative Diseases/therapy
Animals
*Stem Cell Transplantation/methods/trends
*Clinical Trials as Topic/methods

@article {pmid40903966,
year = {2025},
author = {Abbassi, Y and Fink, D and Cei, F and Niccolai, E and Amedei, A},
title = {TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00440},
pmid = {40903966},
issn = {1673-5374},
abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration. Despite extensive research, effective treatments remain elusive, underscoring the need to explore the molecular mechanisms driving disease progression. The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity, encompassing both genetic and sporadic forms, diverse phenotypic presentations, and highly variable progression rates. A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43, which contributes to cellular toxicity, neuroinflammation, and neuronal dysfunction. This review explores the complex interplay between TAR DNA-binding protein 43 pathology, immunity dysregulation, and the gut-brain axis, with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis. Neuroinflammation, mediated by both innate and adaptive immunity, plays a central role in disease pathogenesis, with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity. Additionally, disruptions in gut microbiota composition and intestinal barrier integrity, frequently observed in amyotrophic lateral sclerosis patients, suggest a potential role for the gut-brain axis in modulating neurodegenerative processes. By integrating evidence from emerging studies, our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease. Understanding these interactions could pave the way for novel therapeutic strategies, including microbiome-targeted interventions such as probiotics, dietary modifications, or immune-modulating therapies. Finally, unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation, slowing amyotrophic lateral sclerosis progression, and improving patient outcomes and life quality.},
}

@article {pmid40903965,
year = {2025},
author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M},
title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00368},
pmid = {40903965},
issn = {1673-5374},
abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.},
}

@article {pmid40903956,
year = {2025},
author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L},
title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00274},
pmid = {40903956},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domainlike receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.},
}

@article {pmid40903950,
year = {2025},
author = {Liu, Y and Tang, T and Cai, H and Liu, Z},
title = {Bidirectional communication between the gut microbiota and the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00434},
pmid = {40903950},
issn = {1673-5374},
abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiotabased treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.},
}

@article {pmid40903937,
year = {2025},
author = {Martinez, P and van Zundert, B and Bustos, FJ},
title = {Reevaluating the role of skeletal muscle in amyotrophic lateral sclerosis pathogenesis: Insights from muscle-derived factors.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00567},
pmid = {40903937},
issn = {1673-5374},
}

@article {pmid40903936,
year = {2025},
author = {Shao, N and Zhang, X and Ge, Y and Tang, J and Gao, H and Si, W and Cai, B},
title = {O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00101},
pmid = {40903936},
issn = {1673-5374},
abstract = {Neurodegenerative disorders are typically caused by harmful protein accumulation and nerve cell damage. A post-translational modification called O-linked N-acetylglucosamine ylation acts as a critical regulator in these disorders by controlling protein behavior, cell signaling, and energy balance. This modification is dynamically balanced through the cooperative actions of O-linked N-acetylglucosamine transferase and O-GlcNAcase. In healthy brains, O-GlcNAcylation supports nerve cell function and survival, but its imbalance contributes to disease progression. Notably, the effects of O-GlcNAcylation differ across disorders. This review reveals how O-GlcNAcylation bridges molecular mechanisms to neurodegeneration, as well as the prospects of targeted O-linked N-acetylglucosamine acylation therapy for neurodegenerative diseases. In Alzheimer's disease, it blocks toxic changes in key proteins like tau and amyloid-beta. In Parkinson's disease, it reduces the clumping of alpha-synuclein, yet may disrupt dopamine production. In amyotrophic lateral sclerosis, it protects nerve fiber transport systems. Additionally, O-GlcNAcylation plays an indispensable part in other neurodegenerative conditions, including Huntington's disease, aging, Machado-Joseph disease, multiple sclerosis, and giant axonal neuropathy. New therapies targeting this mechanism include glucosamine supplements and O-GlcNAcase inhibitors, which show clinical promise but face translational challenges.},
}

@article {pmid40903652,
year = {2025},
author = {Koyuncu, S and Dominguez-Canterla, Y and Alis, R and Salarzai, N and Petrovic, D and Flames, N and Vilchez, D},
title = {The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {40903652},
issn = {2662-8465},
support = {VI742/4-2//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; EXC 2030-390661388//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 0.22.2.030MN//Fritz Thyssen Stiftung (Fritz Thyssen Foundation)/ ; CIAICO/2022/195//Generalitat Valenciana (Regional Government of Valencia)/ ; },
abstract = {Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington's disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases.},
}

@article {pmid40903341,
year = {2025},
author = {Vedula, P and Ishizuka, K and Hayashida, A and Sueo, K and Sawa, A},
title = {Stress-induced nuclear GAPDH: Scientific update and clinical application.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00725},
doi = {10.1016/j.neurot.2025.e00725},
pmid = {40903341},
issn = {1878-7479},
abstract = {Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known as a moonlighting protein beyond its original glycolytic function. Stress-induced nuclear translocation of GAPDH has been reproducibly reported, which results in variety types of cellular responses, including cell death and dysfunction. Blocking this stress-induced cascade has been regarded as a target of drug discovery and development for human disease conditions, particularly for neurological and psychiatric diseases. There are promising small compounds that can block this cascade in cell and animal models. Nevertheless, the clinical trials for Parkinson's disease and amyotrophic lateral sclerosis with one of these compounds Omigapil were unsuccessful. Including these failure cases, this review article discussed the scientific frontline of GAPDH, particularly stress-induced nuclear GAPDH, and its potential for clinical applications.},
}

@article {pmid40903205,
year = {2025},
author = {Ng, L and Sweeney, KD and Mercer, SW},
title = {Challenges in reducing the 10-item CARE measure to a two-item version: comparison of patients' preferences with psychometric evaluation in a cross-sectional survey in Scotland.},
journal = {BJGP open},
volume = {},
number = {},
pages = {},
doi = {10.3399/BJGPO.2025.0085},
pmid = {40903205},
issn = {2398-3795},
abstract = {BACKGROUND: The Consultation and Relational Empathy (CARE) Measure is a widely used 10-item measure to assess patients' perceptions of physician empathy. Takahashi et al.'s (2022) recent study proposed a two-item version based on psychometric evaluation of survey responses, without considering patient preferences.

AIM: To apply Takahashi et al's psychometric method to UK data, and compare findings with patients' preferences on the two most important items.

DESIGN AND SETTING: In 2022, a cross-sectional postal survey of 6,291 Scottish adults was conducted.

METHOD: Using Takahashi et al..'s method, psychometric evaluation compared correlations between all possible two-item combinations with the original 10-item CARE measure to identify the optimal two-item combination. Patients were also asked to select the two items they considered most important. Descriptive analysis examined the proportion of patients selecting each item, and level of agreement on the most popular two-item combination.

RESULTS: 1053 (17%) of 6,291 patients responded. Psychometric evaluation identified items 6 ("Showing care and compassion") and 8 ("Explaining things clearly") as the optimal two-item combination (Cronbach's alpha=0.916, correlation=0.953). This differed from patient preferences, with items 3 ("Really listening") and 8 receiving the highest proportion of votes (19% and 17%, respectively). Preferences also varied by age, deprivation level, and consultation complexity. The most popular two-item combination (items 3 and 8) was selected by 10% of respondents, with 90% selecting other combinations.

CONCLUSION: The psychometrically optimal two-item combination did not align with patient preferences. Given variation in patient preferences and low agreement, reducing the CARE Measure to two-items may be inadvisable.},
}

@article {pmid40902435,
year = {2025},
author = {Midya, V and Bello, G and Andrew, AS and Re, DB and Stommel, EW and Arora, M},
title = {Dysregulation of hair-strand-based elemental biodynamics in amyotrophic lateral sclerosis.},
journal = {EBioMedicine},
volume = {119},
number = {},
pages = {105907},
doi = {10.1016/j.ebiom.2025.105907},
pmid = {40902435},
issn = {2352-3964},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disorder and is predominantly diagnosed in older adults. Altered levels of essential and toxic elements have been implicated in ALS pathophysiology; however, little is known about the longitudinal biodynamic patterns of these elements in patients with ALS.

METHODS: Using a single individual hair strand, we generated time series data of 400-800 time points approximately at 2 to 4 hourly resolution on 17 elemental intensities in ALS-positive cases and ALS-negative controls from a national collection and a regional centre in the US (on a total sample of 391, with 295 cases and 96 controls, with median age at hair collection over 60 years). The elements included were Li, Mg, P, S, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Sr, Sn, Ba, and Pb. We analysed the growth increments in single hair strands using laser ablation-inductively coupled plasma-mass spectrometry to create time-resolved signals of elemental exposure and intensity along the hair strand. Two complementary information-theoretic methods, cross-recurrence quantification analysis and transfer entropy-based network analysis, were employed to generate time-resolved features that quantify the synchronisation of multi-element biodynamics.

FINDINGS: Male ALS-positive cases had significantly lower synchronicity in Cu-Zn temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.64, p-value < 0.001, q-value = 0.03). Female ALS-positive cases had lower synchronicity in Cr-Ni temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.59, p-value < 0.001, q-value = 0.46). In both males and females, multiple centrality measures of Cu (that quantify the importance of Cu within a network of all elemental intensities) were significantly lower in ALS-positive cases than in ALS-negative controls [in males, closeness centrality of Cu: log(β) = -0.64, p-value = 0.002, q-value = 0.04; in females, eigenvector centrality of Cu: log(β) = -0.53, p-value = 0.02, q-value = 0.97].

INTERPRETATION: We demonstrate that ALS-positive cases have significantly higher odds of collapse in the synchronisation of elemental biodynamics and worse connectedness in copper-based networks compared to ALS-negative controls.

FUNDING: US National Institutes of Health (P30ES023515, R01ES026033, U2CES030859, U2CES026561, R35ES030435, UL1TR004419, 1OT2NS136938-01, 1R01ES034133-01) and CDC/ATSDR (R01TS000331, R01TS000324 and R01TS000285).},
}

@article {pmid40901987,
year = {2025},
author = {Sun, Z and Li, C and Leitner, D and Wu, M and Zhang, J and Wisniewski, T and Ge, Y},
title = {Age-related Vascular Alterations in the Choroid Plexus: Novel Insights from Pathophysiology and Imaging Studies.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0735},
pmid = {40901987},
issn = {2152-5250},
abstract = {The choroid plexus (ChP), a highly vascularized brain structure responsible for cerebrospinal fluid (CSF) production, undergoes significant age-related changes that may contribute to neurodegenerative diseases involving disrupted immune regulation, fluid homeostasis and waste clearance. Compared to other brain regions, vascular research on the ChP remains limited despite its critical role as a central interface between the blood and CSF. This review focuses on age-related vascular and structural alterations in the ChP from both histopathological and neuroimaging perspectives, and explores their impact on CSF dynamics, immune regulation, and the integrity of the blood-CSF barrier (BCSFB). Rather than shrinking, the aging ChP often enlarges due to dystrophic changes, as shown in volumetric MRI studies. Histological studies reveal epithelial degeneration, basement membrane thickening, and stromal fibrosis in the normal aging process. In dementia such as Alzheimer's disease (AD), proteomic studies have identified upregulation of AD- and immune-related proteins, along with downregulation of proteins linked to CSF clearance and metabolic support. Emerging high-resolution contrast-enhanced MRI techniques now allow in vivo visualization of microvascular changes within the ChP, shedding light on its normal and abnormal aging processes. Understanding these alterations is critical, as they may influence the onset and progression of various neurological diseases such as AD, Parkinson's disease (PD), normal pressure hydrocephalus, and amyotrophic lateral sclerosis (ALS). The recent advancements and challenges described in this study underscore the need for deeper investigation into ChP aging to inform future diagnostic and therapeutic strategies of neurodegenerative diseases.},
}

@article {pmid40901879,
year = {2025},
author = {Sun, G and Li, X and Hu, J and Yang, T and Liu, C and Wang, Z and Li, D and Xu, W},
title = {De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {36},
pages = {e2505320122},
doi = {10.1073/pnas.2505320122},
pmid = {40901879},
issn = {1091-6490},
support = {2020YFA0909200//MOST | National Key Research and Development Program of China (NKPs)/ ; 32101181//MOST | National Natural Science Foundation of China (NSFC)/ ; 32494764//MOST | National Natural Science Foundation of China (NSFC)/ ; 92353302//MOST | National Natural Science Foundation of China (NSFC)/ ; 32170683//MOST | National Natural Science Foundation of China (NSFC)/ ; 82188101//MOST | National Natural Science Foundation of China (NSFC)/ ; 22425704//MOST | National Natural Science Foundation of China (NSFC)/ ; 22JC1410400//Science and Technology Commission of Shanghai Municipality (STCSM)/ ; JCYJ-SHFY-2022-005//Chinese Academy of Sciences, Shanghai Branch (ä¸ç§'院上海分院)/ ; },
mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Protein Binding ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Amyloid/metabolism/chemistry ; Frontotemporal Lobar Degeneration/metabolism ; Protein Stability ; },
abstract = {Pathological aggregation of transactive response DNA binding protein of 43 kDa (TDP-43), primarily driven by its low-complexity domain, is closely associated with various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the therapeutic potential of preventing TDP-43 aggregation, no effective small molecule or biomacromolecule therapeutics have been successfully developed so far. Here, we introduce a protein design strategy that yields de novo designed proteins capable of stabilizing the key amyloidogenic region of TDP-43 in its native helical conformation with nanomolar binding affinity. The binding mechanism was further characterized by the NMR and mutagenesis study. More importantly, we demonstrated that our designed protein binders efficiently reduced TDP-43 amyloid aggregation both in vitro and in cells. Our work provides a strategy for designing protein stabilizer of the native conformation of pathological proteins for preventing its amyloid aggregation, shedding light on the development of potential therapeutic approaches for ALS, FTLD, and other protein aggregation-associated diseases.},
}

*DNA-Binding Proteins/metabolism/chemistry/genetics
Humans
*Protein Aggregation, Pathological/metabolism
Protein Aggregates
Protein Binding
Amyotrophic Lateral Sclerosis/metabolism/genetics
Amyloid/metabolism/chemistry
Frontotemporal Lobar Degeneration/metabolism
Protein Stability

@article {pmid40901491,
year = {2025},
author = {Igarashi, K and Ohue, M},
title = {Protein-ligand affinity prediction via Jensen-Shannon divergence of molecular dynamics simulation trajectories.},
journal = {Biophysics and physicobiology},
volume = {22},
number = {3},
pages = {e220015},
doi = {10.2142/biophysico.bppb-v22.0015},
pmid = {40901491},
issn = {2189-4779},
abstract = {Predicting the binding affinity between proteins and ligands is a critical task in drug discovery. Although various computational methods have been proposed to estimate ligand target affinity, the method of Yasuda et al. (2022) ranks affinities based on the dynamic behavior obtained from molecular dynamics (MD) simulations without requiring structural similarity among ligand substituents. Thus, its applicability is broader than that of relative binding free energy calculations. However, their approach suffers from high computational costs due to the extensive simulation time and the deep learning computations needed for each ligand pair. Moreover, in the absence of experimental ΔG values (oracle), the sign of the correlation can be misinterpreted. In this study, we present an alternative approach inspired by Yasuda et al.'s method, offering an alternative perspective by replacing the distance metric and reducing computational cost. Our contributions are threefold: (1) By introducing the Jensen-Shannon (JS) divergence, we eliminate the need for deep learning-based similarity estimation, thereby significantly reducing computation time; (2) We demonstrate that production run simulation times can be halved while maintaining comparable accuracy; and (3) We propose a method to predict the sign of the correlation between the first principal component (PC1) and ΔG by using coarse ΔG estimations obtained via AutoDock Vina.},
}